{ "meta": { "api_version": "1.0.0", "dataset_version": "2.0.1+unreleased", "live_matches_release": false, "archived_release": { "version": "2.0.1", "version_doi": "10.5281/zenodo.23090261", "date": "2026-10-01", "studies": 428 }, "data_fingerprint": "902cee5f48b5ec3c7b68ab77cd461448d3b00c4f4b77f38a9e1b5affcf85f063", "corpus_snapshot": "2026-11-09T16:23:12+0100", "source_commit": "ddd2837263b4e46b1074542b3dff085b860093b3", "license": "CC-BY-4.0", "cite": "Barton O. Oliver's mTOR Atlas (live data, not an archived version; give corpus_snapshot and source_commit). doi:10.5281/zenodo.22059963", "docs": "https://mtor-atlas.org/api/" }, "count": 526, "data": [ { "sid": "DEM2016", "entities": [ "lysosome", "energy-cellular-stress" ], "authors": [ "constantinos-demetriades", "aurelio-a-teleman" ], "author_names": [ "Constantinos Demetriades", "Aurelio A. Teleman" ], "text": "mTORC1 promotes cell growth and is therefore inactivated upon unfavourable growth conditions. Signalling pathways downstream of most cellular stresses converge on TSC1/2, which serves as an integration point that inhibits mTORC1. The TSC1/2 complex was shown to translocate to lysosomes to inactivate mTORC1 in response to two stresses: amino-acid starvation and growth factor removal. Whether other stresses also regulate TSC2 localization is not known. How TSC2 localization responds to combinations of stresses and other stimuli is also unknown. Various cellular stresses (amino-acid/growth-factor withdrawal, etc.) – mechanistic TSC2 / mTORC1 Mammalian cells Diverse stresses relocate TSC2 to the lysosome → inhibit mTORC1 (a universal response)" }, { "sid": "POL2015", "entities": [ "tsc1-tsc2", "t-cell-differentiation", "rictor", "mtorc1", "mtorc2" ], "authors": [ "jonathan-d-powell", "greg-m-delgoffe", "kristen-n-pollizzi", "adam-t-waickman" ], "author_names": [ "Jonathan D. Powell", "Greg M. Delgoffe", "Kristen N. Pollizzi", "Adam T. Waickman" ], "text": "Activation of mTOR-dependent pathways regulates the specification and differentiation of CD4+ T effector cell subsets. Herein, we show that mTOR complex 1 (mTORC1) and mTORC2 have distinct roles in the generation of CD8+ T cell effector and memory populations. T-cell-specific deletion of Tsc2, Rheb or Rictor; Tsc2/Rictor double deletion; rapamycin 100 ug/kg/day; 2-deoxyglucose 500 mg/kg/day mTORC1 and mTORC2 activity in CD8 T cells and the effector versus memory decision Mouse Constitutive mTORC1 drives glycolytic effectors that cannot become memory; loss of mTORC1 blocks effector differentiation; loss of mTORC2 increases functional memory" }, { "sid": "BAL2019", "entities": [ "tsc1-tsc2", "mtor", "mtorc1", "rheb" ], "authors": [ "stephanie-baulac", "sara-baldassari", "homa-adle-biassette", "mathilde-chipaux" ], "author_names": [ "Stéphanie Baulac", "Sara Baldassari", "Homa Adle-Biassette", "Mathilde Chipaux" ], "text": "Genetic malformations of cortical development (MCDs), such as mild MCDs (mMCD), focal cortical dysplasia (FCD), and hemimegalencephaly (HME), are major causes of severe pediatric refractory epilepsies subjected to neurosurgery. FCD2 are characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) and balloon cells (BCs). Here, we provide a comprehensive assessment of the contribution of germline and somatic variants in a large cohort of surgical MCD cases. None (observational genetic cohort) mTOR pathway activators (MTOR, AKT3, PIK3CA, RHEB) and repressors (DEPDC5, TSC1, TSC2) Human Somatic gain-of-function activator variants in FCD2/HME; strong pS6 in dysmorphic neurons and balloon cells 80 children enrolled; 29 of 62 FCD2/HME cases carried an activator variant; 25 FCD2 cases analysed for pS6 Single centre. Observational: variants not functionally tested here. pS6 is a downstream readout. RHEB-specific case count and allele frequencies were not extracted (gene names were lost in the text conversion); see the paper's tables." }, { "sid": "INOK2003", "entities": [ "rheb" ], "authors": [ "kun-liang-guan", "ken-inoki" ], "author_names": [ "Kun-Liang Guan", "Ken Inoki" ], "text": "Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2. The TSC1 and TSC2 gene products form a functional complex and inhibit phosphorylation of S6K and 4EBP1. These functions of TSC1/TSC2 are likely mediated by mTOR. Here we report that TSC2 is a GTPase-activating protein (GAP) toward Rheb, a Ras family GTPase. Rheb stimulates phosphorylation of S6K and 4EBP1. This function of Rheb is blocked by rapamycin and dominant-negative mTOR. Biochemical/genetic (TSC2 GAP activity toward Rheb) Rheb / TSC2 / mTOR In vitro; Drosophila TSC2 is a GAP for Rheb; Rheb-GTP activates mTOR/S6K/4EBP1 (rapamycin-sensitive)" }, { "sid": "INO2002", "entities": [ "tsc1-tsc2", "akt-pkb", "pi3k", "mtorc1" ], "authors": [ "kun-liang-guan", "ken-inoki" ], "author_names": [ "Kun-Liang Guan", "Ken Inoki" ], "text": "Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the formation of hamartomas in a wide range of human tissues. Mutation in either the TSC1 or TSC2 tumour suppressor gene is responsible for both the familial and sporadic forms of this disease. TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). Biochemical/genetic (Akt phosphorylation of TSC2) TSC2 / Akt / mTOR Human cell lines Akt phosphorylates and inactivates TSC2 → relieves mTOR inhibition (links insulin/growth factors to mTORC1)" }, { "sid": "WAN2017", "entities": [ "rapamycin", "cellular-senescence", "autophagy", "senescence-associated-secretory-phenotype-sasp" ], "authors": [ "rong-wang", "viviana-i-perez" ], "author_names": [ "Rong Wang", "Viviana I. Pérez" ], "text": "Senescent cells contribute to age-related pathology and loss of function, and their selective removal improves physiological function and extends longevity. Rapamycin, an inhibitor of mTOR, inhibits cell senescence in vitro and increases longevity in several species. Nrf2 levels have been shown to decrease with aging and silencing Nrf2 gene induces premature senescence. Therefore, we explored whether Nrf2 is involved in the mechanism by which rapamycin delays cell senescence. Rapamycin (25-250 nM in cells; 4 mg/kg i.p. every other day for 6 weeks in mice), with Nrf2 knockout / re-expression mTOR (via rapamycin); Nrf2 Mouse; human cells Rapamycin lowers SASP and beta-gal staining independently of Nrf2; lowering of p16/p21 and autophagy activation require Nrf2" }, { "sid": "YU2026", "entities": [ "cognition", "rapamycin", "mtor" ], "authors": [ "jiafeng-yu", "yang-yu" ], "author_names": [ "Jiafeng Yu", "Yang Yu" ], "text": "Sepsis-associated encephalopathy (SAE) commonly elicits long-lasting cognitive deterioration. This study investigates whether high-concentration (67%) hydrogen gas protects against SAE by promoting oligodendrocyte maturation and myelination in the medial prefrontal cortex (mPFC). mTOR hyperactivation in the mPFC of SAE mice impeded oligodendrocyte precursor cell (OPC) differentiation, triggered hypomyelination, and precipitated cognitive dysfunction. 67% Hydrogen gas; Rapamycin; NV-5138 (mTOR agonist) mTOR pathway; oligodendrocyte precursor cell differentiation; myelination Mouse In mice, mTOR hyperactivation blocks OPC differentiation and myelination causing cognitive decline; hydrogen + rapamycin suppress mTOR and restore cognition" }, { "sid": "WYA2018", "entities": [ "lysosome", "torin1", "lc3b-map1lc3b", "mtorc1", "autophagy" ], "authors": [ "david-m-sabatini", "gregory-a-wyant", "monther-abu-remaileh", "sze-ham-chan", "nouf-n-laqtom" ], "author_names": [ "David M. Sabatini", "Gregory A. Wyant", "Monther Abu-Remaileh", "Sze Ham Chan", "Nouf N. Laqtom" ], "text": "The lysosome degrades and recycles macromolecules, signals to the master growth regulator mTORC1 [mechanistic target of rapamycin (mTOR) complex 1], and is associated with human disease. We performed quantitative proteomic analyses of rapidly isolated lysosomes and found that nutrient levels and mTOR dynamically modulate the lysosomal proteome. Upon mTORC1 inhibition, NUFIP1 (nuclear fragile X mental retardation-interacting protein 1) redistributes from the nucleus to autophagosomes and lysosomes. Torin1 or nutrient (amino-acid/glucose) starvation; CRISPR loss of NUFIP1, ATG7 or DEPDC5; NUFIP1 W40A (LC3B-binding) and NLS/NES mutants mTORC1 inhibition -> NUFIP1-ZNHIT3 -> LC3B -> ribosome autophagy (ribophagy) Human and mouse cell lines mTORC1 inhibition triggered NUFIP1-dependent autophagic degradation of ribosomes, which supported starvation survival and later mTORC1 reactivation" }, { "sid": "SHI2022", "entities": [ "lychos-gpr155", "cholesterol" ], "authors": [ "douglas-f-covey", "oliver-b-davis", "daniel-k-nomura", "rushika-m-perera", "chun-yan-lim", "hijai-r-shin" ], "author_names": [ "Douglas F. Covey", "Oliver B. Davis", "Daniel K. Nomura", "Rushika M. Perera", "Chun-Yan Lim", "Hijai R. Shin" ], "text": "Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified lysosomal cholesterol signaling (LYCHOS, previously annotated as G protein-coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic target of rapamycin complex 1 (mTORC1). Cholesterol bound to the amino-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation." }, { "sid": "JIN2026B", "entities": [ "hif-1alpha", "cardiac-aging", "rapamycin", "atrial-fibrillation" ], "authors": [ "lingyan-jin", "qiangsun-zheng" ], "author_names": [ "Lingyan Jin", "Qiangsun Zheng" ], "text": "Atrial fibrillation (AF) is an age-related disease. Although rapamycin is a foremost anti-aging therapy with proven efficacy in lifespan extension, its impact on aging-induced atrial remodeling and AF susceptibility was unknown. An aging-induced AF-susceptible mouse model was produced by D-galactose injection followed by a rapamycin diet. Rapamycin significantly reduced aging-induced AF susceptibility and ameliorated atrial electrical and structural remodeling. Rapamycin (dietary) HIF-1α (mTOR-independent); mitochondrial metabolism Mouse Reduced AF susceptibility, improved insulin resistance, restored mitochondrial function and substrate utilisation" }, { "sid": "SAT2010", "entities": [ "rapamycin", "mtor", "mtorc1", "4e-bp1" ], "authors": [ "tatsuhiro-sato", "fuyuhiko-tamanoi" ], "author_names": [ "Tatsuhiro Sato", "Fuyuhiko Tamanoi" ], "text": "Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates a variety of cellular functions such as growth, proliferation and autophagy. In a variety of cancer cells, overactivation of mTOR has been reported. In addition, mTOR inhibitors, such as rapamycin and its derivatives, are being evaluated in clinical trials as anticancer drugs. However, no active mutants of mTOR have been identified in human cancer. Expression of mTOR point mutants S2215Y and R2505P; rapamycin mTOR kinase / mTORC1 Cultured mammalian cells Cancer-derived mTOR mutations make mTORC1 active under starvation; still rapamycin-sensitive" }, { "sid": "LOF2011", "entities": [ "ulk1", "autophagy", "ampk" ], "authors": [ "dario-r-alessi", "mondira-kundu", "bjorn-stork", "antje-s-loffler" ], "author_names": [ "Dario R. Alessi", "Mondira Kundu", "Björn Stork", "Antje S. Löffler" ], "text": "Unc-51-like kinase 1 (Ulk1) plays a central role in autophagy induction. It forms a stable complex with Atg13 and focal adhesion kinase (FAK) family interacting protein of 200 kDa (FIP 200). This complex is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1) in a nutrient-dependent way. AMP-activated protein kinase (AMPK), which is activated by LKB1/Strad/Mo25 upon high AMP levels, stimulates autophagy by inhibiting mTORC1. Recently, it has been described that AMPK and Ulk1 interact and that the latter is phosphorylated by AMPK. Biochemical (ULK1–AMPK) ULK1 / AMPK / mTORC1 Human cells; mouse ULK1 phosphorylates and inhibits AMPK – a negative feedback loop in autophagy signaling" }, { "sid": "KIM2003", "entities": [ "mlst8", "raptor", "mtor", "mtorc1" ], "authors": [ "david-m-sabatini", "do-hyung-kim", "dos-d-sarbassov", "siraj-m-ali", "hediye-erdjument-bromage", "paul-tempst", "robert-r-latek" ], "author_names": [ "David M. Sabatini", "Do-Hyung Kim", "Dos D. Sarbassov", "Siraj M. Ali", "Hediye Erdjument-Bromage", "Paul Tempst", "Robert R. Latek" ], "text": "mTOR and raptor are components of a signaling pathway that regulates mammalian cell growth in response to nutrients and growth factors. Here, we identify a member of this pathway, a protein named GbetaL that binds to the kinase domain of mTOR and stabilizes the interaction of raptor with mTOR. Like mTOR and raptor, GbetaL participates in nutrient- and growth factor-mediated signaling to S6K1, a downstream effector of mTOR, and in the control of cell size. Biochemical – identification of GβL (mLST8) mTOR / raptor / GβL (mLST8) Human cells (biochemistry) GβL binds the mTOR kinase domain and stabilizes the raptor–mTOR interaction; stimulates nutrient-sensitive signaling to S6K1 and cell-size control" }, { "sid": "JIN2026C", "entities": [ "rapamycin", "immune-function", "cellular-senescence" ], "authors": [ "amanda-c-foks", "jill-de-mol" ], "author_names": [ "Amanda C. Foks", "Jill de Mol" ], "text": "Aging is a major risk factor for atherosclerosis and is accompanied by profound changes in the immune system, including effector T cell expansion, senescent cell accumulation, and increased pro-inflammatory signaling. Rapamycin, a promising rejuvenation therapeutic that inhibits mTORC1 and modulates immune aging, was investigated for its potential to attenuate pro-atherogenic immune responses in aged atherosclerotic mice. 80- to 90-week-old male Ldlr-/- mice with established atherosclerotic lesions were treated intraperitoneally with rapamycin or control triweekly for 8 weeks. Rapamycin, intraperitoneal, three times weekly for 8 weeks mTORC1 in immune cells (T cell, B cell and macrophage compartments) Mouse (aged 80-90 week male Ldlr-/-, established atherosclerosis) Rapamycin reduced plaque macrophages and effector T cells, enriched regulatory T cells, lowered germinal-centre B cell and antibody responses, and reduced senescence scores in aortic leukocytes." }, { "sid": "LIS2026", "entities": [ "mtor", "autophagy" ], "authors": [ "guoqing-ouyang" ], "author_names": [ "Guoqing Ouyang" ], "text": "Notoginsenoside R1 (NGR1), a bioactive saponin from Panax notoginseng, was investigated in acetaminophen-induced acute liver injury (AILI). NGR1 treatment activated autophagy via modulation of the MAPK/mTOR pathway, reducing hepatocyte apoptosis and oxidative stress, and attenuating liver injury in mouse models and hepatocyte cultures. Notoginsenoside R1 MAPK/mTOR pathway; autophagy Mouse NGR1 suppresses mTOR to activate autophagy, reducing APAP-induced hepatocyte apoptosis and liver injury" }, { "sid": "GWI2008", "entities": [ "tsc1-tsc2", "raptor", "mtorc1", "energy-cellular-stress", "ampk" ], "authors": [ "reuben-j-shaw", "daniel-f-egan", "benjamin-e-turk", "dana-m-gwinn", "maria-m-mihaylova", "david-b-shackelford" ], "author_names": [ "Reuben J. Shaw", "Daniel F. Egan", "Benjamin E. Turk", "Dana M. Gwinn", "Maria M. Mihaylova", "David B. Shackelford" ], "text": "AMPK is a highly conserved sensor of cellular energy status that is activated under conditions of low intracellular ATP. AMPK responds to energy stress by suppressing cell growth and biosynthetic processes, in part through its inhibition of the rapamycin-sensitive mTOR (mTORC1) pathway. AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1; however, TSC2-deficient cells remain responsive to energy stress. Using a proteomic and bioinformatics approach, we sought to identify additional substrates of AMPK that mediate its effects on growth control. Biochemical/genetic (AMPK phosphorylation of raptor) raptor / mTORC1 / AMPK Human/mouse cells (biochemistry) Under energy stress AMPK phosphorylates raptor → a metabolic checkpoint that suppresses mTORC1" }, { "sid": "BOU2026", "entities": [ "tsc1-tsc2", "tfeb", "mtorc1", "tuberous-sclerosis-complex" ], "authors": [ "david-j-kwiatkowski", "elizabeth-p-henske", "elias-bou-farhat" ], "author_names": [ "David J. Kwiatkowski", "Elizabeth P Henske", "Elias Bou Farhat" ], "text": "Tuberous sclerosis complex (TSC) is an inherited tumor predisposition syndrome caused by pathogenic variants in TSC1 or TSC2, yet no animal model faithfully recapitulates the cardiac rhabdomyomas (CR) that are among its earliest manifestations. We generated a heterozygous TSC2-mutant Yucatan minipig carrying the recurrent pathogenic TSC2 p.Arg505* variant and characterized its cardiac phenotype using histopathology, immunohistochemistry, and RNA sequencing. Genetic (TSC2 p.Arg505* heterozygous mutation) TSC2 / mTORC1 / MITF-TFE Yucatan minipig (Sus scrofa) TSC2-mutant minipigs develop cardiac rhabdomyomas with mTORC1 activation and an MITF/TFE lysosomal signature" }, { "sid": "VITTE2026", "entities": [ "everolimus" ], "authors": [ "giancarlo-maruri-munaretto", "sofia-helena-vitte" ], "author_names": [ "Giancarlo Maruri Munaretto", "Sofia Helena Vitte" ], "text": "Long-term outcomes after heart transplantation remain limited by cardiac allograft vasculopathy (CAV) and calcineurin inhibitor (CNI)-related nephrotoxicity. Everolimus has emerged as a CNI-sparing strategy, yet its net clinical benefit remains debated. To determine whether everolimus-based immunosuppression improves efficacy and safety compared with standard CNI-based therapy in heart transplant recipients. We conducted a systematic review and meta-analysis of randomized controlled trials and comparative observational studies enrolling adult and/or pediatric heart transplant recipients. Everolimus-based immunosuppression (with calcineurin-inhibitor minimisation or withdrawal) vs standard CNI-based therapy mTORC1 (everolimus) Human Reduced cardiac allograft vasculopathy progression and better renal function; mortality neutral; more adverse events and discontinuations" }, { "sid": "LEE2021", "entities": [ "mtorc1", "rheb" ], "authors": [ "stephanie-baulac", "sara-baldassari", "homa-adle-biassette", "mathilde-chipaux", "wei-shern-lee", "richard-j-leventer" ], "author_names": [ "Stéphanie Baulac", "Sara Baldassari", "Homa Adle-Biassette", "Mathilde Chipaux", "Wei Shern Lee", "Richard J Leventer" ], "text": "Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are related malformations with shared etiologies. We report three patients with a spectrum of cortical malformations associated with pathogenic brain-specific somatic Ras homolog enriched in brain (RHEB) variants. The somatic variant load directly correlated with the size of the malformation, with upregulated mTOR activity confirmed in dysplastic tissues. Laser capture microdissection showed enrichment of RHEB variants in dysmorphic neurons and balloon cells. None (observational case series) RHEB (somatic gain-of-function variants) / mTOR activity in dysplastic brain Human Lesion size tracked RHEB variant load (2.6%, 8.9%, 17.6%); strong pS6 in dysmorphic neurons and balloon cells 3 patients (1 new, 2 previously described) Three patients only. Variant effect on Rheb function not tested here. pS6 is an indirect readout of mTOR activity. No microdissection in patient 1 (insufficient tissue); pS6 cell density could not be compared for patient 1." }, { "sid": "ESP2026", "entities": [ "lysosome", "tbk1", "v-atpase", "ulk1", "tfeb", "tax1bp1", "flcn-fnip1-2", "atp6v1b2" ], "authors": [ "roberto-zoncu", "andrea-ballabio", "james-h-hurley", "alessandra-esposito", "gennaro-napolitano", "alessia-calcagni", "jorn-dengjel", "jlenia-monfregola", "rachel-m-jansen" ], "author_names": [ "Roberto Zoncu", "Andrea Ballabio", "James H. Hurley", "Alessandra Esposito", "Gennaro Napolitano", "Alessia Calcagnì", "Jörn Dengjel", "Jlenia Monfregola", "Rachel M. Jansen" ], "text": "Lysosomal adaptation to environmental changes is critical for cellular and metabolic homeostasis and requires coordination by the mTORC1 kinase, which conveys nutritional and stress signals into distinct, substrate-specific outputs. The FLCN-FNIP complex (FLCN:FNIP) serves as a crucial regulator of lysosomal function by selectively controlling the ability of mTORC1 to inhibit transcription factor EB (TFEB), a master regulator of catabolic programs and a known oncogene. Yet how FLCN:FNIP activity is regulated has remained unclear. Genetic and pharmacological perturbation of v-ATPase, TBK1/ULK1, TAX1BP1 and FNIP1 (S296 phospho-mutants); lysosomal stress v-ATPase - TBK1/ULK1 - FNIP1 S296 - FLCN:FNIP - TFEB Human cell lines; follicular lymphoma patient samples Lysosomal stress recruits TBK1/ULK1 to phosphorylate FNIP1, inhibiting FLCN and driving TFEB nuclear translocation; recurrent ATP6V1B2 mutations hyperactivate this axis and promote lymphoma cell proliferation." }, { "sid": "VIL2021", "entities": [ "mtorc1", "protein-synthesis", "s-adenosylmethionine-sam", "methionine", "tumor-growth" ], "authors": [ "issam-ben-sahra", "eunus-s-ali", "umakant-sahu", "brendan-p-ohara", "john-m-asara", "peng-gao", "elodie-villa" ], "author_names": [ "Issam Ben-Sahra", "Eunus S. Ali", "Umakant Sahu", "Brendan P. O'Hara", "John M. Asara", "Peng Gao", "Elodie Villa" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient, growth, and oncogenic signals. We found that mTORC1 stimulates the synthesis of the major methyl donor, S-adenosylmethionine (SAM), through the control of methionine adenosyltransferase 2 alpha (MAT2A) expression. The transcription factor c-MYC, downstream of mTORC1, directly binds to intron 1 of MAT2A and promotes its expression. Genetic/pharmacologic (mTORC1, MAT2A inhibition) mTORC1 / c-MYC / MAT2A / SAM / WTAP / m6A Human cells; mouse xenograft tumors mTORC1 raises SAM production and WTAP levels, increasing m6A mRNA modification and protein synthesis to support cell growth" }, { "sid": "DEOLIVEIRA2026", "entities": [ "mtor", "breast-cancer", "pi3k" ], "authors": [ "antonio-carlos-de-freitas", "beatriz-eda-de-oliveira-isidio" ], "author_names": [ "Antonio Carlos de Freitas", "Beatriz Eda de Oliveira Isídio" ], "text": "Breast cancer is the most prevalent malignant tumor among women. Human papillomavirus (HPV) has been detected in breast tumors since the 1990s, and beyond its oncogenic potential, therapy resistance driven by viral immune evasion in non-anogenital tumors, such as oropharyngeal cancers, highlights the need to investigate viral activity in breast tissues. Among high-risk HPV types, HPV16 is one of the most prevalent and exhibits the highest carcinogenic potential. HPV16 oncogene expression PI3K/AKT/mTOR Human HPV-positive tumours: PI3K mRNA higher, mTOR mRNA lower (association)" }, { "sid": "SIL2026", "entities": [ "t-cell-differentiation", "immune-function", "mtorc1", "rheb" ], "authors": [ "ronjon-chakraverty", "francesca-sillito" ], "author_names": [ "Ronjon Chakraverty", "Francesca Sillito" ], "text": "There is substantial interest in developing novel engineering strategies to promote the sustained metabolic fitness of therapeutic T cells. We previously showed that overexpression of RAS homologue enriched in brain (RHEB), a positive regulator of mammalian target of rapamycin complex 1 (mTORC1), promotes aerobic glycolysis and increases the anti-tumor functions of effector CD8+ T cells. To address whether these effects are conserved in CD4+ T cells, we have now examined how enforced activation of mTORC1 activity affects CD4+ T cell differentiation and function. Retroviral Rheb overexpression in CD4+ T cells, adoptive transfer Rheb / mTORC1 Mouse CD4+ T cells (in vitro and adoptive transfer tumour model) Enforced mTORC1 activity raised CD4+ T cell activation, metabolism and persistence but pushed persisting cells toward exhaustion and reduced tumour clearance." }, { "sid": "BRO1996", "entities": [ "growth-hormone-igf-1-axis", "longevity" ], "authors": [ "holly-m-brown-borg", "andrzej-bartke" ], "author_names": [ "Holly M. Brown-Borg", "Andrzej Bartke" ], "text": "(Brief communication; no formal abstract in PubMed — editorial summary.) This landmark report shows that Ames dwarf mice, which carry a mutation causing combined deficiency of growth hormone, prolactin and thyroid-stimulating hormone, live substantially longer than their normal littermates (both sexes). Genetic – Ames dwarf mutation (GH/prolactin/TSH deficiency) GH/IGF-1 axis (upstream of PI3K-Akt-mTOR) Mouse (Ames dwarf) Substantially longer lifespan vs normal littermates (both sexes) – early evidence linking reduced growth signaling to longevity" }, { "sid": "RIV2026", "entities": [ "rapamycin", "immune-function", "pi3k" ], "authors": [ "beatrice-rivalta", "maria-elena-maccari" ], "author_names": [ "Beatrice Rivalta", "Maria Elena Maccari" ], "text": "Activated PI3K-delta syndrome (APDS) is a rare inborn error of immunity characterized by variable immune dysregulation, recurrent infections, and increased risk of malignancy. Clinical management is challenging. Rapamycin has been widely used off-label to control immune dysregulation, while the selective PI3Kδ inhibitor leniolisib has recently become available as a disease-specific targeted therapy. Real-world data on these treatment approaches remain limited. Rapamycin (off-label) and/or leniolisib (PI3Kdelta inhibitor) PI3Kdelta / mTOR Human (retrospective registry, 95 APDS patients) Both drugs were associated with similar response rates for lymphoproliferation (67% vs 64%); treatment-limiting adverse events occurred only with rapamycin." }, { "sid": "KOR2011", "entities": [ "lysosome", "mtorc1", "autophagy" ], "authors": [ "viktor-i-korolchuk", "david-c-rubinsztein", "vojo-deretic", "fiona-menzies", "cahir-okane" ], "author_names": [ "Viktor I. Korolchuk", "David C. Rubinsztein", "Vojo Deretic", "Fiona Menzies", "Cahir O'Kane" ], "text": "mTOR (mammalian target of rapamycin) signalling and macroautophagy (henceforth autophagy) regulate numerous pathological and physiological processes, including cellular responses to altered nutrient levels. However, the mechanisms regulating mTOR and autophagy remain incompletely understood. Lysosomes are dynamic intracellular organelles intimately involved both in the activation of mTOR complex 1 (mTORC1) signalling and in degrading autophagic substrates. Nutrient starvation / intracellular pH change; manipulation of lysosome positioning Lysosome positioning / mTORC1 / autophagy Human cell line (HeLa) Peripheral lysosomes accompany active mTORC1; perinuclear clustering on starvation lowers mTORC1 signalling and raises autophagosome formation and fusion." }, { "sid": "PEN2011", "entities": [ "tsc1-tsc2", "v-atpase", "tfeb", "rapamycin", "mtorc1" ], "authors": [ "james-brugarolas", "samuel-pena-llopis" ], "author_names": [ "James Brugarolas", "Samuel Peña-Llopis" ], "text": "Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is an important, highly conserved, regulator of cell growth. Ancient among the signals that regulate mTORC1 are nutrients. Amino acids direct mTORC1 to the surface of the late endosome/lysosome, where mTORC1 becomes receptive to other inputs. However, the interplay between endosomes and mTORC1 is poorly understood. Here, we report the discovery of a network that links mTORC1 to a critical component of the late endosome/lysosome, the V-ATPase. Tsc2 or Tsc1 loss (genetic), rapamycin, Raptor knockdown; Tfeb knockdown mTORC1 -> TFEB -> V-ATPase genes Mouse cells and mouse liver; human HeLa cells mTORC1 activation increased V-ATPase and lysosomal gene expression and endocytosis in a TFEB-dependent way; under low serum it increased TFEB nuclear localisation" }, { "sid": "HSI2012", "entities": [ "eif4e", "prostate-cancer", "ribosome-biogenesis", "mtorc1", "protein-synthesis", "4e-bp1", "tumor-growth" ], "authors": [ "davide-ruggero", "kevan-m-shokat", "matthew-r-janes", "andrew-c-hsieh", "yi-liu", "nicholas-t-ingolia" ], "author_names": [ "Davide Ruggero", "Kevan M. Shokat", "Matthew R. Janes", "Andrew C. Hsieh", "Yi Liu", "Nicholas T. Ingolia" ], "text": "The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. Oncogenic mTOR modulation + ribosome profiling mTOR / 4E-BP–eIF4E translation Mouse models + human prostate cancer Oncogenic mTOR reprograms translation of a specific gene set driving proliferation, metabolism and invasion/metastasis" }, { "sid": "BOU2020", "entities": [ "mtor" ], "authors": [ "nathalie-bouquier", "vincent-ollendorff", "julie-perroy" ], "author_names": [ "Nathalie Bouquier", "Vincent Ollendorff", "Julie Perroy" ], "text": "mTOR signaling is an essential nutrient and energetic sensing pathway. Here we describe AIMTOR, a sensitive genetically encoded BRET (Bioluminescent Resonance Energy Transfer) biosensor to study mTOR activity in living cells. As a proof of principle, we show in both cell lines and primary cell cultures that AIMTOR BRET intensities are modified by mTOR activity changes induced by specific inhibitors and activators of mTORC1 including amino acids and insulin. We further engineered several versions of AIMTOR enabling subcellular-specific assessment of mTOR activities. Genetically encoded BRET biosensor (AIMTOR) -- tool, not a drug intervention mTOR activity (live, subcellular) Human (HEK293); mouse (neurons, muscle) Enables real-time single-cell/subcellular measurement of mTOR activity dynamics" }, { "sid": "CHEN2026C", "entities": [ "tsc1-tsc2", "chaperone-mediated-autophagy", "cellular-senescence", "mtorc1", "senescence-associated-secretory-phenotype-sasp" ], "authors": [ "xianglong-chen", "yukun-zhang" ], "author_names": [ "Xianglong Chen", "Yukun Zhang" ], "text": "Intervertebral disc degeneration (IDD) is a leading cause of low back pain with incompletely understood mechanisms. Although autophagy dysfunction is a documented contributor to IDD, the precise pathobiological role of chaperone-mediated autophagy (CMA) remains poorly understood. Here, we demonstrate that CMA activity is downregulated in nucleus pulposus cells (NPCs) from IDD patients and IL-1beta-induced rat intervertebral disc cell models, causing cytoplasmic accumulation of a novel CMA substrate, Midnolin (MIDN). MIDN knockdown (shRNA), LAMP2A overexpression (CMA activation), rapamycin TSC2 / mTORC1 (via midnolin, MIDN) Human cells; rat Impaired CMA -> MIDN accumulation -> TSC2 degradation -> mTORC1 hyperactivation -> senescence, SASP and matrix loss; blocked by MIDN knockdown, LAMP2A overexpression or rapamycin" }, { "sid": "JAC2006", "entities": [ "sin1-mapkap1" ], "authors": [ "estela-jacinto", "bing-su" ], "author_names": [ "Estela Jacinto", "Bing Su" ], "text": "Mammalian target of rapamycin (mTOR) controls cell growth and proliferation via the raptor-mTOR (TORC1) and rictor-mTOR (TORC2) protein complexes. Recent biochemical studies suggested that TORC2 is the elusive PDK2 for Akt/PKB Ser473 phosphorylation in the hydrophobic motif. Phosphorylation at Ser473, along with Thr308 of its activation loop, is deemed necessary for Akt function, although the regulatory mechanisms and physiological importance of each phosphorylation site remain to be fully understood. Here, we report that SIN1/MIP1 is an essential TORC2/PDK2 subunit. Biochemical/genetic (SIN1/MIP1) mTORC2 (rictor-mTOR) / Akt Ser473 Mammalian cells SIN1 maintains rictor–mTOR (mTORC2) integrity and controls Akt Ser473 phosphorylation and substrate specificity" }, { "sid": "BOB2026", "entities": [ "longevity", "mtor" ], "authors": [ "natalia-bobok" ], "author_names": [ "Natalia Bobok" ], "text": "The mechanistic target of rapamycin (mTOR) pathway is an important integrator of processes involved in aging and longevity, coordinating nutrient sensing, metabolic adaptation, and cellular stress responses. This review presents a three-section framework in which mTOR functions as a dynamic signaling hub coordinating multiple biological processes underlying the aging process. none (narrative review) mTORC1 / mTORC2 signalling across hallmarks of ageing Model organisms and human associative data (review) Argues mTOR is a context-dependent hub in ageing, with causal evidence in model organisms and associative evidence in humans." }, { "sid": "ALI2020", "entities": [ "nucleotide-synthesis", "erk-rsk-mapk" ], "authors": [ "issam-ben-sahra", "eunus-s-ali", "umakant-sahu", "brendan-p-ohara", "john-m-asara", "peng-gao", "elodie-villa" ], "author_names": [ "Issam Ben-Sahra", "Eunus S. Ali", "Umakant Sahu", "Brendan P. O'Hara", "John M. Asara", "Peng Gao", "Elodie Villa" ], "text": "The RAS-ERK/MAPK (RAS-extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway integrates growth-promoting signals to stimulate cell growth and proliferation, at least in part, through alterations in metabolic gene expression. However, examples of direct and rapid regulation of the metabolic pathways by the RAS-ERK pathway remain elusive. Genetic (PFAS T619A); ERK pathway activation RAS / ERK2 / PFAS (de novo purine synthesis) Human cancer cells; mouse tumors ERK2 phosphorylates PFAS at T619 to stimulate de novo purine synthesis, supporting cell proliferation and tumor growth" }, { "sid": "CHI2012", "entities": [ "t-cell-differentiation", "mtor", "immune-function" ], "authors": [ "hongbo-chi" ], "author_names": [ "Hongbo Chi" ], "text": "The evolutionarily conserved kinase mTOR (mammalian target of rapamycin) couples cell growth and metabolism to environmental inputs in eukaryotes. T cells depend on mTOR signalling to integrate immune signals and metabolic cues for their proper maintenance and activation. Under steady-state conditions, mTOR is actively controlled by multiple inhibitory mechanisms, and this enforces normal T cell homeostasis. Antigen recognition by naive CD4(+) and CD8(+) T cells triggers mTOR activation, which in turn programmes the differentiation of these cells into functionally distinct lineages. Not applicable (review) mTOR / mTORC1 & mTORC2 Review mTOR integrates immune and metabolic cues to program T-cell homeostasis, activation and differentiation" }, { "sid": "CHEN2026", "entities": [ "fgf21" ], "authors": [ "kewei-chen", "wanying-chen" ], "author_names": [ "Kewei Chen", "Wanying Chen" ], "text": "Chronic wound healing disorders remain a significant clinical challenge, largely due to the limited effectiveness of conventional therapeutic strategies. Emerging evidence suggests that engineered exosomes represent a promising cell-free therapeutic approach. This study aimed to elucidate the mechanisms by which FGF21-modified adipose-derived mesenchymal stem cell (ADSC) exosomes promote wound healing. ADSCs overexpressing FGF21 were established using genetic engineering, and FGF21-enriched exosomes (Exo@FGF21) were isolated and characterized. FGF21-modified ADSC exosomes AMPK/mTOR Mouse + Human (fibroblasts in vitro) Promotes wound healing via fibroblast glycolysis, with AMPK activated and mTOR signaling suppressed" }, { "sid": "KRA2018", "entities": [ "longevity", "rapamycin", "immune-function", "mtorc1" ], "authors": [ "dean-l-kellogg-jr", "martin-a-javors", "adriana-d-benavides", "ellen-kraig", "nicolas-musi", "qianqian-liu" ], "author_names": [ "Dean L. Kellogg Jr.", "Martin A. Javors", "Adriana D. Benavides", "Ellen Kraig", "Nicolas Musi", "Qianqian Liu" ], "text": "Inhibition of the mechanistic target of rapamycin (mTOR) pathway by rapamycin (RAPA), an FDA-approved immunosuppressive drug used as a clinical therapy to prevent solid organ allograft rejection, enhances longevity in mice. Importantly, RAPA was efficacious even when initiated in relatively old animals, suggesting that mTOR inhibition could potentially slow the progression of aging-associated pathologies in older humans (Harrison et al., 2009; Miller et al., 2011). However, the safety and tolerability of RAPA in older human subjects have not yet been demonstrated. Rapamycin (oral, daily, ~8 weeks) mTOR / mTORC1 Human – healthy older adults (age 70–95, n=25) Well tolerated; NO rise in blood glucose / insulin resistance in the short window – groundwork for larger geroprotection trials Rapamycin 1 mg daily orally (single dose tested; blood levels monitored in first 4 subjects), ~8-16 weeks; placebo-controlled. n=25 randomised (11 rapamycin, 14 placebo analysed); healthy older adults aged 70-95. Established feasibility and safety of daily low-dose rapamycin in older adults; no serious adverse events; groundwork for larger geroprotection trials. Small sample -> single 1 mg dose chosen; short duration; feasibility (not efficacy) study." }, { "sid": "GKO2013", "entities": [ "eif4e", "protein-synthesis", "4e-bp1" ], "authors": [ "davide-ruggero", "nahum-sonenberg", "christos-g-gkogkas" ], "author_names": [ "Davide Ruggero", "Nahum Sonenberg", "Christos G. Gkogkas" ], "text": "Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is thought to cause autism spectrum disorders (ASDs). The mammalian target of rapamycin (mTOR) is strongly implicated in ASDs by means of upstream signalling; however, downstream regulatory mechanisms are ill-defined. Here we show that knockout of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2)-an eIF4E repressor downstream of mTOR-or eIF4E overexpression leads to increased translation of neuroligins, which are postsynaptic proteins that are causally linked to ASDs. Eif4ebp2 knockout; eIF4E overexpression; 4EGI-1 (icv); Nlgn1/Nlgn2 knockdown 4E-BP2 / eIF4E (eIF4F complex) Mouse Loss of 4E-BP2 increased neuroligin translation and E/I ratio and caused autism-like behaviour; eIF4F inhibition reversed it" }, { "sid": "XIA2026", "entities": [ "longevity", "mtor", "ampk" ], "authors": [ "cheng-hu", "tianxiong-xiao" ], "author_names": [ "Cheng Hu", "Tianxiong Xiao" ], "text": "Nutrient-sensing pathways, including mTOR, AMPK, Sirtuins, and insulin/IGF-1 signaling, are central regulators orchestrating adult stem cell (ASC) fate by dynamically modulating cellular metabolism. This review proposes a framework that integrates these pathways into a cohesive network that dictates the metabolic transitions between quiescence, activation, and differentiation in ASCs. Age-related dysregulation of this network leads to metabolic imbalance and stem cell exhaustion, underpinning tissue degeneration. N/A (review); discusses mTOR inhibitors, AMPK activators, NAD+ precursors, dietary strategies as ASC-rejuvenating interventions mTOR / AMPK / Sirtuins / IGF-1 nutrient-sensing network Review (multiple species/systems) Integrated nutrient-sensing network governs adult stem cell quiescence/activation/differentiation; dysregulation drives stem cell exhaustion and aging" }, { "sid": "MAX2009", "entities": [ "eif4e", "protein-synthesis" ], "authors": [ "john-blenis", "xiaoju-max-ma" ], "author_names": [ "John Blenis", "Xiaoju Max Ma" ], "text": "The process of translation requires substantial cellular resources. Cells have therefore evolved complex mechanisms to control overall protein synthesis as well as the translation of specific mRNAs that are crucial for cell growth and proliferation. At the heart of this process is the mammalian target of rapamycin (mTOR) signalling pathway, which senses and responds to nutrient availability, energy sufficiency, stress, hormones and mitogens to modulate protein synthesis. Not applicable (review) mTOR / 4E-BP / S6K translation machinery Review Reviews how mTOR senses nutrients/energy/hormones to control protein synthesis" }, { "sid": "HEI1991", "entities": [ "rapamycin", "mtor" ], "authors": [ "michael-n-hall", "joseph-heitman" ], "author_names": [ "Michael N. Hall", "Joseph Heitman" ], "text": "FK506 and rapamycin are related immunosuppressive compounds that block helper T cell activation by interfering with signal transduction. In vitro, both drugs bind and inhibit the FK506-binding protein (FKBP) proline rotamase. Saccharomyces cerevisiae cells treated with rapamycin irreversibly arrested in the G1 phase of the cell cycle. An FKBP-rapamycin complex is concluded to be the toxic agent because (i) strains that lack FKBP proline rotamase, encoded by FPR1, were viable and fully resistant to rapamycin and (ii) FK506 antagonized rapamycin toxicity in vivo. Rapamycin (FKBP-rapamycin); genetic (FPR1, TOR) FKBP / TOR Yeast (S. cerevisiae) FKBP-rapamycin complex arrests cells in G1; identified FKBP and TOR as targets – a foundational discovery" }, { "sid": "MON1999", "entities": [ "s6k1" ], "authors": [ "george-thomas", "ernst-hafen", "sara-c-kozma", "jacques-montagne" ], "author_names": [ "George Thomas", "Ernst Hafen", "Sara C. Kozma", "Jacques Montagne" ], "text": "Cell proliferation requires cell growth; that is, cells only divide after they reach a critical size. However, the mechanisms by which cells grow and maintain their appropriate size have remained elusive. Drosophila deficient in the S6 kinase gene (dS6K) exhibited an extreme delay in development and a severe reduction in body size. These flies had smaller cells rather than fewer cells. The effect was cell-autonomous, displayed throughout larval development, and distinct from that of ribosomal protein mutants (Minutes). dS6K gene deletion Body size; cell size; developmental timing Drosophila melanogaster Loss of dS6K -> smaller cells and body, delayed development" }, { "sid": "GAO2002", "entities": [ "tsc1-tsc2", "mtorc1", "s6k1" ], "authors": [ "duojia-pan", "xinsheng-gao" ], "author_names": [ "Duojia Pan", "Xinsheng Gao" ], "text": "Target of Rapamycin (TOR) mediates a signalling pathway that couples amino acid availability to S6 kinase (S6K) activation, translational initiation and cell growth. Here, we show that tuberous sclerosis 1 (Tsc1) and Tsc2, tumour suppressors that are responsible for the tuberous sclerosis syndrome, antagonize this amino acid-TOR signalling pathway. We show that Tsc1 and Tsc2 can physically associate with TOR and function upstream of TOR genetically. In Drosophila melanogaster and mammalian cells, loss of Tsc1 and Tsc2 results in a TOR-dependent increase of S6K activity. Loss of Tsc1/Tsc2 (genetic) TOR-dependent S6K activity; response to amino acid starvation Drosophila melanogaster; mammalian cells Tsc1/Tsc2 loss increases TOR-dependent S6K activity and makes it resistant to amino acid withdrawal" }, { "sid": "GAO2026", "entities": [ "tfeb", "astragaloside-iv", "mtor", "gadd45alpha" ], "authors": [ "peng-gao", "zhenpeng-qiu" ], "author_names": [ "Peng Gao", "Zhenpeng Qiu" ], "text": "Tacrolimus-induced chronic nephrotoxicity (TICN) is mediated in part through calcineurin-dependent TFEB phosphorylation. Astragaloside IV (AS-IV) significantly reactivated TFEB and restored tacrolimus-impaired renal function, autophagy flux, and DNA repair. TFEB knockdown reversed AS-IV effects. AS-IV does not affect calcineurin but inhibits mTOR (which phosphorylates TFEB Ser211), thereby activating TFEB via the mTOR-TFEB-GADD45alpha axis. Astragaloside IV mTOR / TFEB / GADD45alpha / autophagy In vitro (renal cells) TFEB reactivation, restored autophagy flux, improved renal function markers, attenuation of nephrotoxicity" }, { "sid": "BER2006", "entities": [ "huntingtons-disease", "rapamycin", "autophagy" ], "authors": [ "david-c-rubinsztein", "brinda-ravikumar", "zdenek-berger", "fiona-menzies", "cahir-okane" ], "author_names": [ "David C. Rubinsztein", "Brinda Ravikumar", "Zdenek Berger", "Fiona Menzies", "Cahir O'Kane" ], "text": "Many neurodegenerative diseases are caused by intracellular, aggregate-prone proteins, including polyglutamine-expanded huntingtin in Huntington's disease (HD) and mutant tau in fronto-temporal dementia/tauopathy. Previously, we showed that rapamycin, an autophagy inducer, enhances mutant huntingtin fragment clearance and attenuated toxicity. Here we show much wider applications for this approach. Rapamycin enhances the autophagic clearance of different proteins with long polyglutamines and a polyalanine-expanded protein, and reduces their toxicity. Rapamycin mTOR (autophagy induction) Mammalian cell lines; Drosophila Rapamycin increased autophagic clearance and reduced toxicity of polyQ/polyA proteins and tau" }, { "sid": "FON2010", "entities": [ "growth-hormone-igf-1-axis", "longevity", "caloric-restriction", "mtorc1" ], "authors": [ "linda-partridge", "valter-d-longo", "luigi-fontana" ], "author_names": [ "Linda Partridge", "Valter D. Longo", "Luigi Fontana" ], "text": "When the food intake of organisms such as yeast and rodents is reduced (dietary restriction), they live longer than organisms fed a normal diet. A similar effect is seen when the activity of nutrient-sensing pathways is reduced by mutations or chemical inhibitors. In rodents, both dietary restriction and decreased nutrient-sensing pathway activity can lower the incidence of age-related loss of function and disease, including tumors and neurodegeneration. Not applicable (review – dietary restriction / nutrient-sensing inhibition) Nutrient-sensing pathways (incl. TOR, insulin/IGF) Review (yeast to humans) Dietary restriction and reduced nutrient-sensing activity extend lifespan and reduce age-related disease" }, { "sid": "CAS2009", "entities": [ "mtor" ], "authors": [ "j-silvio-gutkind", "rogerio-m-castilho" ], "author_names": [ "J. Silvio Gutkind", "Rogerio M Castilho" ], "text": "Epidermal integrity is a complex process established during embryogenesis and maintained throughout the organism lifespan by epithelial stem cells. Although Wnt regulates normal epithelial stem cell renewal, aberrant Wnt signaling can contribute to cancerous growth. Here, we explored the consequences of persistent expressing Wnt1 in an epidermal compartment that includes the epithelial stem cells. Surprisingly, Wnt caused the rapid growth of the hair follicles, but this was followed by epithelial cell senescence, disappearance of the epidermal stem cell compartment, and progressive hair loss. Wnt1 overexpression; rapamycin rescue mTOR Mouse (epidermal stem cells) Wnt→mTOR drives stem-cell senescence/exhaustion and hair loss; rapamycin reverses it not stated n=25 mutant and wild-type littermates Wnt1 expression caused terminal differentiation of HF after 90 days, leading to progressive hair loss. No nuclear β-catenin staining could be observed, possibly due to strong membrane signal or limited nuclear β-catenin; further investigation is warranted on the contribution of particular Wnt1 receptors." }, { "sid": "SAC2011", "entities": [ "mtor", "mtorc1", "mtorc2" ], "authors": [ "lewis-c-cantley", "abdelhafid-saci" ], "author_names": [ "Lewis C. Cantley", "Abdelhafid Saci" ], "text": "Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that exists in two separate complexes, mTORC1 and mTORC2, that function to control cell size and growth in response to growth factors, nutrients, and cellular energy levels. Low molecular weight GTP-binding proteins of the Rheb and Rag families are key regulators of the mTORC1 complex, but regulation of mTORC2 is poorly understood. Here, we report that Rac1, a member of the Rho family of GTPases, is a critical regulator of both mTORC1 and mTORC2 in response to growth-factor stimulation. Genetic/biochemical (Rac1) Rac1 / mTORC1 / mTORC2 Mammalian cells Rac1 is a critical regulator of both mTORC1 and mTORC2, controlling cell size" }, { "sid": "FER2024", "entities": [ "lysosome", "mtorc1" ], "authors": [ "constantinos-demetriades", "stephanie-a-fernandes", "peter-gollwitzer", "julian-nuchel", "sabine-wilhelm", "jiyoung-pan" ], "author_names": [ "Constantinos Demetriades", "Stephanie A. Fernandes", "Peter Gollwitzer", "Julian Nüchel", "Sabine Wilhelm", "Jiyoung Pan" ], "text": "Amino acid (AA) availability is a robust determinant of cell growth through controlling mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity. According to the predominant model in the field, AA sufficiency drives the recruitment and activation of mTORC1 on the lysosomal surface by the heterodimeric Rag GTPases, from where it coordinates the majority of cellular processes. Importantly, however, the teleonomy of the proposed lysosomal regulation of mTORC1 and where mTORC1 acts on its effector proteins remain enigmatic. Pharmacological and genetic perturbation of lysosomal amino-acid sensing (Rag pathway) and lysosomal proteolysis Lysosomal vs non-lysosomal mTORC1 pools Human cell lines (HEK293FT, WI-26 SV40 fibroblasts); mouse embryonic fibroblasts (WT, RagA/B-KO) Lysosomal mTORC1 is fed by local lysosomal proteolysis and cytoplasmic mTORC1 by external amino acids, and the two phosphorylate distinct substrates." }, { "sid": "WOL2015", "entities": [ "leucine" ], "authors": [ "david-m-sabatini", "robert-a-saxton", "lynne-chantranupong", "rachel-l-wolfson", "kuang-shen", "sonia-m-scaria" ], "author_names": [ "David M. Sabatini", "Robert A. Saxton", "Lynne Chantranupong", "Rachel L. Wolfson", "Kuang Shen", "Sonia M. Scaria" ], "text": "Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanosine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, aGTPase-activating protein; GATOR2, a positive regulator of unknown function; and Sestrin2, a GATOR2-interacting protein that inhibits mTORC1 signaling. Biochemical/genetic (Sestrin2) Sestrin2 / GATOR2 / Rag / mTORC1 Mammalian cells Sestrin2 is a leucine sensor for mTORC1; leucine (not arginine) binding relieves Sestrin2 inhibition" }, { "sid": "OKA2013", "entities": [ "renal-cell-carcinoma-rcc", "mtor", "everolimus" ], "authors": [ "shigehiro-ohdo", "hiroyuki-okazaki" ], "author_names": [ "Shigehiro Ohdo", "Hiroyuki Okazaki" ], "text": "Circadian clock systems regulate many biologic functions, including cell division and hormone secretion in mammals. In this study, we explored the effects of circadian control on the pivot cell growth regulatory mTOR, the activity of which is deregulated in tumor cells compared with normal cells. Specifically, we investigated whether the antitumor effect of an mTOR inhibitor could be improved by changing its dosing schedule in RenCa tumor-bearing mice. Everolimus dosed at different times of day mTOR; Fbxw7; DBP Mouse Dosing everolimus at the mTOR peak improved survival of tumour-bearing mice" }, { "sid": "MAJ2012", "entities": [ "cognition", "rapamycin", "s6k1" ], "authors": [ "randy-strong", "arlan-richardson", "salvatore-oddo", "smita-majumder" ], "author_names": [ "Randy Strong", "Arlan Richardson", "Salvatore Oddo", "Smita Majumder" ], "text": "Understanding the factors that contribute to age-related cognitive decline is imperative, particularly as age is the major risk factor for several neurodegenerative disorders. Levels of several cytokines increase in the brain during aging, including IL-1β, whose levels positively correlate with cognitive deficits. Previous reports show that reducing the activity of the mammalian target of rapamycin (mTOR) extends lifespan in yeast, nematodes, Drosophila, and mice. Encapsulated rapamycin in diet (14 mg/kg food), from 2 or from 15 months of age to 18 months mTOR Mouse (C57BL6/129svj) Early lifelong rapamycin prevents age-dependent spatial learning/memory decline; late start (15 months) does not reverse it" }, { "sid": "BO2026", "entities": [ "mtor", "autophagy" ], "authors": [ "su-bo" ], "author_names": [ "Su Bo" ], "text": "Gambogic acid (GA), a natural xanthonoid compound, was investigated for its anticancer activity in lung cancer via mTOR signaling inhibition using computational and in vitro approaches. GA demonstrated high lipophilicity and docking interactions with mTOR pathway components, resulting in anti-proliferative and pro-apoptotic effects in lung cancer cell lines. Gambogic acid mTOR signaling pathway Human (cell line) Cytotoxic and pro-apoptotic in lung cancer cells; docking implicates the AKT-S6K1 (RPS6KB1) axis; mTOR inhibition not directly measured" }, { "sid": "YIN2026", "entities": [ "lysosome" ], "authors": [ "jian-yin" ], "author_names": [ "Jian Yin" ], "text": "The proton-coupled amino-acid transporter SLC36A1 (hPAT1) is an atypical H+-driven carrier and mediates the intestinal absorption of a wide array of zwitterionic amino-acid analogs, including many compounds with central nervous-system (CNS) activity, as well as the activation of the mTORC1 pathway and the export of amino acids from lysosomes, thereby maintaining cellular amino-acid homeostasis. Structural/biochemical (cryo-EM of SLC36A1/PAT1, apo + 3 substrate-bound states) SLC36A1 (PAT1) / lysosomal amino acid efflux / mTORC1 activation Human (recombinant protein, cryo-EM; no animal/cell phenotype data) Reveals the structural basis for the substrate promiscuity of PAT1; its role in lysosomal amino acid export and mTORC1 activation is prior work" }, { "sid": "MIAO2026", "entities": [ "rapamycin", "mtor", "autophagy" ], "authors": [ "zheng-cao", "chenjiao-miao" ], "author_names": [ "Zheng Cao", "Chenjiao Miao" ], "text": "1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl) benzene (EDPrB), a highly polluting fluorinated liquid-crystal monomer (FLCM), accumulates in the kidneys over the long term. Exposure to EDPrB can induce inflammatory responses and fibrosis in human renal cortical proximal tubule epithelial cells (HK-2), posing a risk of nephrotoxicity. Our study investigates the renal injury induced by EDPrB in male Kunming mice after 70-day exposure at 13, 130, and 1300 ug/kg bw/day. EDPrB (fluorinated liquid crystal monomer) / Rapamycin mTOR-autophagy Mouse + Human cell line In mice and HK-2 cells, mTOR hyperactivation causes autophagy dysregulation leading to CKD" }, { "sid": "JEW2015", "entities": [ "glutamine", "leucine" ], "authors": [ "kun-liang-guan", "jenna-l-jewell", "young-chul-kim", "hyun-woo-park" ], "author_names": [ "Kun-Liang Guan", "Jenna L. Jewell", "Young Chul Kim", "Hyun Woo Park" ], "text": "The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates environmental and intracellular signals to regulate cell growth. Amino acids stimulate mTORC1 activation at the lysosome in a manner thought to be dependent on the Rag small guanosine triphosphatases (GTPases), the Ragulator complex, and the vacuolar H(+)-adenosine triphosphatase (v-ATPase). We report that leucine and glutamine stimulate mTORC1 by Rag GTPase-dependent and -independent mechanisms, respectively. Biochemical/genetic mTORC1 / Rag GTPases Mammalian cells Leucine activates mTORC1 via the Rags; glutamine activates it Rag-independently – differential regulation" }, { "sid": "BCH2026", "entities": [ "rapamycin", "mtorc1" ], "authors": [ "vincent-giguere", "wafa-bchir", "julie-st-pierre" ], "author_names": [ "Vincent Giguère", "Wafa B'chir", "Julie St-Pierre" ], "text": "Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), remains a major health concern world-wide. Hepatic steatosis manifests by the aberrant accumulation of lipids in hepatocytes. We have previously shown that pharmacological inhibition of mTOR complex 1 (mTORC1) by rapamycin, a widely utilized potent immunosuppressant, induces MASLD under normal conditions. Chloroquine co-treatment with rapamycin ERRα (Esrra) / mTORC1 Mouse Chloroquine co-treatment attenuates rapamycin-induced hepatic steatosis in an ERRα-dependent manner" }, { "sid": "DEN2001", "entities": [ "mtor", "energy-cellular-stress", "s6k1" ], "authors": [ "george-thomas", "sara-c-kozma", "patrick-b-dennis" ], "author_names": [ "George Thomas", "Sara C. Kozma", "Patrick B. Dennis" ], "text": "The bacterial macrolide rapamycin is an efficacious anticancer agent against solid tumors. In a hypoxic environment, the increase in mass of solid tumors is dependent on the recruitment of mitogens and nutrients. When nutrient concentrations change, particularly those of essential amino acids, the mammalian Target of Rapamycin (mTOR) functions in regulatory pathways that control ribosome biogenesis and cell growth. In bacteria, ribosome biogenesis is independently regulated by amino acids and adenosine triphosphate (ATP). Lowering intracellular ATP mTOR signalling (S6K1 readout per MeSH); mTOR kinase Human cell lines; in vitro Lower ATP -> reduced mTOR pathway signalling" }, { "sid": "ZHO2001", "entities": [ "metformin", "energy-cellular-stress", "ampk" ], "authors": [], "author_names": [], "text": "Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Metformin AMPK (→ ACC; indirect mTORC1) Rat; hepatocytes; skeletal muscle Metformin activates AMPK, explaining its glucose- and lipid-lowering effects" }, { "sid": "PEN2000", "entities": [ "insulin", "s6k1" ], "authors": [ "george-thomas", "sara-c-kozma", "mario-pende" ], "author_names": [ "George Thomas", "Sara C. Kozma", "Mario Pende" ], "text": "Insulin controls glucose homeostasis by regulating glucose use in peripheral tissues, and its own production and secretion in pancreatic beta cells. These responses are largely mediated downstream of the insulin receptor substrates, IRS-1 and IRS-2 (refs 4-8), through distinct signalling pathways. Although a number of effectors of these pathways have been identified, their roles in mediating glucose homeostasis are poorly defined. Germline S6K1 knockout Beta-cell size, insulin secretion, glucose tolerance Mouse Loss of S6K1 reduces beta-cell size and insulin output, causing glucose intolerance" }, { "sid": "SZW2021", "entities": [ "mtorc1", "mtorc2" ], "authors": [ "estela-jacinto", "angelia-szwed" ], "author_names": [ "Estela Jacinto", "Angelia Szwed" ], "text": "Cells metabolize nutrients for biosynthetic and bioenergetic needs to fuel growth and proliferation. The uptake of nutrients from the environment and their intracellular metabolism is a highly controlled process that involves cross talk between growth signaling and metabolic pathways. Despite constant fluctuations in nutrient availability and environmental signals, normal cells restore metabolic homeostasis to maintain cellular functions and prevent disease. A central signaling molecule that integrates growth with metabolism is the mechanistic target of rapamycin (mTOR). Not applicable (review) mTORC1 / mTORC2 Review Reviews how mTORC1/2 integrate growth signaling with metabolism" }, { "sid": "ARR2015", "entities": [], "authors": [ "dudley-w-lamming", "sebastian-i-arriola-apelo", "emma-l-baar", "nicole-e-cummings", "cassidy-p-pumper" ], "author_names": [ "Dudley W. Lamming", "Sebastian I. Arriola Apelo", "Emma L. Baar", "Nicole E. Cummings", "Cassidy P. Pumper" ], "text": "Inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA-approved drug rapamycin has been shown to promote lifespan and delay age-related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long-term prophylactic use of rapamycin as a therapy for age-related diseases. Rapamycin – alternative/intermittent dosing regimens mTORC1 (vs mTORC2) Mouse Intermittent regimens and rapalogs inhibit mTORC1 while largely sparing glucose tolerance and immune function; no survival endpoint was measured 2 mg/kg rapamycin administered daily (1x/day), weekly (1x/7 days), once every three days (1x/3 days), or once every five days (1x/5 days) to 9-week-old male C57BL/6J mice for 2-8 weeks. 9-11 male C57BL/6J mice per treatment group for glucose tolerance tests; 3-6 mice per group for blood rapamycin concentration; 4-9 mice per group for insulin/HOMA2 measurements; 6 mice per treatment for islet analysis. Daily rapamycin treatment significantly impaired glucose tolerance (20–116% increase in blood glucose, 71% increase in AUC), while weekly (1x/7 days) or 1x/5 days rapamycin treatment did not impair glucose tolerance. Rapamycin 1x/3 days significantly impaired glucose tolerance. Daily rapamycin inhibited both mTORC1 (S6 S240/244) and mTORC2 (AKT S473) signaling, while weekly rapamycin only inhibited mTORC1. No lifespan or healthspan endpoint. Side-effect endpoints only; benefit retention is inferred, not tested." }, { "sid": "GOU2023", "entities": [ "lysosome", "rag-gtpases", "mtorc1" ], "authors": [ "roberto-zoncu", "claire-goul" ], "author_names": [ "Roberto Zoncu", "Claire Goul" ], "text": "The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders. Not applicable (review) mTORC1 nutrient-sensing machinery Review Reviews the molecular basis of nutrient sensing by mTORC1 and its role in metabolism and disease" }, { "sid": "ANI2011", "entities": [ "longevity", "rapamycin", "tumor-growth" ], "authors": [ "mikhail-v-blagosklonny", "vladimir-n-anisimov" ], "author_names": [ "Mikhail V. Blagosklonny", "Vladimir N. Anisimov" ], "text": "The nutrient-sensing TOR (target of rapamycin) pathway is involved in cellular and organismal aging. Rapamycin, an inhibitor of TOR, extends lifespan in yeast, fruit flies and genetically heterogeneous mice. Here, we demonstrate that lifelong administration of rapamycin extends lifespan in female 129/Sv mice characterized by normal mean lifespan of 2 y. Importantly, rapamycin was administrated intermittently (2 weeks per month) starting from the age of 2 mo. Rapamycin, intermittent (2 weeks per month), lifelong from 2 months of age mTOR (TOR) Mouse (female 129/Sv) Increased lifespan, reduced age-related weight gain, delayed spontaneous cancer" }, { "sid": "EFE2012", "entities": [ "rag-gtpases", "mtorc1", "autophagy" ], "authors": [ "david-m-sabatini", "roberto-zoncu", "rachel-l-wolfson", "alejo-efeyan" ], "author_names": [ "David M. Sabatini", "Roberto Zoncu", "Rachel L. Wolfson", "Alejo Efeyan" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates organismal growth in response to many environmental cues, including nutrients and growth factors. Cell-based studies showed that mTORC1 senses amino acids through the RagA-D family of GTPases (also known as RRAGA, B, C and D), but their importance in mammalian physiology is unknown. Here we generate knock-in mice that express a constitutively active form of RagA (RagA(GTP)) from its endogenous promoter. RagA(GTP/GTP) mice develop normally, but fail to survive postnatal day 1. Genetic – constitutively active RagA(GTP) knock-in mTORC1 / Rag GTPases Mouse (RagA GTP knock-in) Constitutive RagA→mTORC1 blocks fasting-induced autophagy in neonates → death on postnatal day 1 when fasted not stated not stated Treatment of pups at birth with rapamycin significantly delayed the death of fasted RagA GTP/GTP neonates from ~14 h to ~21 h (p<0.01). not stated" }, { "sid": "HAR2004", "entities": [ "insulin", "irs-1-irs-2" ], "authors": [ "greg-m-findlay", "laura-s-harrington", "richard-f-lamb" ], "author_names": [ "Greg M. Findlay", "Laura S. Harrington", "Richard F. Lamb" ], "text": "Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Genetic loss of TSC1/TSC2; S6K1 activity manipulation S6K1 -> IRS-1 -> PI3K/Akt Mammalian cells Sustained S6K1 activity depletes IRS-1 and uncouples the insulin receptor from PI3K" }, { "sid": "MAN2014", "entities": [ "everolimus", "immune-function" ], "authors": [ "joan-b-mannick", "lloyd-b-klickstein", "david-j-glass" ], "author_names": [ "Joan B. Mannick", "Lloyd B. Klickstein", "David J. Glass" ], "text": "Inhibition of the mammalian target of rapamycin (mTOR) pathway extends life span in all species studied to date, and in mice delays the onset of age-related diseases and comorbidities. However, it is unknown if mTOR inhibition affects aging or its consequences in humans. To begin to assess the effects of mTOR inhibition on human aging-related conditions, we evaluated whether the mTOR inhibitor RAD001 ameliorated immunosenescence (the decline in immune function during aging) in elderly volunteers, as assessed by their response to influenza vaccination. Everolimus (RAD001), low dose mTORC1 Human – elderly adults, RCT Improved influenza vaccine response (~20%) and reduced PD-1 expression on T cells" }, { "sid": "HUA2013", "entities": [ "cognition", "rictor", "actin-cytoskeleton", "mtorc2" ], "authors": [ "mauro-costa-mattioli", "kresimir-krnjevic", "wei-huang" ], "author_names": [ "Mauro Costa-Mattioli", "Krešimir Krnjević", "Wei Huang" ], "text": "A major goal of biomedical research is the identification of molecular and cellular mechanisms that underlie memory storage. Here we report a previously unknown signaling pathway that is necessary for the conversion from short- to long-term memory. The mammalian target of rapamycin (mTOR) complex 2 (mTORC2), which contains the regulatory protein Rictor (rapamycin-insensitive companion of mTOR), was discovered only recently and little is known about its function. Conditional postnatal forebrain Rictor deletion; dTORC2-deficient flies; actin-polymerisation rescue; mTORC2-activating compound mTORC2 / Rictor; actin polymerisation Mouse; Drosophila Rictor deletion impairs long-term memory and late-phase LTP; restoring actin polymerisation rescues both" }, { "sid": "GUR2017", "entities": [ "lipid-synthesis" ], "authors": [ "michael-n-hall", "yakir-guri", "markus-h-heim", "paul-jenoe", "suzette-moes" ], "author_names": [ "Michael N. Hall", "Yakir Guri", "Markus H. Heim", "Paul Jenoe", "Suzette Moes" ], "text": "Dysregulated mammalian target of rapamycin (mTOR) promotes cancer, but underlying mechanisms are poorly understood. We describe an mTOR-driven mouse model that displays hepatosteatosis progressing to hepatocellular carcinoma (HCC). Longitudinal proteomic, lipidomics, and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, leading to steatosis and tumor development. In particular, mTORC2 stimulated sphingolipid (glucosylceramide) and glycerophospholipid (cardiolipin) synthesis. Genetic mTOR-driven mouse model mTORC2 Mouse; cells Hepatic mTORC2 promotes de novo fatty-acid/lipid synthesis (sphingolipids, glycerophospholipids) driving steatosis → hepatocellular carcinoma" }, { "sid": "CHU1992", "entities": [], "authors": [ "john-blenis", "gerald-r-crabtree" ], "author_names": [ "John Blenis", "Gerald R. Crabtree" ], "text": "The macrolide rapamycin blocks cell cycle progression in yeast and various animal cells by an unknown mechanism. We demonstrate that rapamycin blocks the phosphorylation and activation of the 70 kd S6 protein kinases (pp70S6K) in a variety of animal cells. The structurally related drug FK506 had no effect on pp70S6K activation but at high concentrations reversed the rapamycin-induced block, confirming the requirement for the rapamycin and FK506 receptor, FKBP. Rapamycin (± FK506) FKBP / p70 S6 kinase T cells; in vitro Rapamycin blocks activation of the p70 S6 kinases; FK506 reverses it (FKBP-dependent)" }, { "sid": "SCI2014", "entities": [ "mtorc1", "mtorc2" ], "authors": [ "junichi-sadoshima", "sebastiano-sciarretta" ], "author_names": [ "Junichi Sadoshima", "Sebastiano Sciarretta" ], "text": "The protein kinase mammalian or mechanistic target of rapamycin (mTOR) is an atypical serine/threonine kinase that exerts its main cellular functions by interacting with specific adaptor proteins to form 2 different multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 regulates protein synthesis, cell growth and proliferation, autophagy, cell metabolism, and stress responses, whereas mTORC2 seems to regulate cell survival and polarity. The mTOR pathway plays a key regulatory function in cardiovascular physiology and pathology. Not applicable (review) mTORC1 / mTORC2 Review Reviews mTOR roles in cardiac physiology and disease" }, { "sid": "WANG2026", "entities": [ "t-cell-differentiation", "integrated-stress-response", "immune-function", "mtorc1" ], "authors": [ "xingrong-du", "jing-wang", "linling-he" ], "author_names": [ "Xingrong Du", "Jing Wang", "Linling He" ], "text": "Amino acid sufficiency is critical for T cell metabolic reprogramming, yet how T cells maintain amino acid homeostasis remains poorly defined. Here, we identify the CORVET and HOPS (CORVET/HOPS) tethering complexes as essential upstream regulators. In activated T cells, they sustain intracellular amino acid levels by promoting macropinocytosis to acquire extracellular nutrients. This function enables dual signaling outcomes: suppression of the integrated stress response (ISR) and activation of mTORC1, which together license metabolic plasticity and effector function. Genetic ablation of CORVET/HOPS subunits VPS18 or VPS11; BIM deletion; enforced mTORC1 activity CORVET/HOPS tethering complexes; mTORC1; integrated stress response Mouse (T cells, in vitro and in vivo) CORVET/HOPS loss causes amino acid scarcity, ISR activation and mTORC1 failure, abrogating T cell immunity" }, { "sid": "HAG2012", "entities": [ "rictor", "lipid-synthesis", "akt-pkb", "srebp1-srebp2", "mtorc2" ], "authors": [ "michael-n-hall", "charles-betz", "asami-hagiwara", "marion-cornu", "nadine-cybulski", "markus-a-ruegg" ], "author_names": [ "Michael N. Hall", "Charles Betz", "Asami Hagiwara", "Marion Cornu", "Nadine Cybulski", "Markus A. Rüegg" ], "text": "Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Liver-specific rictor knockout (mTORC2 loss) Hepatic Akt Ser473, glucokinase, SREBP1c; glycolysis, lipogenesis, gluconeogenesis; blood glucose, insulin, lipids Mouse Loss of hepatic mTORC2 lowers Akt signalling, glycolysis and lipogenesis and causes hyperglycaemia and hyperinsulinaemia" }, { "sid": "XIE2026", "entities": [ "bisphenol-a", "glutamine", "ampk" ], "authors": [ "jiayuan-xie", "ning-jiao" ], "author_names": [ "Jiayuan Xie", "Ning Jiao" ], "text": "Bisphenol A (BPA) disrupts intestinal homeostasis and promotes epithelial injury in piglets. Glutamine (Gln) is a vital energy substrate for intestinal epithelial cells. Piglet and porcine intestinal epithelial cell models were used. BPA exposure impaired intestinal morphology and barrier integrity, with reduced tight junction protein expression, decreased epithelial renewal capacity, altered JNK/MAPK signaling and disrupted mitochondrial structure and energy metabolism. Dietary glutamine supplementation AMPK-mTOR; mitochondrial energy metabolism Pig Improved tight junction expression, epithelial renewal and mitochondrial function under BPA stress" }, { "sid": "WALTER2026", "entities": [ "everolimus", "pancreatic-neuroendocrine-tumor" ], "authors": [ "jaume-capdevila", "thomas-walter" ], "author_names": [ "Jaume Capdevila", "Thomas Walter" ], "text": "Peptide receptor radionuclide and targeted therapy are both approved treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs), but clinical evidence for preferred sequencing is scarce. The COMPETE trial evaluated the efficacy and harms of peptide receptor radionuclide therapy ([177Lu]Lu-edotreotide) versus targeted molecular therapy (everolimus) in patients with advanced, progressive, somatostatin receptor-positive GEP NETs. Everolimus (mTOR inhibitor) vs [177Lu]Lu-edotreotide mTORC1 Human PRRT ([177Lu]Lu-edotreotide) gave longer PFS than everolimus, with fewer grade 3-4 treatment-related adverse events, in treatment-naive or pretreated SSTR-positive GEP-NETs" }, { "sid": "YAO2026", "entities": [ "spinal-cord-injury", "hif-1alpha", "akt-pkb", "salvianolic-acid-b" ], "authors": [ "susu-zhang" ], "author_names": [ "Susu Zhang" ], "text": "Spinal cord injury (SCI) is a devastating condition with limited treatment options. Salvianolic acid B (SalB), a natural compound from Salvia miltiorrhiza, shows therapeutic potential but its mechanisms in SCI remain unclear. This study combined network pharmacology, molecular docking and in vivo experiments using a rat SCI model, applying the AKT inhibitor capivasertib (AZD5363) for mechanistic verification. Network analysis identified 188 SalB-SCI common targets primarily in the AKT pathway, and molecular docking predicted strong binding between SalB and AKT1. Salvianolic acid B; capivasertib (AZD5363) as AKT inhibitor control AKT/mTOR/HIF-1α; AKT1; angiogenesis Rat Improved motor function, reduced tissue damage, enhanced neuronal survival and angiogenesis; abolished by AKT inhibition" }, { "sid": "CUI2026", "entities": [ "mitophagy", "forsythoside-a", "ferroptosis", "mtor", "ascl1" ], "authors": [ "xiaoli-cui" ], "author_names": [ "Xiaoli Cui" ], "text": "Forsythoside A (FTA), the primary bioactive component of Forsythiae Fructus, exhibits anti-inflammatory and antioxidant activity. Hypertensive nephropathy (HN) models were established in C57BL/6 mice and NRK-52E cells using Ang II. FTA mitigated Ang II-induced renal injury by reducing renal dysfunction markers (Cr, BUN, Alb/Cr), restoring renal tissue architecture and decreasing inflammatory markers, without exerting antihypertensive effects. RNA sequencing revealed associations with mTOR and ASCL1. Forsythoside A ASCL1-CCNB1/mTOR; mitophagy; ferroptosis Mouse; rat kidney epithelial cells Reduced renal dysfunction markers and inflammation; increased mitophagy, decreased ferroptosis" }, { "sid": "ATK2004", "entities": [ "renal-cell-carcinoma-rcc", "temsirolimus" ], "authors": [ "michael-b-atkins", "matthew-l-sherman" ], "author_names": [ "Michael B. Atkins", "Matthew L. Sherman" ], "text": "To evaluate the efficacy, safety, and pharmacokinetics of multiple doses of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma (RCC). Patients (n = 111) were randomly assigned to receive 25, 75, or 250 mg CCI-779 weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, survival, and adverse events. Blood samples were collected to determine CCI-779 pharmacokinetics. Temsirolimus (CCI-779) 25, 75 or 250 mg IV weekly mTORC1 (via FKBP12) Human Antitumour activity (7% objective response, median TTP 5.8 mo, median OS 15.0 mo), no dose-response for efficacy or toxicity" }, { "sid": "BEN2008", "entities": [ "mitochondrial-biogenesis", "rictor", "raptor", "akt-pkb", "mtorc1" ], "authors": [ "michael-n-hall", "c-florian-bentzinger", "shuo-lin", "markus-a-ruegg" ], "author_names": [ "Michael N. Hall", "C. Florian Bentzinger", "Shuo Lin", "Markus A. Rüegg" ], "text": "Mammalian target of rapamycin (mTOR) is a central controller of cell growth. mTOR assembles into two distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. Here we show that the mTORC1 component raptor is critical for muscle function and prolonged survival. In contrast, muscles lacking the mTORC2 component rictor are indistinguishable from wild-type controls. Raptor-deficient muscles become progressively dystrophic, are impaired in their oxidative capacity, and contain increased glycogen stores, but they express structural components indicative of oxidative muscle fibers. Genetic – muscle-specific raptor KO (and rictor KO) mTORC1 (raptor) vs mTORC2 (rictor) Mouse (muscle raptor/rictor KO) In mice, raptor loss (not rictor) causes progressive muscular dystrophy and metabolic changes – mTORC1 essential for muscle" }, { "sid": "CHA2007", "entities": [ "ulk1", "rapamycin", "lc3b-map1lc3b", "autophagy" ], "authors": [ "edmond-y-w-chan", "sharon-a-tooze" ], "author_names": [ "Edmond Y. W. Chan", "Sharon A. Tooze" ], "text": "Autophagy is a vital response to nutrient starvation. Here, we screened a kinase-specific siRNA library using an autophagy assay in human embryonic kidney 293 cells that measures lipidation of the marker protein GFP-LC3 following amino acid starvation. This screen identified ULK1 in addition to other novel candidates that could be confirmed with multiple siRNAs. Knockdown of ULK1, but not the related kinase ULK2, inhibited the autophagic response. Also, ULK1 knockdown inhibited rapamycin-induced autophagy consistent with a role downstream of mTOR. siRNA knockdown of ULK1 (kinome screen); ULK1 overexpression and deletion mutants; amino-acid starvation or rapamycin to induce autophagy ULK1 Human cells (HEK293, HeLa) ULK1 knockdown decreased starvation- and rapamycin-induced autophagy (GFP-LC3 lipidation); ULK2 knockdown did not" }, { "sid": "SAB1994", "entities": [ "rapamycin", "mtor" ], "authors": [ "david-m-sabatini", "hediye-erdjument-bromage", "paul-tempst" ], "author_names": [ "David M. Sabatini", "Hediye Erdjument-Bromage", "Paul Tempst" ], "text": "The immunosuppressants rapamycin and FK506 bind to the same intracellular protein, the immunophilin FKBP12. The FKB12-FK506 complex interacts with and inhibits the Ca(2+)-activated protein phosphatase calcineurin. The target of the FKBP12-rapamycin complex has not yet been identified. We report that a protein complex containing 245 kDa and 35 kDa components, designated rapamycin and FKBP12 targets 1 and 2 (RAFT1 and RAFT2), interacts with FKBP12 in a rapamycin-dependent manner. Biochemical (FKBP12-rapamycin affinity purification) RAFT1 (mTOR/FRAP) / FKBP12 Rat brain tissue (biochemical purification) Identifies RAFT1 (mammalian TOR) as the FKBP12-rapamycin target, homologous to yeast TORs" }, { "sid": "UMX2004", "entities": [ "irs-1-irs-2", "s6k1" ], "authors": [ "george-thomas", "sara-c-kozma", "sung-hee-um" ], "author_names": [ "George Thomas", "Sara C. Kozma", "Sung Hee Um" ], "text": "Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced beta-cell mass. Genetic – S6K1 knockout S6K1 (downstream of mTORC1) Mouse (S6K1 KO) S6K1 loss protects against age- and diet-induced obesity and enhances insulin sensitivity" }, { "sid": "SAR2006", "entities": [ "rapamycin", "rictor", "akt-pkb", "mtorc2" ], "authors": [ "david-m-sabatini", "dos-d-sarbassov", "siraj-m-ali", "andrew-l-markhard", "peggy-p-hsu", "shomit-sengupta" ], "author_names": [ "David M. Sabatini", "Dos D. Sarbassov", "Siraj M. Ali", "Andrew L. Markhard", "Peggy P. Hsu", "Shomit Sengupta" ], "text": "The drug rapamycin has important uses in oncology, cardiology, and transplantation medicine, but its clinically relevant molecular effects are not understood. When bound to FKBP12, rapamycin interacts with and inhibits the kinase activity of a multiprotein complex composed of mTOR, mLST8, and raptor (mTORC1). The distinct complex of mTOR, mLST8, and rictor (mTORC2) does not interact with FKBP12-rapamycin and is not thought to be rapamycin sensitive. mTORC2 phosphorylates and activates Akt/PKB, a key regulator of cell survival. Rapamycin (prolonged treatment) mTORC2 / Akt Multiple human/mouse cell lines Prolonged rapamycin inhibits mTORC2 assembly and Akt/PKB in some cells – mTORC2 is not always rapamycin-insensitive" }, { "sid": "EVA2026", "entities": [ "rictor", "raptor", "pten", "mtorc2" ], "authors": [ "jennifer-hong", "simone-evans", "meijie-li" ], "author_names": [ "Jennifer Hong", "Simone Evans", "Meijie Li" ], "text": "Peripheral neuropathy affects over 18 million adults in the U.S., but therapeutic outcomes are poor due to a lack of regenerative treatments. Pten is a strong negative regulator of cell growth, and Pten-KO drives axonal regeneration in various neuronal subtypes potentially via downstream regulation of stability of the microtubule (MT) cytoskeleton, a vital component of axonal growth. Genetic: Pten knockout with Raptor (mTORC1) or Rictor (mTORC2) co-deletion mTORC2 (RICTOR); microtubule cytoskeleton; PTEN Mouse (peripheral sensory neuron cultures) mTORC2, not mTORC1, mediates PTEN-dependent microtubule polymerization and neuronal hypertrophy at the growth cone" }, { "sid": "GUR2016", "entities": [ "mtor" ], "authors": [ "michael-n-hall", "yakir-guri" ], "author_names": [ "Michael N. Hall", "Yakir Guri" ], "text": "Cancer is a complex disease and a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that target cancer-specific signaling pathways. However, the clinical benefits of such drugs are at best transient due to tumors displaying intrinsic or adaptive resistance. The underlying compensatory pathways that allow cancer cells to circumvent a drug blockade are poorly understood. We review here recent studies suggesting that mammalian TOR (mTOR) signaling is a major compensatory pathway conferring resistance to many cancer drugs. Not applicable (review) mTOR Review mTOR signaling is a major compensatory pathway conferring resistance to targeted cancer drugs" }, { "sid": "MAR2014", "entities": [ "rapamycin", "mtor", "immune-function", "mtorc1", "mtorc2" ], "authors": [ "antoine-marcais", "thierry-walzer" ], "author_names": [ "Antoine Marçais", "Thierry Walzer" ], "text": "Interleukin 15 (IL-15) controls both the homeostasis and the peripheral activation of natural killer (NK) cells. The molecular basis for this duality of action remains unknown. Here we found that the metabolic checkpoint kinase mTOR was activated and boosted bioenergetic metabolism after exposure of NK cells to high concentrations of IL-15, whereas low doses of IL-15 triggered only phosphorylation of the transcription factor STAT5. mTOR stimulated the growth and nutrient uptake of NK cells and positively fed back on the receptor for IL-15. NK-cell-specific Mtor deletion; acute TAT-Cre deletion; oral rapamycin 100 ug/day; PP242 (1 uM) and Ku-0063794 (3 uM) in vitro; IL-15 dose titration; anti-CD122 blockade mTORC1 and mTORC2 activity in NK cells (pS6, p4E-BP1, pAkt Ser473, pmTOR Ser2448/2481) and NK cell development, metabolism and cytotoxicity Mouse and human (human NK cells in vitro) Loss or inhibition of mTOR reduced NK cell proliferation, maturation, nutrient uptake, granzyme B and cytotoxicity, while leaving IL-12/IL-18-driven IFN-gamma intact" }, { "sid": "MOR2013", "entities": [ "oxidative-phosphorylation" ], "authors": [ "nahum-sonenberg", "masahiro-morita", "julie-st-pierre" ], "author_names": [ "Nahum Sonenberg", "Masahiro Morita", "Julie St-Pierre" ], "text": "mRNA translation is thought to be the most energy-consuming process in the cell. Translation and energy metabolism are dysregulated in a variety of diseases including cancer, diabetes, and heart disease. However, the mechanisms that coordinate translation and energy metabolism in mammals remain largely unknown. The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates mRNA translation and other anabolic processes. Genetic/pharmacologic (mTORC1 / 4E-BP) mTORC1 / 4E-BP Mammalian cells mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translation" }, { "sid": "FEL2009", "entities": [ "pp242", "atp-competitive-mtor-inhibitors", "rapamycin", "akt-pkb", "mtorc1", "mtorc2" ], "authors": [ "davide-ruggero", "kevan-m-shokat", "robbie-loewith", "zachary-a-knight", "morris-e-feldman" ], "author_names": [ "Davide Ruggero", "Kevan M. Shokat", "Robbie Loewith", "Zachary A. Knight", "Morris E. Feldman" ], "text": "The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. ATP-competitive mTOR active-site inhibitors (vs rapamycin) mTORC1 & mTORC2 Mouse fibroblasts + primary cells Active-site inhibitors block rapamycin-resistant outputs of mTORC1/2 (e.g. 4E-BP1), unlike rapamycin" }, { "sid": "IYE2012", "entities": [], "authors": [ "david-b-solit", "gopa-iyer" ], "author_names": [ "David B. Solit", "Gopa Iyer" ], "text": "Cancer drugs often induce dramatic responses in a small minority of patients. We used whole-genome sequencing to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations was a loss-of-function mutation in TSC1 (tuberous sclerosis complex 1), a regulator of mTOR pathway activation. Everolimus (mTOR inhibitor) mTOR / TSC1 Human – metastatic bladder cancer patient + tumor sequencing Loss-of-function TSC1 mutation explains an exceptional everolimus response; TSC1 mutated in ~8% of bladder cancers Everolimus (mTOR inhibitor) in a phase II trial; whole-genome/targeted tumor sequencing of an exceptional responder. 1 exceptional responder + targeted sequencing of additional bladder tumors; 3 further TSC1-nonsense tumors identified (2 minor responders: 17% and 24% regression; 1 with 7%). Loss-of-function TSC1 mutation underlies the exceptional everolimus response. TSC1-mutant tumors stayed on everolimus longer (7.7 vs 2.0 months, p=0.004) with improved time to recurrence (4.1 vs 1.8 months). Inference from rare responders; basis of mTOR-inhibitor sensitivity beyond TSC1/2 loss still incompletely understood." }, { "sid": "HOL2005", "entities": [], "authors": [ "john-blenis", "steven-p-gygi", "marina-k-holz" ], "author_names": [ "John Blenis", "Steven P. Gygi", "Marina K. Holz" ], "text": "In response to nutrients, energy sufficiency, hormones, and mitogenic agents, S6K1 phosphorylates several targets linked to translation. However, the molecular mechanisms whereby S6K1 is activated, encounters substrate, and contributes to translation initiation are poorly understood. We show that mTOR and S6K1 maneuver on and off the eukaryotic initiation factor 3 (eIF3) translation initiation complex in a signal-dependent, choreographed fashion. When inactive, S6K1 associates with the eIF3 complex, while the S6K1 activator mTOR/raptor does not. Biochemical mTOR / S6K1 / eIF3 Mammalian cells mTOR and S6K1 dynamically associate with eIF3 to control translation preinitiation via ordered phosphorylation" }, { "sid": "EGA2010", "entities": [], "authors": [ "reuben-j-shaw", "benoit-viollet", "daniel-f-egan", "malene-hansen", "mondira-kundu", "john-m-asara", "dana-m-gwinn", "maria-m-mihaylova", "david-b-shackelford" ], "author_names": [ "Reuben J. Shaw", "Benoit Viollet", "Daniel F. Egan", "Malene Hansen", "Mondira Kundu", "John M. Asara", "Dana M. Gwinn", "Maria M. Mihaylova", "David B. Shackelford" ], "text": "Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Genetic/biochemical (AMPK–ULK1) AMPK / ULK1 / mTORC1 Mammalian cells (+ C. elegans) AMPK phosphorylates ULK1 to connect energy sensing to autophagy/mitophagy" }, { "sid": "SRI2026", "entities": [ "mitochondrial-biogenesis", "mtorc1" ], "authors": [ "savraj-s-grewal", "shrivani-sriskanthadevan-pirahas" ], "author_names": [ "Savraj S. Grewal", "Shrivani Sriskanthadevan-Pirahas" ], "text": "Animals must adapt their growth to fluctuations in nutrient availability to ensure proper development. While nutrient-sensing tissues coordinate organismal growth through interorgan signaling, the metabolic changes within these tissues that mediate whole-body growth control remain poorly understood. Using Drosophila larvae, we show that TOR (target of rapamycin), a conserved nutrient-sensing kinase, controls developmental growth through regulation of the mitochondrial genome transcription factor TFAM, which controls mitochondrial bioenergetic capacity. Genetic manipulation of TOR signaling in the fat body (Drosophila) TOR → TFAM (mitochondrial transcription factor A) Drosophila melanogaster (larvae) TOR suppresses TFAM protein levels in the fat body; this axis controls organismal developmental growth" }, { "sid": "VER2026", "entities": [ "lc3b-map1lc3b", "mtor", "p62-sqstm1", "autophagy", "beclin-1-becn1" ], "authors": [ "madhav-nilakhanth-mugale" ], "author_names": [ "Madhav Nilakhanth Mugale" ], "text": "In a CCl4-induced chronic liver injury rat model, testosterone propionate was found to preserve autophagic flux and mitochondrial function. Androgen deprivation worsened hepatic damage, while testosterone treatment maintained the LC3B/p62/Beclin-1/mTOR axis and protected mitochondrial quality control and reduced apoptosis. Testosterone propionate mTOR / LC3B / p62 / Beclin-1 autophagy axis Rat Testosterone maintains mTOR-regulated autophagy and mitochondrial integrity; androgen deprivation impairs autophagy and worsens liver fibrosis" }, { "sid": "LIU2015", "entities": [], "authors": [ "john-blenis", "lewis-c-cantley", "wenyi-wei", "bing-su" ], "author_names": [ "John Blenis", "Lewis C. Cantley", "Wenyi Wei", "Bing Su" ], "text": "mTOR serves as a central regulator of cell growth and metabolism by forming two distinct complexes, mTORC1 and mTORC2. Although mechanisms of mTORC1 activation by growth factors and amino acids have been extensively studied, the upstream regulatory mechanisms leading to mTORC2 activation remain largely elusive. Here, we report that the pleckstrin homology (PH) domain of SIN1, an essential and unique component of mTORC2, interacts with the mTOR kinase domain to suppress mTOR activity. Biochemical/genetic (SIN1 PH domain) mTORC2 / SIN1 / PtdIns(3,4,5)P3 Mammalian cells PIP3 binds the SIN1 PH domain to relieve suppression of mTOR → activates mTORC2" }, { "sid": "LIST2026", "entities": [ "growth-hormone-igf-1-axis", "longevity" ], "authors": [ "john-j-kopchick", "darlene-e-berryman", "edward-o-list" ], "author_names": [ "John J. Kopchick", "Darlene E. Berryman", "Edward O. List" ], "text": "Interventions that disrupt growth hormone (GH) action are recognized as some of the most potent methods for extending lifespan. Accordingly, GH receptor antagonists (GHA) represent potential therapeutics to improve healthspan. Somavert (Pegvisomant for injection), used for treating patients with acromegaly, is currently the only FDA approved GHA. Transgenic growth hormone receptor antagonist (bovine GH G119K), lifelong expression Growth hormone receptor (GHR) / GH-IGF-1 axis upstream of PI3K-Akt-mTOR Mouse (GHA transgenic, both sexes) Extended median and maximal lifespan in both sexes; reduced frailty and greater grip strength at 2 years despite increased adiposity" }, { "sid": "MAN2021", "entities": [ "mtor", "immune-function", "mtorc1", "rtb101" ], "authors": [ "joan-b-mannick", "dean-quinn", "sarb-shergill" ], "author_names": [ "Joan B. Mannick", "Dean Quinn", "Sarb Shergill" ], "text": "The COVID-19 pandemic highlights the need for therapies that improve immune function in older adults, including interferon (IFN)-induced antiviral immunity that declines with age. In a previous phase 2a trial, RTB101 (previously known as BEZ235), an oral mechanistic target of rapamycin (mTOR) inhibitor, was observed to increase IFN-induced antiviral gene expression and decrease the incidence of respiratory tract infections (RTIs) in older adults. RTB101 (BEZ235), oral mTOR inhibitor; ± everolimus mTOR (TORC1/2) Human – phase 2b + phase 3 RCT (n=1024) Phase 3 FAILED its primary endpoint (no reduction in symptomatic respiratory infections, 26 vs 25%); antiviral genes still upregulated RTB101 5 or 10 mg once daily (+/- everolimus in phase 2b); phase 3 used RTB101 10 mg once daily; oral, placebo-controlled. Phase 2b + phase 3 across >1500 adults aged >=65 (phase 3 n=1024). Phase 3 primary endpoint (proportion with >=1 clinically symptomatic respiratory illness) NOT met; RTB101 still upregulated IFN-induced antiviral gene expression. Biomarker moved, clinical outcome did not. FDA changed the primary endpoint between phase 2b and phase 3 (symptom-based vs lab-confirmed), complicating comparison; positive biomarker did not translate to clinical benefit." }, { "sid": "JOS2024", "entities": [ "mtorc1", "tuberous-sclerosis-complex", "autophagy" ], "authors": [ "alexander-j-valvezan", "jay-n-joshi" ], "author_names": [ "Alexander J. Valvezan", "Jay N. Joshi" ], "text": "Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a master metabolic regulator that is active in nearly all proliferating eukaryotic cells; however, it is unclear whether mTORC1 activity changes throughout the cell cycle. We find that mTORC1 activity oscillates from lowest in mitosis/G1 to highest in S/G2. The interphase oscillation is mediated through the TSC complex but is independent of major known regulatory inputs, including Akt and Mek/Erk signaling. By contrast, suppression of mTORC1 activity in mitosis does not require the TSC complex. Partial mTORC1 inhibition; nutrient reduction; cell-cycle synchronization mTORC1 / TSC complex Human & mouse cell lines mTORC1 activity oscillates across the cell cycle (low mitosis/G1, high S/G2); low-mTORC1 G1 cells are more sensitive to autophagy induction" }, { "sid": "AWARE2026", "entities": [ "rapamycin", "alzheimers-disease" ], "authors": [ "ai-ling-lin", "chetan-aware" ], "author_names": [ "Ai-Ling Lin", "Chetan Aware" ], "text": "Carriers of the apolipoprotein E4 (APOE4) allele often develop cerebrovascular dysfunction and broader systemic alterations decades before the onset of Alzheimer's disease (AD) pathology or clinical symptoms. Early interventions that can improve these functions may help delay or slow AD progression. In this study, we repurposed rapamycin (sirolimus), an FDA-approved medication with anti-aging properties, to target APOE4 associated multisystem dysfunction. Low-dose rapamycin (sirolimus) 1 mg/day for 4 weeks mTORC1 (systemic), with cerebral blood flow as primary readout Human (cognitively normal adults 45-65, APOE4 carriers vs non-carriers) Increased cerebral blood flow (>15% across multiple regions) and improved metabolic/inflammatory profiles in APOE4 carriers only; genotype-dependent, uncontrolled pilot." }, { "sid": "SAN2008", "entities": [ "rag-gtpases", "mtorc1" ], "authors": [ "david-m-sabatini", "yasemin-sancak", "carson-c-thoreen", "liron-bar-peled", "timothy-r-peterson", "robert-a-lindquist" ], "author_names": [ "David M. Sabatini", "Yasemin Sancak", "Carson C. Thoreen", "Liron Bar-Peled", "Timothy R. Peterson", "Robert A Lindquist" ], "text": "The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins--a family of four related small guanosine triphosphatases (GTPases)--interact with mTORC1 in an amino acid-sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. Genetic/biochemical (Rag GTPases) Rag GTPases / raptor / mTORC1 Human cell lines Rag GTPases interact with raptor in an amino-acid-sensitive way and are necessary for amino-acid activation of mTORC1" }, { "sid": "ORE2006", "entities": [ "everolimus", "akt-pkb", "mtorc1", "irs-1-irs-2" ], "authors": [ "neal-rosen", "jose-baselga", "kathryn-oreilly" ], "author_names": [ "Neal Rosen", "José Baselga", "Kathryn O'Reilly" ], "text": "Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. mTOR inhibition (rapamycin) mTOR / IRS-1 / Akt / RTK Cancer cell lines and patient tumours (RAD001/everolimus-treated) mTOR inhibition relieves S6K1-IRS1 feedback and induces upstream RTK signalling, activating Akt (a resistance mechanism). Shown in cancer cell lines AND confirmed in patient tumours treated with RAD001 - a human pharmacodynamic readout, not only cell culture." }, { "sid": "LAW2019", "entities": [], "authors": [ "roberto-zoncu", "rosalie-e-lawrence", "james-h-hurley", "ashley-m-thelen", "do-jin-kim", "chun-yan-lim" ], "author_names": [ "Roberto Zoncu", "Rosalie E. Lawrence", "James H. Hurley", "Ashley M. Thelen", "Do Jin Kim", "Chun-Yan Lim" ], "text": "The tumor suppressor folliculin (FLCN) enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) activating protein (GAP) activity toward the GTPase RagC. Concomitant with mTORC1 inactivation by starvation, FLCN relocalizes from the cytosol to lysosomes. Structural/biochemical (FLCN complex) FLCN–FNIP2 / RagC / mTORC1 Structure; cells The lysosomal folliculin complex acts as a GAP for RagC, a checkpoint in nutrient-dependent mTORC1 activation" }, { "sid": "VEL2026", "entities": [ "caloric-restriction", "mtorc1" ], "authors": [ "roman-v-kondratov", "nikkhil-velingkaar" ], "author_names": [ "Roman V. Kondratov", "Nikkhil Velingkaar" ], "text": "Interest in fasting-based diets to improve metabolic health is growing. Caloric restriction (CR) with one meal per day includes an extended fasting component that contributes to its metabolic and longevity benefits, yet the role of fasting within CR remains unclear. Here, we compare CR with a fasting-refeeding-fasting (FRF) regimen while controlling food intake and fasting duration. Caloric restriction (one meal/day) vs matched fasting-refeeding-fasting (FRF) regimen Hepatic mTOR signaling, ketogenesis and circadian metabolic gene coordination Mouse CR engages anticipatory, clock-aligned metabolic control and improves glucose/fatty-acid metabolism, whereas FRF tracks direct nutrient cues and causes glucose intolerance and hepatic steatosis." }, { "sid": "YAN2026B", "entities": [ "cellular-senescence", "mtorc1", "lkb1-stk11", "autophagy", "ampk" ], "authors": [ "yang-yang", "xiaoming-yang" ], "author_names": [ "Yang Yang", "Xiaoming Yang" ], "text": "Liver aging significantly impairs hepatic function and regenerative capacity, increasing the risk of morbidity and mortality from chronic liver diseases. Identifying molecular regulators of these processes may reveal promising therapeutic targets. Although Hepassocin (HPS), a hepatokine with known hepatoprotective functions, has minimal effects on liver homeostasis in adult mice, its role in long-term liver maintenance remains unclear. In this study, we observed a decrease in circulating and intrahepatic HPS levels in both aged mice and elderly humans. Hepassocin (HPS/FGL1) genetic knockout; exogenous HPS administration; AMPK agonist AICAR AMPK (via ANXA2-ERK-p90RSK-LKB1 axis); mTOR activity Mouse (aged, 12-month, HPS-knockout); human liver tissue (correlative) HPS activates AMPK/LKB1 and restrains mTOR; aged HPS-KO mice show elevated mTOR activity, impaired autophagy, exacerbated senescence and failed liver regeneration; AICAR or exogenous HPS rescues the phenotype" }, { "sid": "BAR2012", "entities": [ "lysosome" ], "authors": [ "david-m-sabatini", "roberto-zoncu", "liron-bar-peled" ], "author_names": [ "David M. Sabatini", "Roberto Zoncu", "Liron Bar-Peled" ], "text": "The mTOR Complex 1 (mTORC1) pathway regulates cell growth in response to numerous cues, including amino acids, which promote mTORC1 translocation to the lysosomal surface, its site of activation. The heterodimeric RagA/B-RagC/D GTPases, the Ragulator complex that tethers the Rags to the lysosome, and the v-ATPase form a signaling system that is necessary for amino acid sensing by mTORC1. Amino acids stimulate the binding of guanosine triphosphate to RagA and RagB but the factors that regulate Rag nucleotide loading are unknown. Biochemical/genetic (Ragulator) Ragulator / Rag GTPases / mTORC1 Mammalian cells Ragulator is a GEF for RagA/B, activating the Rags to signal amino-acid levels to mTORC1 at the lysosome" }, { "sid": "SOL2014", "entities": [ "longevity", "mtorc1", "macronutrient-ratio" ], "authors": [ "stephen-j-simpson", "david-a-sinclair", "samantha-m-solon-biet" ], "author_names": [ "Stephen J. Simpson", "David A. Sinclair", "Samantha M. Solon-Biet" ], "text": "The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Dietary – 25 diets varying protein:carb:fat, ad libitum Nutrient/mTOR signaling (dietary protein) Mouse (25 ad libitum diets) Macronutrient ratio (low protein, high carb), not calorie intake, optimizes cardiometabolic health and longevity 25 ad libitum diets differing in protein (5%–60%), fat (16%–75%), carbohydrate (16%–75%), and energy (8, 13, or 17 kJ/g of food) fed over a lifetime 858 mice across 25 diets Median lifespan increased by approximately 30% (from 95 to 125 weeks) as the protein-to-carbohydrate ratio decreased; not influenced by total calorie intake not stated" }, { "sid": "MOT2008", "entities": [ "renal-cell-carcinoma-rcc", "everolimus", "tumor-growth" ], "authors": [ "robert-j-motzer", "david-lebwohl" ], "author_names": [ "Robert J. Motzer", "David Lebwohl" ], "text": "Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy. Everolimus (RAD001) mTORC1 Human – phase III RCT (RECORD-1), metastatic renal cell carcinoma Everolimus improved progression-free survival vs placebo after VEGF-targeted therapy failure" }, { "sid": "JAN2010", "entities": [ "pp242", "atp-competitive-mtor-inhibitors", "mtorc1", "mtorc2" ], "authors": [ "matthew-r-janes", "david-a-fruman" ], "author_names": [ "Matthew R. Janes", "David A. Fruman" ], "text": "Targeting the mammalian target of rapamycin (mTOR) protein is a promising strategy for cancer therapy. The mTOR kinase functions in two complexes, TORC1 (target of rapamycin complex-1) and TORC2 (target of rapamycin complex-2); however, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. We compared rapamycin with PP242, an inhibitor of the active site of mTOR in both TORC1 and TORC2 (hereafter referred to as TORC1/2), in models of acute leukemia harboring the Philadelphia chromosome (Ph) translocation. PP242 (ATP-competitive TORC1/2 inhibitor) vs rapamycin mTORC1 & mTORC2 Leukemia cells; mouse (Ph+ ALL) TORC1/2 active-site inhibition selectively targets leukemia cells more effectively than rapamycin" }, { "sid": "BUR1998", "entities": [], "authors": [ "david-m-sabatini" ], "author_names": [ "David M. Sabatini" ], "text": "The complex of rapamycin with its intracellular receptor, FKBP12, interacts with RAFT1/FRAP/mTOR, the in vivo rapamycin-sensitive target and a member of the ataxia telangiectasia mutated (ATM)-related family of kinases that share homology with the catalytic domain of phosphatidylinositol 3-kinase. The function of RAFT1 in the rapamycin-sensitive pathway and its connection to downstream components of the pathway, such as p70 S6 kinase and 4E-BP1, are poorly understood. Biochemical (in vitro kinase assay) RAFT1/mTOR / p70 S6K / 4E-BP1 In vitro RAFT1/mTOR directly phosphorylates p70 S6K and 4E-BP1 – connects mTOR to translational regulators" }, { "sid": "SHW2004", "entities": [ "lkb1-stk11", "ampk" ], "authors": [ "reuben-j-shaw", "lewis-c-cantley" ], "author_names": [ "Reuben J. Shaw", "Lewis C. Cantley" ], "text": "AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status found in all eukaryotic cells. AMPK is activated by stimuli that increase the cellular AMP/ATP ratio. Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity in mammalian cells has remained elusive. Here we present biochemical and genetic evidence indicating that the LKB1 serine/threonine kinase, the gene inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant regulator of AMPK activation in several mammalian cell types. LKB1 loss (LKB1-null MEFs); in vitro phosphorylation of AMPK by LKB1 LKB1 -> AMPK (AMPKalpha Thr172) Mouse embryonic fibroblasts; in vitro kinase assays LKB1 directly phosphorylates and activates AMPK; without LKB1, AMPK is not activated by energy stress and cells are more prone to apoptosis" }, { "sid": "KUB2012", "entities": [ "insulin", "akt-pkb", "mtorc1", "s6k1" ], "authors": [ "hiroyuki-kubota", "shinya-kuroda", "shinsuke-uda" ], "author_names": [ "Hiroyuki Kubota", "Shinya Kuroda", "Shinsuke Uda" ], "text": "One of the unique characteristics of cellular signaling pathways is that a common signaling pathway can selectively regulate multiple cellular functions of a hormone; however, this selective downstream control through a common signaling pathway is poorly understood. Here we show that the insulin-dependent AKT pathway uses temporal patterns multiplexing for selective regulation of downstream molecules. Pulse and sustained insulin stimulations were simultaneously encoded into transient and sustained AKT phosphorylation, respectively. Pulse versus sustained insulin stimulation AKT; S6K; G6Pase; GSK3-beta Rat (hepatoma cell line) S6K selectively decodes transient AKT signalling; G6Pase decodes sustained; GSK3-beta decodes both" }, { "sid": "SAX2017", "entities": [ "mtor", "mtorc1", "mtorc2" ], "authors": [ "david-m-sabatini", "robert-a-saxton" ], "author_names": [ "David M. Sabatini", "Robert A. Saxton" ], "text": "The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. Not applicable (review) mTORC1 / mTORC2 Review Comprehensive review of mTOR in growth, metabolism and autophagy; deregulation in cancer, diabetes and aging" }, { "sid": "SAB2017", "entities": [ "mtor" ], "authors": [ "david-m-sabatini" ], "author_names": [ "David M. Sabatini" ], "text": "In my PNAS Inaugural Article, I describe the development of the mTOR field, starting with efforts to understand the mechanism of action of the drug rapamycin, which ~25 y ago led to the discovery of the mTOR protein kinase. I focus on insights that we have contributed and on work that has been particularly influential to me, as well as provide some personal reflections and stories. Not applicable (historical review) mTOR Review Personal historical account of the mTOR field from rapamycin's mechanism to discovery of the mTOR kinase" }, { "sid": "KAL2026", "entities": [ "tsc1-tsc2", "akt-pkb", "mtorc1" ], "authors": [ "brendan-d-manning", "krystle-c-kalafut", "madi-y-cisse", "yann-cormerais", "karen-e-inouye", "samuel-c-lapp", "gokhan-s-hotamslgil" ], "author_names": [ "Brendan D. Manning", "Krystle C. Kalafut", "Madi Y. Cissé", "Yann Cormerais", "Karen E. Inouye", "Samuel C. Lapp", "Gökhan S. Hotamışlıgil" ], "text": "The nutrient-sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway controls cellular and organismal growth and metabolism, and aberrant activation is linked to human disease, including metabolic disease. Cellular studies have established regulatory mechanisms influencing mTORC1 activation, but the physiological signals that control mTORC1 at the organismal and tissue levels are less well-defined. mTORC1 is dynamically regulated by fasting and feeding in metabolic tissues, with both nutrients and insulin proposed to activate mTORC1 in response to feeding. Liver-specific AKT and TSC2 genetic manipulation; dietary protein and feeding/fasting manipulation Hepatic mTORC1 via the AKT-TSC2 axis Mouse (liver-specific) AKT-TSC2 phosphorylation is the main insulin route to hepatic mTORC1 but is dispensable for feeding-induced activation, which instead requires dietary protein; hepatic mTORC1 was not elevated in diet-induced obesity." }, { "sid": "STR2012", "entities": [ "curcumin", "longevity", "mct-oil", "oxaloacetic-acid", "green-tea-extract", "resveratrol" ], "authors": [ "randy-strong", "richard-a-miller", "david-e-harrison", "james-l-kirkland", "david-a-sinclair", "clinton-astle", "nancy-l-nadon" ], "author_names": [ "Randy Strong", "Richard A. Miller", "David E. Harrison", "James L. Kirkland", "David A. Sinclair", "Clinton Astle", "Nancy L. Nadon" ], "text": "The National Institute on Aging Interventions Testing Program (ITP) was established to evaluate agents that are hypothesized to increase life span and/or health span in genetically heterogeneous mice. Each compound is tested in parallel at three test sites. It is the goal of the ITP to publish all results, negative or positive. Resveratrol, green tea extract, curcumin, oxaloacetic acid, MCT oil (dietary) Nutrient/aging pathways (not mTOR-specific) Mouse (genetically heterogeneous, NIA ITP, 3 sites) Lifespan test: these compounds did not robustly extend lifespan (largely negative ITP result)" }, { "sid": "BRU1999", "entities": [ "foxo", "akt-pkb" ], "authors": [ "john-blenis", "anne-brunet" ], "author_names": [ "John Blenis", "Anne Brunet" ], "text": "Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase Akt, which then phosphorylates and inactivates components of the apoptotic machinery, including BAD and Caspase 9. In this study, we demonstrate that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors. In the presence of survival factors, Akt phosphorylates FKHRL1, leading to FKHRL1's association with 14-3-3 proteins and FKHRL1's retention in the cytoplasm. Akt/PKB overexpression + survival-factor withdrawal (genetic) Akt / FOXO (FKHRL1) Mammalian cell lines; primary neurons (in vitro) Akt phosphorylates FKHRL1 (FOXO), blocking its nuclear translocation and Fas-ligand-driven apoptosis upon survival-factor withdrawal" }, { "sid": "DOR2006", "entities": [ "pdcd4", "protein-synthesis", "s6k1" ], "authors": [ "michele-pagano", "n-valerio-dorrello" ], "author_names": [ "Michele Pagano", "N. Valerio Dorrello" ], "text": "The tumor suppressor programmed cell death protein 4 (PDCD4) inhibits the translation initiation factor eIF4A, an RNA helicase that catalyzes the unwinding of secondary structure at the 5' untranslated region (5'UTR) of messenger RNAs (mRNAs). In response to mitogens, PDCD4 was rapidly phosphorylated on Ser67 by the protein kinase S6K1 and subsequently degraded via the ubiquitin ligase SCF(betaTRCP). Biochemical/genetic (S6K1, βTRCP, PDCD4) S6K1 / PDCD4 / eIF4A Mammalian cells S6K1 phosphorylates PDCD4 (Ser67) triggering βTRCP-mediated degradation → promotes translation and cell growth" }, { "sid": "HAR2014", "entities": [ "longevity", "acarbose" ], "authors": [ "randy-strong", "richard-a-miller", "david-e-harrison", "clinton-astle", "kevin-flurkey", "nancy-l-nadon" ], "author_names": [ "Randy Strong", "Richard A. Miller", "David E. Harrison", "Clinton Astle", "Kevin Flurkey", "Nancy L. Nadon" ], "text": "Four agents--acarbose (ACA), 17-α-estradiol (EST), nordihydroguaiaretic acid (NDGA), and methylene blue (MB)--were evaluated for lifespan effects in genetically heterogeneous mice tested at three sites. Acarbose increased male median lifespan by 22% (P < 0.0001), but increased female median lifespan by only 5% (P = 0.01). This sexual dimorphism in ACA lifespan effect could not be explained by differences in effects on weight. Maximum lifespan (90th percentile) increased 11% (P < 0.001) in males and 9% (P = 0.001) in females. Acarbose, 17-α-estradiol, NDGA, methylene blue (dietary/pharmacologic) Metabolic/aging pathways Mouse (genetically heterogeneous, NIA ITP, 3 sites) Acarbose extended male median lifespan by 22% (female 5%); EST and NDGA extended lifespan preferentially in males Acarbose at 1000 mg kg −1 diet (1000 ppm) from 4 months of age not stated Male median lifespan increased by 22% (P < 0.0001); female median lifespan increased by 5% (P = 0.01) (pooled data). not stated" }, { "sid": "CAS2017", "entities": [ "cholesterol", "slc38a9" ], "authors": [ "brian-m-castellano", "douglas-f-covey", "oliver-b-davis", "ofer-moldavski", "daniel-k-nomura", "rushika-m-perera", "ashley-m-thelen" ], "author_names": [ "Brian M. Castellano", "Douglas F. Covey", "Oliver B. Davis", "Ofer Moldavski", "Daniel K. Nomura", "Rushika M. Perera", "Ashley M. Thelen" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that becomes activated at the lysosome in response to nutrient cues. Here, we identify cholesterol, an essential building block for cellular growth, as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein, SLC38A9, is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Moreover, SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function." }, { "sid": "MAN2018", "entities": [ "everolimus", "immune-function", "mtorc1", "rtb101" ], "authors": [ "joan-b-mannick", "lloyd-b-klickstein", "david-j-glass", "dean-quinn" ], "author_names": [ "Joan B. Mannick", "Lloyd B. Klickstein", "David J. Glass", "Dean Quinn" ], "text": "Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. Low-dose mTOR inhibitor (RAD001 + RTB101/BEZ235), 6 weeks TORC1 Human – phase 2a RCT (n=264, elderly) Combined low-dose TORC1 inhibition enhanced immune function and reduced infection rates in the elderly" }, { "sid": "ZHANG2026", "entities": [ "tsc1-tsc2", "tfeb", "mtorc1", "tumor-growth" ], "authors": [ "andrea-ballabio", "wen-xing-ding", "chen-zhang" ], "author_names": [ "Andrea Ballabio", "Wen-Xing Ding", "Chen Zhang" ], "text": "Hepatocellular carcinoma (HCC) is heterogeneous, and hepatocyte plasticity is linked to poorer patient outcomes. A subset of human HCC harboring Tuberous Sclerosis Complex 1 (TSC1) mutations exhibits more aggressive behavior. TFEB is a master regulator of lysosomal biogenesis and cell fate. Loss of hepatic Tsc1 led to increased phosphorylation of S6 and 4EBP1, with paradoxical increases in TFEB nuclear translocation and activation. Tsc1 knockout (mTORC1 hyperactivation) mTORC1-TFEB Mouse + Human Promotes hepatocyte plasticity and high-grade HCC malignancy" }, { "sid": "CAO2026B", "entities": [ "dihydromyricetin" ], "authors": [ "peng-cao", "guozhong-lyu", "yunwei-wang" ], "author_names": [ "Peng Cao", "Guozhong Lyu", "Yunwei Wang" ], "text": "This study investigated whether dihydromyricetin (DHM) attenuates fibrosis-associated features in hypertrophic scar (HS) and whether these effects are accompanied by changes in PI3K/AKT/mTOR-related signalling. Network pharmacology identified overlapping targets between DHM and HS, highlighting AKT1 as a candidate hub target; molecular docking and 50-ns molecular dynamics simulation indicated a stable predicted DHM-AKT1 interaction. Dihydromyricetin; LY294002 (PI3K inhibitor) PI3K/AKT/mTOR; AKT1 Rabbit; human fibroblasts Reduced fibrotic marker expression and scar elevation index; decreased AKT and mTOR phosphorylation" }, { "sid": "SANG2026", "entities": [ "gator2", "pkm2", "mtorc1", "methionine" ], "authors": [ "zixin-sang", "jie-wang", "jiaqi-zhao" ], "author_names": [ "Zixin Sang", "Jie Wang", "Jiaqi Zhao" ], "text": "Methionine (Met) plays a pivotal role in numerous cellular functions. Methionine restriction has been demonstrated to provide metabolic benefits in aging, obesity, diabetes and as an adjunct to cancer therapy. However, the methionine-sensing proteins and how cells directly sense the methionine level have remained elusive. In this study, we developed a photoaffinity analogue of methionine to capture proteins that specifically recognize and sense methionine in living cells. Photoaffinity methionine analogue (chemoproteomic capture); methionine restriction/repletion PKM2 / GATOR2 / mTORC1 (methionine sensing) Human cells (biochemistry / chemoproteomics) PKM2 binds free methionine via a dedicated pocket and relays methionine availability to mTORC1 through GATOR2, independently of PKM2 enzymatic activity" }, { "sid": "LIU2020", "entities": [ "longevity", "mtor", "mtorc1", "autophagy", "mtorc2" ], "authors": [ "david-m-sabatini", "grace-y-liu" ], "author_names": [ "David M. Sabatini", "Grace Y. Liu" ], "text": "The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway's central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. Not applicable (review) mTOR Review Reviews mTOR integrating nutrition, growth, ageing and disease via protein synthesis and autophagy" }, { "sid": "BANERJEE2026", "entities": [ "pi3k" ], "authors": [ "chandrayee-banerjee", "manoj-tongra" ], "author_names": [ "Chandrayee Banerjee", "Manoj Tongra" ], "text": "Multiple Sclerosis (MS) is a chronic immune-mediated neurodegenerative disorder characterized by demyelination, axonal injury, and progressive neurological dysfunction. Emerging evidence identifies PI3K/Akt/mTOR and JAK/STAT pathways as interconnected regulators of neuroinflammation and immune dysregulation in MS. mTOR inhibitors (proposed therapeutic) PI3K/Akt/mTOR-JAK/STAT axis N/A (review) PI3K/Akt/mTOR-JAK/STAT crosstalk drives neuroinflammation in MS; mTOR inhibition proposed as treatment" }, { "sid": "SAR2004", "entities": [ "rictor", "mtor", "akt-pkb", "actin-cytoskeleton", "mtorc2" ], "authors": [ "david-m-sabatini", "do-hyung-kim", "dos-d-sarbassov", "siraj-m-ali", "hediye-erdjument-bromage", "paul-tempst", "david-a-guertin", "robert-r-latek" ], "author_names": [ "David M. Sabatini", "Do-Hyung Kim", "Dos D. Sarbassov", "Siraj M. Ali", "Hediye Erdjument-Bromage", "Paul Tempst", "David A. Guertin", "Robert R. Latek" ], "text": "The mammalian TOR (mTOR) pathway integrates nutrient- and growth factor-derived signals to regulate growth, the process whereby cells accumulate mass and increase in size. mTOR is a large protein kinase and the target of rapamycin, an immunosuppressant that also blocks vessel restenosis and has potential anticancer applications. mTOR interacts with the raptor and GbetaL proteins to form a complex that is the target of rapamycin. Here, we demonstrate that mTOR is also part of a distinct complex defined by the novel protein rictor (rapamycin-insensitive companion of mTOR). Biochemical/genetic (rictor) mTORC2 (rictor) / actin cytoskeleton Human cells + Drosophila Defines rictor-mTOR (mTORC2) as a rapamycin-insensitive, raptor-independent pathway regulating the cytoskeleton" }, { "sid": "LAB2015", "entities": [ "rapamycin", "cellular-senescence", "mtorc1", "senescence-associated-secretory-phenotype-sasp", "4e-bp1" ], "authors": [ "pankaj-kapahi", "judith-campisi", "yuji-ikeno", "remi-martin-laberge" ], "author_names": [ "Pankaj Kapahi", "Judith Campisi", "Yuji Ikeno", "Remi-Martin Laberge" ], "text": "The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-associated secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. Rapamycin (mTORC1 inhibition) mTORC1 / IL1A / SASP Human cells + mouse xenografts Rapamycin blunts the pro-tumorigenic senescence-associated secretory phenotype by suppressing IL1A translation" }, { "sid": "KIN2026", "entities": [ "t-cell-differentiation", "mtorc1" ], "authors": [ "tomohide-kinoshita", "shohei-hori" ], "author_names": [ "Tomohide Kinoshita", "Shohei Hori" ], "text": "Regulatory T (Treg) cell differentiation and function rely on stable expression of the master transcription factor Foxp3. While Foxp3 expression is epigenetically stabilized through DNA demethylation of an enhancer (the Treg-specific demethylated region, TSDR), the mechanisms underlying this process remain unclear. Here, we show that strong and sustained T cell receptor (TCR) signaling promotes TSDR demethylation, stabilizes Foxp3 expression, and confers suppressive activity in in vitro-induced Treg (iTreg) cells through activation of mTORC1. mTORC1 inactivation (genetic/pharmacological) and TET2/TET3 deficiency in TCR-stimulated iTreg cells mTORC1 -> translational control of TET2/TET3 -> Foxp3 TSDR demethylation Mouse (in vitro-induced regulatory T cells, with in vivo confirmation) TCR-driven mTORC1 raises TET2/TET3 translation to demethylate the Foxp3 TSDR enhancer and epigenetically stabilize Foxp3 expression; mTORC1 inactivation increases methylated-TSDR Foxp3+ T cells." }, { "sid": "MAR2012", "entities": [ "tfeb", "mtorc1", "autophagy", "ragulator" ], "authors": [ "rosa-puertollano" ], "author_names": [ "Rosa Puertollano" ], "text": "The mammalian target of rapamycin (MTOR) protein kinase complex is a key component of a pathway that regulates cell growth and proliferation in response to energy levels, hypoxia, nutrients and insulin. Inhibition of MTORC1 strongly induces autophagy by regulating the activity of the ULK protein kinase complex that is required for the formation of autophagosomes. However, the participation of MTORC1 in the expression of autophagy genes has not been characterized. Genetic/pharmacologic (mTORC1) mTORC1 / TFEB Human cells mTORC1 phosphorylates TFEB to block its nuclear transport → transcriptional control of autophagy genes" }, { "sid": "KNO2026", "entities": [ "leucine-bcaa-restriction", "mtorc1", "methionine", "macronutrient-ratio" ], "authors": [ "dudley-w-lamming", "bailey-a-knopf" ], "author_names": [ "Dudley W. Lamming", "Bailey A. Knopf" ], "text": "Despite widespread recommendations for higher protein intake during aging, increasing evidence suggests that dietary protein restriction (PR) promotes metabolic health, healthspan, and lifespan across diverse organisms. Mechanistic studies further demonstrate that restriction of specific amino acids, particularly methionine, isoleucine, and valine, recapitulates many of the benefits of PR, highlighting the specific amino acid composition of the diet as a key determinant of aging. None (narrative review) — synthesizes dietary protein restriction and restriction of methionine/isoleucine/valine Nutrient-sensing pathways including mTORC1 Cross-species (yeast, worm, fly, rodent, human) Protein restriction and restriction of specific essential amino acids improve metabolic health, healthspan and lifespan, with amino-acid composition (not just quantity) as a key determinant." }, { "sid": "PAR2014", "entities": [], "authors": [ "kun-liang-guan", "andrei-v-budanov", "michael-karin", "anita-parmigiani" ], "author_names": [ "Kun-Liang Guan", "Andrei V. Budanov", "Michael Karin", "Anita Parmigiani" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a sensor of different environmental conditions and regulator of cell growth, metabolism, and autophagy. mTORC1 is activated by Rag GTPases, working as RagA:RagB and RagC:RagD heterodimers. Rags control mTORC1 activity by tethering mTORC1 to the lysosomes where it is activated by Rheb GTPase. RagA:RagB, active in its GTP-bound form, is inhibited by GATOR1 complex, a GTPase-activating protein, and GATOR1 is in turn negatively regulated by GATOR2 complex. Biochemical/genetic (Sestrins) Sestrins / GATOR / Rag / mTORC1 Mammalian cells Sestrins inhibit mTORC1 kinase activation through the GATOR complex" }, { "sid": "KIM2019", "entities": [ "mtor", "mtorc1", "mtorc2" ], "authors": [ "kun-liang-guan", "joungmok-kim" ], "author_names": [ "Kun-Liang Guan", "Joungmok Kim" ], "text": "The highly conserved protein kinase mechanistic target of rapamycin (mTOR; originally known as mammalian target of rapamycin) is a central cell growth regulator connecting cellular metabolism and growth with a wide range of environmental inputs as part of mTOR complex 1 (mTORC1) and mTORC2. Not applicable (review) mTORC1 / mTORC2 Review Reviews landmark mTOR discoveries and its role as a central hub of nutrient signalling and cell growth" }, { "sid": "BAT2013", "entities": [ "tsc1-tsc2", "rapamycin", "mtorc1", "tuberous-sclerosis-complex" ], "authors": [ "helen-s-bateup", "bernardo-l-sabatini" ], "author_names": [ "Helen S. Bateup", "Bernardo L. Sabatini" ], "text": "Neural circuits are regulated by activity-dependent feedback systems that tightly control network excitability and which are thought to be crucial for proper brain development. Defects in the ability to establish and maintain network homeostasis may be central to the pathogenesis of neurodevelopmental disorders. Here, we examine the function of the tuberous sclerosis complex (TSC)-mTOR signaling pathway, a common target of mutations associated with epilepsy and autism spectrum disorder, in regulating activity-dependent processes in the mouse hippocampus. Tsc1 deletion (lentiviral/AAV Cre, CaMKIIa-Cre); rapamycin TSC1/TSC2 -> mTORC1 Mouse Tsc1 loss weakened inhibitory synapses, raised E/I ratio and network excitability; rapamycin reversed it" }, { "sid": "LV2026", "entities": [ "mtor", "cgas-sting-pathway" ], "authors": [ "nianyin-lv", "liyun-shi" ], "author_names": [ "Nianyin Lv", "Liyun Shi" ], "text": "Lamtor5 (late endosomal/lysosomal adapter, MAPK and mTOR activator 5) was identified as an age-dependent factor controlling innate immune cell function. Age-associated Lamtor5 decline impairs mTOR-dependent macrophage signaling, triggering cGAS-mediated paracrine inflammatory senescence. Restoring Lamtor5 in aged mice rescued immunosenescence and attenuated systemic aging phenotypes. Lamtor5 overexpression / restoration Lamtor5 / mTORC1 Ragulator complex / cGAS-STING Mouse Decline of Lamtor5 reduces mTOR activity in aging macrophages, promoting immunosenescence; Lamtor5 restoration reverses aging phenotypes" }, { "sid": "TAN2002", "entities": [ "eif4e", "rapamycin", "mtor", "4e-bp1" ], "authors": [ "nahum-sonenberg", "anne-claude-gingras", "shao-jun-tang", "erin-m-schuman" ], "author_names": [ "Nahum Sonenberg", "Anne-Claude Gingras", "Shao-Jun Tang", "Erin M. Schuman" ], "text": "Many forms of long-lasting behavioral and synaptic plasticity require the synthesis of new proteins. For example, long-term potentiation (LTP) that endures for more than an hour requires both transcription and translation. The signal-transduction mechanisms that couple synaptic events to protein translational machinery during long-lasting synaptic plasticity, however, are not well understood. Rapamycin (bath application to hippocampal slices) mTOR Rat; mouse (hippocampal slices and cultured neurons) Rapamycin reduced late-phase LTP and blocked BDNF-induced potentiation; early LTP unchanged" }, { "sid": "VAL2019", "entities": [ "mtorc1" ], "authors": [ "brendan-d-manning", "alexander-j-valvezan" ], "author_names": [ "Brendan D. Manning", "Alexander J. Valvezan" ], "text": "The protein kinase complex mechanistic target of rapamycin complex 1 (mTORC1) serves as a key conduit between growth signals and the metabolic processes underlying cell growth. The activation state of mTORC1 is controlled by intracellular nutrients and energy, as well as exogenous hormones and growth factors, thereby integrating local and systemic growth signals. Here we discuss the molecular logic of the mTORC1 signalling network and its importance in coupling growth signals to the control of cellular metabolism. Not applicable (review) mTORC1 Review Frames mTORC1 as a metabolic rheostat coupling growth signals to cellular metabolism" }, { "sid": "SUZ2008", "entities": [], "authors": [ "chikako-suzuki" ], "author_names": [ "Chikako Suzuki" ], "text": null }, { "sid": "HON2026", "entities": [ "tfeb", "mtorc1", "ragulator" ], "authors": [ "sen-hong", "xiaochun-li" ], "author_names": [ "Sen Hong", "Xiaochun Li" ], "text": "The transmembrane 6 superfamily (TM6SF) comprises two members: TM6SF1, a ubiquitously expressed lysosomal membrane protein of unknown function, and TM6SF2, an endoplasmic reticulum protein required for bulk lipidation of Apolipoprotein B-containing lipoproteins. Here, we used cryo-electron microscopy (cryo-EM) to determine the structure of human TM6SF1 at 2.9-Å resolution. TM6SF1 forms a polytopic homodimer, with each protomer comprising 10 transmembrane helices (TMs). TMs 1-6 form a pocket that accommodates a cholesterol molecule. TM6SF1 loss-of-function; cholesterol depletion TM6SF1 / LAMTOR1 / mTORC1 Human (HEK293 cells); cryo-EM structural study Loss of TM6SF1 reduces mTORC1 signaling (S6K1/4E-BP1 phosphorylation) and activates TFEB, in a cholesterol-dependent manner" }, { "sid": "HU2026", "entities": [ "akt-pkb", "mtorc1" ], "authors": [ "hongliang-li", "yufeng-hu" ], "author_names": [ "Hongliang Li", "Yufeng Hu" ], "text": "Excessive unnecessary protein accumulation in cardiomyocyte is a leading contributor for pathological cardiac hypertrophy and has been found closely regulated by the mTORC1 (mechanistic target of rapamycin complex 1) signaling and lysosome transmembrane proteins. However, the precise regulatory mechanism stratifying mTORC1 signaling and the specific functions of lysosomal proteins in protein homeostasis of cardiomyocytes remain largely unidentified. We screened lysosomal genes conserved in mice, rats, and humans. LAPTM4A overexpression and cardiomyocyte-specific knockout (AAV9); magnolol (LAPTM4A suppressor) mTORC1-p70S6K/4EBP1 via LAPTM4A-NEDD4L-driven K63 ubiquitination of AKT Rat and mouse cardiomyocytes (TAC hypertrophy model) LAPTM4A boosts mTORC1-driven protein synthesis to promote pathological cardiac hypertrophy; cardiomyocyte LAPTM4A deletion attenuates TAC-induced hypertrophy/fibrosis." }, { "sid": "FRI2006", "entities": [ "sin1-mapkap1" ], "authors": [ "david-m-sabatini", "carson-c-thoreen", "maria-a-frias" ], "author_names": [ "David M. Sabatini", "Carson C. Thoreen", "Maria A Frias" ], "text": "The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that participates in at least two distinct multiprotein complexes, mTORC1 and mTORC2 . These complexes play important roles in the regulation of cell growth, proliferation, survival, and metabolism. mTORC2 is a hydrophobic motif kinase for the cell-survival protein Akt/PKB and, here, we identify mSin1 as a component of mTORC2 but not mTORC1. mSin1 is necessary for the assembly of mTORC2 and for its capacity to phosphorylate Akt/PKB. Biochemical/genetic (mSin1) mTORC2 / mSin1 / Akt Mammalian cells mSin1 is required for Akt/PKB phosphorylation; its isoforms define three distinct mTORC2 complexes" }, { "sid": "YAN2006", "entities": [ "sin1-mapkap1" ], "authors": [ "kun-liang-guan", "ken-inoki", "qian-yang", "tsuneo-ikenoue" ], "author_names": [ "Kun-Liang Guan", "Ken Inoki", "Qian Yang", "Tsuneo Ikenoue" ], "text": "Target of rapamycin (TOR) is an evolutionally conserved protein kinase in eukaryotes and a central cell growth controller. TOR exists in two distinct complexes, termed TORC1 and TORC2. Mammalian TORC2 has recently been shown to possess kinase activity toward the C-terminal hydrophobic site of Akt/PKB. Here, we report that Sin1 is an essential component of TORC2 but not of TORC1, and functions similarly to Rictor, the defining member of TORC2, in complex formation and kinase activity. Biochemical/genetic (Sin1) TORC2 / Sin1 / Akt Mammalian cells Sin1 is an essential TORC2 component required for complex formation and kinase activity toward Akt" }, { "sid": "GUE2007", "entities": [ "renal-cell-carcinoma-rcc", "mtor", "mtorc1", "mtorc2" ], "authors": [ "david-m-sabatini", "david-a-guertin" ], "author_names": [ "David M. Sabatini", "David A. Guertin" ], "text": "The mammalian target of rapamycin (mTOR) has emerged as a critical effector in cell-signaling pathways commonly deregulated in human cancers. This has led to the prediction that mTOR inhibitors may be useful in oncology, and derivatives of one such molecule, rapamycin (from which mTOR derives its name), are currently in clinical development. In this review, we discuss recent progress in understanding mTOR signaling, paying particular attention to its relevance in cancer. We further discuss the use of rapamycin in oncology and conclude with a discussion on the future of mTOR-targeted therapy. Not applicable (review) mTOR Review Reviews the role of mTOR in cancer and the rationale for rapalog therapy" }, { "sid": "LI2026C", "entities": [ "tsc1-tsc2", "mtorc1", "tuberous-sclerosis-complex" ], "authors": [ "thomas-l-li", "helen-s-bateup", "dirk-hockemeyer" ], "author_names": [ "Thomas L. Li", "Helen S. Bateup", "Dirk Hockemeyer" ], "text": "Tuberous sclerosis complex (TSC) is a genetic neurodevelopmental disorder characterized by focal brain malformations called cortical tubers, which are associated with severe, intractable epilepsy. Tubers are thought to result from somatic second-hit mutations that disrupt the TSC1 or TSC2 genes in neural progenitor cells, driving hyperactive mTORC1 signalling. Glial abnormalities are commonly observed in tubers; however, whether glia actively cause disease or merely result from chronic seizure activity has remained unclear. TSC2 loss-of-function (hyperactive mTORC1) in human iPSC brain organoids mTORC1 Human iPSC-derived brain organoids plus resected patient cortical tuber tissue Hyperactive mTORC1 cell-autonomously biases neural progenitors toward enlarged, pro-inflammatory reactive astrocytes (reduced glutamate transporters, raised cytokines and APOE/CLU), independent of seizures." }, { "sid": "BEN2013", "entities": [ "nucleotide-synthesis" ], "authors": [ "brendan-d-manning", "issam-ben-sahra", "john-m-asara" ], "author_names": [ "Brendan D. Manning", "Issam Ben-Sahra", "John M. Asara" ], "text": "Cellular growth signals stimulate anabolic processes. The mechanistic target of rapamycin complex 1 (mTORC1) is a protein kinase that senses growth signals to regulate anabolic growth and proliferation. Activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. Biochemical/genetic (mTORC1 / S6K1) mTORC1 / S6K1 / CAD (pyrimidine synthesis) Mammalian cells mTORC1 via S6K1 stimulates de novo pyrimidine synthesis (CAD phosphorylation) to support growth" }, { "sid": "KHA2014", "entities": [ "longevity", "rapamycin", "mtorc1" ], "authors": [ "roman-v-kondratov", "rohini-v-khapre" ], "author_names": [ "Roman V. Kondratov", "Rohini V. Khapre" ], "text": "The circadian clock, an internal time-keeping system, has been linked with control of aging, but molecular mechanisms of regulation are not known. BMAL1 is a transcriptional factor and core component of the circadian clock; BMAL1 deficiency is associated with premature aging and reduced lifespan. Here we report that activity of mammalian Target of Rapamycin Complex 1 (mTORC1) is increased upon BMAL1 deficiency both in vivo and in cell culture. Bmal1 knockout; rapamycin treatment mTORC1; BMAL1 Mouse BMAL1 deficiency increases mTORC1 activity; rapamycin extends Bmal1-/- lifespan by 50%" }, { "sid": "BAT2022", "entities": [ "mtorc1", "mtorc2" ], "authors": [ "michael-n-hall", "timm-maier", "stefania-battaglioni" ], "author_names": [ "Michael N. Hall", "Timm Maier", "Stefania Battaglioni" ], "text": "The target of rapamycin (TOR), discovered 30 years ago, is a highly conserved serine/threonine protein kinase that plays a central role in regulating cell growth and metabolism. It is activated by nutrients, growth factors, and cellular energy. TOR forms two structurally and functionally distinct complexes, TORC1 and TORC2. TOR signaling activates cell growth, defined as an increase in biomass, by stimulating anabolic metabolism while inhibiting catabolic processes. With emphasis on mammalian TOR (mTOR), we comprehensively reviewed the literature and identified all reported direct substrates. Not applicable (review) TORC1 / TORC2 substrates Review Reviews mTOR substrate phosphorylation in the control of cell growth" }, { "sid": "JON2005", "entities": [ "cellular-senescence", "energy-cellular-stress", "ampk" ], "authors": [ "russell-g-jones", "craig-b-thompson" ], "author_names": [ "Russell G. Jones", "Craig B. Thompson" ], "text": "Replicative cell division is an energetically demanding process that can be executed only if cells have sufficient metabolic resources to support a doubling of cell mass. Here we show that proliferating mammalian cells have a cell-cycle checkpoint that responds to glucose availability. The glucose-dependent checkpoint occurs at the G(1)/S boundary and is regulated by AMP-activated protein kinase (AMPK). This cell-cycle arrest occurs despite continued amino acid availability and active mTOR. Glucose deprivation; AMPK activation AMPK -> p53 (Ser15) Mammalian cell lines AMPK imposes a reversible p53-dependent G1/S arrest; sustained activation leads to senescence" }, { "sid": "BJE2010", "entities": [ "longevity", "rapamycin", "mtorc1", "autophagy" ], "authors": [ "linda-partridge", "ivana-bjedov" ], "author_names": [ "Linda Partridge", "Ivana Bjedov" ], "text": "The target of rapamycin (TOR) pathway is a major nutrient-sensing pathway that, when genetically downregulated, increases life span in evolutionarily diverse organisms including mammals. The central component of this pathway, TOR kinase, is the target of the inhibitory drug rapamycin, a highly specific and well-described drug approved for human use. We show here that feeding rapamycin to adult Drosophila produces the life span extension seen in some TOR mutants. Increase in life span by rapamycin was associated with increased resistance to both starvation and paraquat. Rapamycin (feeding) TOR Drosophila melanogaster Feeding rapamycin extends fly lifespan via autophagy and reduced translation Rapamycin administered by feeding from early adulthood at 50, 200, and 400 μM; 200 μM produced the largest increase in median life span. Concentration in flies fed 200 μM food was 3.3 ± 0.2 ng/mg wet weight. Flies of diverse genetic (w1118, yw, ovoD mutant) and cytoplasmic (Wolbachia-free) backgrounds, and both sexes were tested. Significant life span extension occurred at 50, 200, and 400 μM rapamycin, with 200 μM producing the largest increase in median life span. Rapamycin also significantly increased stress resistance (starvation, paraquat) and elevated triacylglyceride (TAG) levels, while reducing female fecundity in a dose-dependent manner. not stated" }, { "sid": "NAP2020", "entities": [], "authors": [ "andrea-ballabio", "alessandra-esposito", "gennaro-napolitano", "alessia-calcagni", "jlenia-monfregola", "lukas-a-huber", "mariana-de-araujo", "taras-stasyk" ], "author_names": [ "Andrea Ballabio", "Alessandra Esposito", "Gennaro Napolitano", "Alessia Calcagnì", "Jlenia Monfregola", "Lukas A. Huber", "Mariana de Araujo", "Taras Stasyk" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) is a key metabolic hub that controls the cellular response to environmental cues by exerting its kinase activity on multiple substrates. However, whether mTORC1 responds to diverse stimuli by differentially phosphorylating specific substrates is poorly understood. Here we show that transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is phosphorylated by mTORC1 via a substrate-specific mechanism that is mediated by Rag GTPases. Genetic (FLCN / mTORC1) mTORC1 / TFEB / FLCN Human cells; mouse A substrate-specific mTORC1 pathway phosphorylates TFEB and underlies Birt-Hogg-Dubé syndrome" }, { "sid": "HAN2007", "entities": [ "longevity", "foxo", "caloric-restriction", "protein-synthesis", "s6k1" ], "authors": [ "malene-hansen", "cynthia-kenyon" ], "author_names": [ "Malene Hansen", "Cynthia Kenyon" ], "text": "Many conditions that shift cells from states of nutrient utilization and growth to states of cell maintenance extend lifespan. We have carried out a systematic lifespan analysis of conditions that inhibit protein synthesis. We find that reducing the levels of ribosomal proteins, ribosomal-protein S6 kinase or translation-initiation factors increases the lifespan of Caenorhabditis elegans. These perturbations, as well as inhibition of the nutrient sensor target of rapamycin (TOR), which is known to increase lifespan, all increase thermal-stress resistance. RNAi / mutation of ribosomal proteins, rsks-1 (S6K), translation-initiation factors and TOR TOR-S6K-translation axis C. elegans Reduced translation (incl. S6K knockdown) increases lifespan and thermal-stress resistance; DAF-16-dependent or -independent depending on the factor" }, { "sid": "CHEN2026B", "entities": [ "immune-function", "akt-pkb", "pi3k", "mtorc1" ], "authors": [ "wei-chen" ], "author_names": [ "Wei Chen" ], "text": "OLR1 was upregulated in colorectal cancer (CRC) and negatively associated with CD8+ T-cell infiltration. Knockdown of OLR1 significantly enhanced the antitumor function of CD8+ T cells. Mechanistically, IGF2BP3 stabilized OLR1 mRNA in an m6A modification-dependent manner, thereby activating the PI3K/AKT/mTOR pathway to inhibit the antitumor activity of CD8+ T cells and promote immune evasion in CRC. OLR1 knockdown; IGF2BP3 modulation PI3K/AKT/mTOR pathway; OLR1; IGF2BP3; m6A RNA modification Human m6A-stabilized OLR1 activates PI3K/AKT/mTOR to suppress CD8+ T cell function and enable CRC immune evasion; OLR1 knockdown restores T cell anti-tumor activity" }, { "sid": "CUI2025", "entities": [ "raptor", "rag-gtpases", "mtorc1", "rheb", "ragulator" ], "authors": [ "andrea-ballabio", "james-h-hurley", "alessandra-esposito", "gennaro-napolitano", "zhicheng-cui" ], "author_names": [ "Andrea Ballabio", "James H. Hurley", "Alessandra Esposito", "Gennaro Napolitano", "Zhicheng Cui" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) integrates growth factor (GF) and nutrient signals to stimulate anabolic processes connected to cell growth and inhibit catabolic processes such as autophagy. GF signalling through the tuberous sclerosis complex regulates the lysosomally localized small GTPase RAS homologue enriched in brain (RHEB). Direct binding of RHEB-GTP to the mTOR kinase subunit of mTORC1 allosterically activates the kinase by inducing a large-scale conformational change. Here we reconstituted mTORC1 activation on membranes by RHEB, RAGs and Ragulator. Structural/biochemical reconstitution (cryo-EM, membrane-bound complex) mTORC1-Rheb-Rag-Ragulator activation complex on membranes Human proteins, cell-free reconstitution on synthetic membranes; validation in inducible RAPTOR-knockout mouse embryonic fibroblasts Four-step model of mTORC1 recruitment and activation on the lysosomal membrane, integrating growth-factor (Rheb) and nutrient (Rag-Ragulator) signals into one docking/activation mechanism" }, { "sid": "CAC2010", "entities": [ "rapamycin", "alzheimers-disease", "mtorc1", "autophagy" ], "authors": [ "randy-strong", "arlan-richardson", "salvatore-oddo", "antonella-caccamo" ], "author_names": [ "Randy Strong", "Arlan Richardson", "Salvatore Oddo", "Antonella Caccamo" ], "text": "Accumulation of amyloid-beta (Abeta) and Tau is an invariant feature of Alzheimer disease (AD). The upstream role of Abeta accumulation in the disease pathogenesis is widely accepted, and there is strong evidence showing that Abeta accumulation causes cognitive impairments. However, the molecular mechanisms linking Abeta to cognitive decline remain to be elucidated. Here we show that the buildup of Abeta increases the mammalian target of rapamycin (mTOR) signaling, whereas decreasing mTOR signaling reduces Abeta levels, thereby highlighting an interrelation between mTOR signaling and Abeta. Genetic/pharmacologic (amyloid-β; mTOR) mTOR / amyloid-β / Tau 3xTg-AD transgenic mice Amyloid-β accumulation increases mTOR signaling, linking Aβ to cognitive impairment" }, { "sid": "BIS2013", "entities": [ "lymphangioleiomyomatosis", "everolimus", "renal-angiomyolipoma", "mtorc1", "tuberous-sclerosis-complex" ], "authors": [ "michael-d-frost", "john-j-bissler", "klemens-budde", "david-lebwohl", "tarek-sahmoud", "elena-belousova" ], "author_names": [ "Michael D. Frost", "John J. Bissler", "Klemens Budde", "David Lebwohl", "Tarek Sahmoud", "Elena Belousova" ], "text": "Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. Everolimus mTORC1 Human – phase 3 RCT (EXIST-2, n=118, TSC/LAM) Everolimus reduced angiomyolipoma size vs placebo in TSC/LAM" }, { "sid": "KID2013", "entities": [ "rapamycin", "lipid-synthesis", "cholesterol", "mtorc1", "srebp1-srebp2" ], "authors": [ "steven-j-bensinger", "yoko-kidani" ], "author_names": [ "Steven J. Bensinger", "Yoko Kidani" ], "text": "Newly activated CD8(+) T cells reprogram their metabolism to meet the extraordinary biosynthetic demands of clonal expansion; however, the signals that mediate metabolic reprogramming remain poorly defined. Here we demonstrate an essential role for sterol regulatory element-binding proteins (SREBPs) in the acquisition of effector-cell metabolism. Without SREBP signaling, CD8(+) T cells were unable to blast, which resulted in attenuated clonal expansion during viral infection. T-cell-specific Scap deletion; SREBP1/SREBP2 siRNA; constitutively active SREBP1a/SREBP2; rapamycin 100 nM; LY294002; cholesterol-methyl-beta-cyclodextrin supplementation SREBP processing and the lipogenic gene programme in activated T cells, downstream of PI3K and mTOR Mouse Loss of SREBP activity blocked T-cell blastogenesis, glycolytic and respiratory reprogramming and antiviral clonal expansion; rapamycin blocked SREBP activation upstream" }, { "sid": "GUE2020", "entities": [ "mtorc1" ], "authors": [ "moises-santillan", "jose-g-guerrero-morin" ], "author_names": [ "Moisés Santillán", "José G Guerrero-Morín" ], "text": "Crosstalk between the circadian clock clockwork and cellular metabolic regulatory networks is crucial to ensure an adequate response of an organism to the day/night cycle. mTOR (mammalian/mechanistic target of rapamycin) is a master growth regulator and sensor of nutrient status, which is part of the mTOR complex 1 (mTORC1). While the circadian clock confers rhythmicity to the mTOR protein by regulating its degradation rate, mTORC1 activity diminishes period and augments amplitude of circadian oscillations at the cellular level by a currently unknown mechanism. None (simulation) mTORC1; BMAL1 translation and localisation In silico Model predicts translational control sets amplitude and localisation control sets period" }, { "sid": "DEMMINGS2026", "entities": [ "integrated-stress-response", "parkinsons-disease", "sestrin2", "mtorc1", "mtorc2", "redd1-ddit4" ], "authors": [ "sean-p-cregan", "matthew-d-demmings", "joy-zhao" ], "author_names": [ "Sean P. Cregan", "Matthew D. Demmings", "Joy Zhao" ], "text": "The integrated stress response (ISR) enables cells to adapt to diverse cellular stresses, but during chronic or unresolved stress it becomes maladaptive and is implicated in neurodegenerative diseases, including Parkinson disease (PD). The mechanisms underlying maladaptive ISR-driven neurodegeneration, however, remain poorly defined. Here, we find a critical pathway by which chronic ISR activation promotes neurodegeneration in neurotoxin and alpha-synucleinopathy models of PD in vitro and in vivo. Chronic integrated stress response / ATF4 activation (neurotoxin and alpha-synuclein models) ATF4 -> SESN2, DDIT4, TRIB3 -> mTORC1 and mTORC2 Mouse Parkinson disease models; cultured neurons Sustained ATF4 signalling suppresses both mTOR complexes and drives dopaminergic neuron death via PUMA" }, { "sid": "KWI2002", "entities": [ "tsc1-tsc2", "rapamycin", "mtorc1", "tuberous-sclerosis-complex", "s6k1" ], "authors": [ "david-j-kwiatkowski" ], "author_names": [ "David J. Kwiatkowski" ], "text": "Tuberous sclerosis (TSC) is a autosomal dominant genetic disorder caused by mutations in either TSC1 or TSC2, and characterized by benign hamartoma growth. We developed a murine model of Tsc1 disease by gene targeting. Tsc1 null embryos die at mid-gestation from a failure of liver development. Tsc1 heterozygotes develop kidney cystadenomas and liver hemangiomas at high frequency, but the incidence of kidney tumors is somewhat lower than in Tsc2 heterozygote mice. Liver hemangiomas were more common, more severe and caused higher mortality in female than in male Tsc1 heterozygotes. Tsc1 gene targeting (null and heterozygous) Embryonic survival; kidney and liver tumours; S6K/S6 phosphorylation Mus musculus Tsc1 loss -> embryonic lethality (null), tumours and female-biased mortality (heterozygotes), constitutive rapamycin-sensitive S6K activation" }, { "sid": "MOS2018", "entities": [ "mtor" ], "authors": [ "michael-n-hall", "dirk-mossmann" ], "author_names": [ "Michael N. Hall", "Dirk Mossmann" ], "text": "Oncogenic signalling and metabolic alterations are interrelated in cancer cells. mTOR, which is frequently activated in cancer, controls cell growth and metabolism. mTOR signalling regulates amino acid, glucose, nucleotide, fatty acid and lipid metabolism. Conversely, metabolic inputs, such as amino acids, activate mTOR. In this Review, we discuss how mTOR signalling rewires cancer cell metabolism and delineate how changes in metabolism, in turn, sustain mTOR signalling and tumorigenicity. Several drugs are being developed to perturb cancer cell metabolism. Not applicable (review) mTOR Review Reviews the reciprocal (mutual) control between mTOR signalling and cellular metabolism in cancer" }, { "sid": "BETZ2013", "entities": [ "lysosome", "mtor", "mtorc1" ], "authors": [ "michael-n-hall", "charles-betz" ], "author_names": [ "Michael N. Hall", "Charles Betz" ], "text": "Target of rapamycin (TOR) forms two conserved, structurally distinct kinase complexes termed TOR complex 1 (TORC1) and TORC2. Each complex phosphorylates a different set of substrates to regulate cell growth. In mammals, mTOR is stimulated by nutrients and growth factors and inhibited by stress to ensure that cells grow only during favorable conditions. Studies in different organisms have reported localization of TOR to several distinct subcellular compartments. Notably, the finding that mTORC1 is localized to the lysosome has significantly enhanced our understanding of mTORC1 regulation. Not applicable (review) TORC1 / TORC2 (subcellular localization) Review Reviews where the mTOR complexes localize and what they do at each site" }, { "sid": "EIS2016", "entities": [ "cardiac-aging", "longevity", "atg5", "spermidine", "autophagy" ], "authors": [ "tobias-eisenberg", "frank-madeo", "junichi-sadoshima", "sabrina-buttner", "frauke-neff", "didac-carmona-gutierrez", "sabrina-schroeder", "christoph-magnes", "christoph-ruckenstuhl", "jorn-dengjel", "luca-scorrano", "martin-hrabe-de-angelis", "johannes-beckers", "helmut-fuchs", "valerie-gailus-durner", "marion-horsch", "kristin-moreth", "birgit-rathkolb", "jan-rozman" ], "author_names": [ "Tobias Eisenberg", "Frank Madeo", "Junichi Sadoshima", "Sabrina Büttner", "Frauke Neff", "Didac Carmona-Gutierrez", "Sabrina Schroeder", "Christoph Magnes", "Christoph Ruckenstuhl", "Jörn Dengjel", "Luca Scorrano", "Martin Hrabě de Angelis", "Johannes Beckers", "Helmut Fuchs", "Valérie Gailus-Durner", "Marion Horsch", "Kristin Moreth", "Birgit Rathkolb", "Jan Rozman" ], "text": "Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Oral spermidine supplementation (with cardiomyocyte Atg5 knockout as genetic test) Autophagy/mitophagy (Atg5-dependent) Mouse (plus Dahl salt-sensitive rat model and a human dietary questionnaire cohort) Spermidine extends mouse lifespan and is cardioprotective in an autophagy-dependent manner; the human arm is observational dietary correlation only." }, { "sid": "BYF2005", "entities": [ "mtorc1", "s6k1", "vps34-pik3c3" ], "authors": [ "maya-p-byfield", "jonathan-m-backer" ], "author_names": [ "Maya P. Byfield", "Jonathan M. Backer" ], "text": "Mammalian cells respond to nutrient deprivation by inhibiting energy consuming processes, such as proliferation and protein synthesis, and by stimulating catabolic processes, such as autophagy. p70 S6 kinase (S6K1) plays a central role during nutritional regulation of translation. S6K1 is activated by growth factors such as insulin, and by mammalian target of rapamycin (mTOR), which is itself regulated by amino acids. The Class IA phosphatidylinositol (PI) 3-kinase plays a well recognized role in the regulation of S6K1. hVps34 overexpression, siRNA knockdown and inhibitory antibody microinjection; amino-acid/glucose starvation; AMPK activation hVps34 -> mTOR/S6K1 (nutrient-regulated input) Human and hamster cell lines (HeLa, CHO) hVps34 is inhibited by nutrient starvation and AMPK and is required for S6K1 and 4E-BP1 phosphorylation, acting as a nutrient-regulated input to mTOR independent of insulin/class I PI3K-Akt." }, { "sid": "SU2026", "entities": [ "akt-pkb", "pi3k", "mtorc1" ], "authors": [ "yanhong-su", "jun-zhang" ], "author_names": [ "Yanhong Su", "Jun Zhang" ], "text": "Myocardial ischemia/reperfusion injury (MIRI) leads to life-threatening myocardial infarction. Necroptosis is involved in MIRI. DLX6-AS1 overexpression caused cell damage and necroptosis and increased the expression of PI3K, p-PI3K, AKT, p-AKT, mTOR and p-mTOR. DLX6-AS1 inhibition suppressed necroptosis and cell damage through the PI3K/AKT/mTOR signaling pathway. Myocardial ischemia-reperfusion injury induces necroptosis, and DLX6-AS1 promotes this process through the PI3K/AKT/mTOR signaling pathway. DLX6-AS1 overexpression/inhibition PI3K/AKT/mTOR pathway; RIP1; RIP3; MLKL Mouse; Rat DLX6-AS1 activates PI3K/AKT/mTOR, promoting necroptosis in cardiac I/R injury; knockdown is cardioprotective" }, { "sid": "DIB2013B", "entities": [ "gator1" ], "authors": [ "ingrid-e-scheffer", "samuel-f-berkovic", "leanne-m-dibbens" ], "author_names": [ "Ingrid E. Scheffer", "Samuel F. Berkovic", "Leanne M. Dibbens" ], "text": null }, { "sid": "HARA2002", "entities": [ "raptor", "mtor", "mtorc1", "s6k1" ], "authors": [ "joseph-avruch", "kazuyoshi-yonezawa", "xiaomeng-long", "kenta-hara", "noriko-oshiro-rapley", "sujuti-hidayat", "chiharu-tokunaga" ], "author_names": [ "Joseph Avruch", "Kazuyoshi Yonezawa", "Xiaomeng Long", "Kenta Hara", "Noriko Oshiro-Rapley", "Sujuti Hidayat", "Chiharu Tokunaga" ], "text": "mTOR controls cell growth, in part by regulating p70 S6 kinase alpha (p70alpha) and eukaryotic initiation factor 4E binding protein 1 (4EBP1). Raptor is a 150 kDa mTOR binding protein that also binds 4EBP1 and p70alpha. The binding of raptor to mTOR is necessary for the mTOR-catalyzed phosphorylation of 4EBP1 in vitro, and it strongly enhances the mTOR kinase activity toward p70alpha. Rapamycin or amino acid withdrawal increases, whereas insulin strongly inhibits, the recovery of 4EBP1 and raptor on 7-methyl-GTP Sepharose. Biochemical/genetic (raptor; C. elegans RNAi) mTOR / raptor / 4EBP1 / S6K Human cells + C. elegans Raptor binds mTOR and its substrates (4EBP1, p70S6K) and is required for mTOR-catalyzed phosphorylation" }, { "sid": "XIA2011", "entities": [], "authors": [ "david-carling", "steven-j-gamblin" ], "author_names": [ "David Carling", "Steven J. Gamblin" ], "text": null }, { "sid": "ZEN2013", "entities": [ "t-cell-differentiation", "immune-function", "mtorc1" ], "authors": [ "hongbo-chi", "hu-zeng" ], "author_names": [ "Hongbo Chi", "Hu Zeng" ], "text": "The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T-cell fate decisions. The activation of mTOR, which is the catalytic subunit of the mTORC1 and mTORC2 complexes, delivers an obligatory signal for the proper activation and differentiation of effector CD4(+) T cells, whereas in the regulatory T-cell (T(reg)) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of T(reg)-cell de novo differentiation and population expansion. Genetic (mTORC1 in Treg cells) mTORC1 Mouse mTORC1 couples immune signals and metabolic programming to establish regulatory T-cell function not stated not stated not stated Normal health status of Cd4 cre Raptor fl/fl mice was likely due to impaired activation of conventional T cells, to be described elsewhere." }, { "sid": "NES2001", "entities": [ "pten", "akt-pkb", "mtorc1", "temsirolimus", "tumor-growth" ], "authors": [ "charles-l-sawyers" ], "author_names": [ "Charles L. Sawyers" ], "text": "Recent evidence places the FRAP/mTOR kinase downstream of the phosphatidyl inositol 3-kinase/Akt-signaling pathway, which is up-regulated in multiple cancers because of loss of the PTEN tumor suppressor gene. We performed biological and biochemical studies to determine whether PTEN-deficient cancer cells are sensitive to pharmacologic inhibition of FRAP/mTOR by using the rapamycin derivative CCI-779. CCI-779 (temsirolimus); PTEN loss; constitutively active Akt PTEN/Akt -> mTOR Mouse cells, human cancer cell lines, mouse tumour models PTEN-null tumours are preferentially growth-inhibited by mTOR inhibition" }, { "sid": "POD2001", "entities": [ "pten", "mtorc1", "tumor-growth" ], "authors": [ "john-blenis", "charles-l-sawyers", "katrina-podsypanina", "ramon-parsons" ], "author_names": [ "John Blenis", "Charles L. Sawyers", "Katrina Podsypanina", "Ramon Parsons" ], "text": "PTEN phosphatase acts as a tumor suppressor by negatively regulating the phosphoinositide 3-kinase (PI3K) signaling pathway. It is unclear which downstream components of this pathway are necessary for oncogenic transformation. In this report we show that transformed cells of PTEN(+/-) mice have elevated levels of phosphorylated Akt and activated p70/S6 kinase associated with an increase in proliferation. Pharmacological inactivation of mTOR/RAFT/FRAP reduced neoplastic proliferation, tumor size, and p70/S6 kinase activity, but did not affect the status of Akt. Pharmacological mTOR inhibitor mTOR -> p70 S6K Pten+/- mice mTOR inhibition reduces neoplasia and normalises S6K activity in Pten+/- mice" }, { "sid": "ROD2011", "entities": [ "atp-competitive-mtor-inhibitors", "akt-pkb", "mtorc1", "mtorc2" ], "authors": [ "vanessa-s-rodrik-outmezguine", "neal-rosen", "jose-baselga" ], "author_names": [ "Vanessa S. Rodrik-Outmezguine", "Neal Rosen", "José Baselga" ], "text": "mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of receptor tyrosine kinases (RTK), leading to subsequent phosphoinositide 3-kinase activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. ATP-competitive mTOR kinase inhibitors mTORC1/2 / AKT / RTK Cancer cells In cancer cell lines, mTOR kinase inhibition causes feedback-dependent biphasic AKT regulation (transient inhibition then RTK-driven rebound)" }, { "sid": "NAT2026", "entities": [ "mtor", "everolimus", "akt-pkb", "pi3k", "tumor-growth" ], "authors": [ "j-silvio-gutkind", "cherie-ann-o-nathan", "priyatosh-nath" ], "author_names": [ "J. Silvio Gutkind", "Cherie-Ann O. Nathan", "Priyatosh Nath" ], "text": "Resistance to immunotherapy remains a major clinical challenge in TP53-mutant head and neck squamous cell carcinoma (HNSCC), a disease subset characterized by immune exclusion, high recurrence, and poor outcomes. Given the constitutive activation of PI3K/AKT/mTOR signaling in TP53-mutant HNSCC and its role in disease progression, we investigated whether mTOR inhibition (mTORi) could overcome immune resistance and improve outcomes. Everolimus (mTOR inhibitor) mTOR / PI3K-AKT-mTOR axis; downstream HIF-1α/VEGFA, PD-1/PD-L1 Mouse (syngeneic TP53-mutant HNSCC models) Reprograms immune-cold tumor microenvironment to an immune-active state; suppresses tumor growth" }, { "sid": "MOT2026", "entities": [ "mitophagy", "longevity", "rictor", "mtorc2", "methionine" ], "authors": [ "arnab-mukhopadhyay", "simran-motwani" ], "author_names": [ "Arnab Mukhopadhyay", "Simran Motwani" ], "text": "Adaptive modulation of physiological traits in response to dietary fluctuations is essential for organismal fitness and is governed by complex gene-diet interactions that remain mechanistically unexplored. Here, we identify the conserved mTORC2 component RICTOR as a critical regulator of dietary plasticity in Caenorhabditis elegans. Loss of rict-1/RICTOR confers enhanced osmotic stress tolerance and longevity on vitamin B12-rich bacterial diets containing optimal methionine. rict-1 (RICTOR) loss of function; vitamin B12-rich bacterial diet mTORC2 (RICTOR), methionine cycle, mitophagy C. elegans Loss of rict-1 extends lifespan and osmotic-stress tolerance on B12-rich diets; requires METR-1, MMCM-1, succinate-driven mitochondrial fragmentation and mitophagy" }, { "sid": "NAR2011", "entities": [ "lysosome", "mtor", "rag-gtpases", "cellular-senescence", "autophagy", "senescence-associated-secretory-phenotype-sasp" ], "authors": [ "masako-narita", "masashi-narita" ], "author_names": [ "Masako Narita", "Masashi Narita" ], "text": "Protein synthesis and autophagic degradation are regulated in an opposite manner by mammalian target of rapamycin (mTOR), whereas under certain conditions it would be beneficial if they occurred in unison to handle rapid protein turnover. We observed a distinct cellular compartment at the trans side of the Golgi apparatus, the TOR-autophagy spatial coupling compartment (TASCC), where (auto)lysosomes and mTOR accumulated during Ras-induced senescence. Disruption of mTOR localisation to the TASCC; amino-acid and Rag GTPase manipulation mTOR spatial coupling with autolysosomes (TASCC); SASP (IL-6/IL-8) Human and mouse cells (Ras-induced senescent fibroblasts, macrophages, podocytes) Co-localising mTOR with autolysosomes at the trans-Golgi supports mass synthesis of secreted proteins; disrupting it reduces IL-6/8 synthesis." }, { "sid": "VAL2017", "entities": [ "nucleotide-synthesis", "tumor-growth" ], "authors": [ "brendan-d-manning", "alexander-j-valvezan", "john-m-asara", "david-j-kwiatkowski", "marc-turner", "elizabeth-p-henske" ], "author_names": [ "Brendan D. Manning", "Alexander J. Valvezan", "John M. Asara", "David J. Kwiatkowski", "Marc Turner", "Elizabeth P Henske" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) supports proliferation through parallel induction of key anabolic processes, including protein, lipid, and nucleotide synthesis. We hypothesized that these processes are coupled to maintain anabolic balance in cells with mTORC1 activation, a common event in human cancers. Loss of the tuberous sclerosis complex (TSC) tumor suppressors results in activation of mTORC1 and development of the tumor syndrome TSC. Genetic/pharmacologic (mTORC1; TSC loss) mTORC1 / nucleotide synthesis Cancer cells; tumor mTORC1 couples nucleotide synthesis to demand, creating a targetable metabolic vulnerability in TSC-null cancer" }, { "sid": "PRE2021", "entities": [ "lysosome", "tsc1-tsc2", "breast-cancer", "mtorc1" ], "authors": [ "constantinos-demetriades", "aurelio-a-teleman", "viktor-i-korolchuk", "ralf-baumeister", "bernadette-carroll", "mirja-tamara-prentzell", "julian-r-sampson", "kathrin-thedieck", "lukas-a-huber", "mariana-de-araujo", "alexander-m-heberle", "laura-brohee", "gianluca-figlia" ], "author_names": [ "Constantinos Demetriades", "Aurelio A. Teleman", "Viktor I. Korolchuk", "Ralf Baumeister", "Bernadette Carroll", "Mirja Tamara Prentzell", "Julian R. Sampson", "Kathrin Thedieck", "Lukas A. Huber", "Mariana de Araujo", "Alexander M Heberle", "Laura Brohée", "Gianluca Figlia" ], "text": "Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. G3BP1/G3BP2 knockout/knockdown; G3bp1 inhibition in zebrafish G3BP1/2 tethering of the TSC complex to lysosomes; mTORC1 Human and mouse cells; zebrafish; breast cancer patient data (correlative) Loss of G3BPs releases TSC from lysosomes and makes mTORC1 hyperactive to amino acids and insulin." }, { "sid": "HAN2008", "entities": [ "longevity", "foxo", "mtor", "caloric-restriction", "autophagy" ], "authors": [ "malene-hansen", "cynthia-kenyon", "monica-driscoll" ], "author_names": [ "Malene Hansen", "Cynthia Kenyon", "Monica Driscoll" ], "text": "In many organisms, dietary restriction appears to extend lifespan, at least in part, by down-regulating the nutrient-sensor TOR (Target Of Rapamycin). TOR inhibition elicits autophagy, the large-scale recycling of cytoplasmic macromolecules and organelles. In this study, we asked whether autophagy might contribute to the lifespan extension induced by dietary restriction in C. elegans. We find that dietary restriction and TOR inhibition produce an autophagic phenotype and that inhibiting genes required for autophagy prevents dietary restriction and TOR inhibition from extending lifespan. Dietary restriction (eat-2), TOR RNAi, RNAi against autophagy genes; daf-2 mutants TOR / autophagy / PHA-4 / DAF-16 Caenorhabditis elegans Autophagy is required for lifespan extension by dietary restriction and TOR inhibition but is not sufficient on its own." }, { "sid": "XU2026", "entities": [ "rapamycin" ], "authors": [ "yi-ji", "jiangyuan-zhou", "yulang-xu" ], "author_names": [ "Yi Ji", "Jiangyuan Zhou", "Yulang Xu" ], "text": "Sirolimus is the cornerstone therapy for Kaposiform hemangioendothelioma (KHE). This multicentre study evaluated whether anatomical location independently predicts radiologic response to sirolimus monotherapy in KHE without Kasabach-Merritt phenomenon (KMP). 21 patients with head and neck KHE without KMP and 50 matched patients with non-head and neck KHE were treated with sirolimus monotherapy across five tertiary referral centres in China. Sirolimus monotherapy mTOR Human 100% 12-month radiologic response and 81% near-complete involution in head/neck KHE; no progression" }, { "sid": "COS2009", "entities": [ "eif4e", "cognition", "mtorc1", "protein-synthesis", "4e-bp1" ], "authors": [ "nahum-sonenberg", "mauro-costa-mattioli" ], "author_names": [ "Nahum Sonenberg", "Mauro Costa-Mattioli" ], "text": "Long-lasting forms of synaptic plasticity and memory are dependent on new protein synthesis. Recent advances obtained from genetic, physiological, pharmacological, and biochemical studies provide strong evidence that translational control plays a key role in regulating long-term changes in neural circuits and thus long-term modifications in behavior. Translational control is important for regulating both general protein synthesis and synthesis of specific proteins in response to neuronal activity. None (review) Translational control (mTORC1/4E-BP/eIF4E and eIF2alpha pathways) in neurons Multiple (review) Review: translational control regulates long-lasting synaptic plasticity and memory" }, { "sid": "ABD2026", "entities": [ "rapamycin", "age-related-pathology", "mtor", "cellular-senescence" ], "authors": [ "adam-b-salmon", "parveez-ahamed-abdul-azees", "chih-ko-yeh" ], "author_names": [ "Adam B. Salmon", "Parveez Ahamed Abdul-Azees", "Chih-Ko Yeh" ], "text": "The aging of salivary glands (SGs) leads to xerostomia, impaired oral defenses, and a compromised quality of life, yet the biology of human submandibular gland (SMG) aging remains poorly understood due to limited availability of human tissues and differences in anatomy and physiology between rodent and human SGs. The common marmoset (Callithrix jacchus) is a short-lived non-human primate (NHP) with SMG histology that closely resembles humans and has the potential to provide a translational model for investigating SG aging. Chronic oral rapamycin Age-related structure of the submandibular gland (acini, fibrosis, lipid, apoptosis, senescence) Common marmoset (Callithrix jacchus) Partial preservation of acinar structure; less fibrosis, lipid accumulation, apoptosis and senescence" }, { "sid": "KRISTIANSEN2026", "entities": [ "s6k1" ], "authors": [ "kristian-kjr-vissing", "jonas-boritz-kristiansen" ], "author_names": [ "Kristian Kjær Vissing", "Jonas Boritz Kristiansen" ], "text": "Aging is associated with impaired skeletal muscle mass and function, often attributed to reduced sensitivity to anabolic stimuli. This study investigated whether aging influences the sensitivity of key anabolic signaling pathways to mechanical tension development in skeletal muscle. Using an ex vivo model, extensor digitorum longus (EDL) muscles from adult (16 weeks) and old (24 months) female mice were subjected to a standardized passive stretch protocol, with contralateral muscles serving as controls. Passive mechanical stretch mTORC1 (p70S6K, rpS6, 4E-BP1) Mouse mTORC1 mechanosensitivity preserved with aging; differential anabolic pathway response" }, { "sid": "KEN2016", "entities": [ "longevity", "mtor", "mtorc1", "insulin-resistance" ], "authors": [ "dudley-w-lamming", "brian-k-kennedy" ], "author_names": [ "Dudley W. Lamming", "Brian K. Kennedy" ], "text": "Since the discovery that rapamycin, a small molecule inhibitor of the protein kinase mTOR (mechanistic target of rapamycin), can extend the lifespan of model organisms including mice, interest in understanding the physiological role and molecular targets of this pathway has surged. While mTOR was already well known as a regulator of growth and protein translation, it is now clear that mTOR functions as a central coordinator of organismal metabolism in response to both environmental and hormonal signals. Not applicable (review) mTOR Review Reviews mTOR as a central coordinator of organismal metabolism and aging" }, { "sid": "HAL2012", "entities": [ "longevity", "cognition", "rapamycin", "mtor", "mtorc1" ], "authors": [ "randy-strong", "arlan-richardson", "natalia-podlutskaya", "veronica-galvan", "stacy-a-hussong", "jonathan-j-halloran" ], "author_names": [ "Randy Strong", "Arlan Richardson", "Natalia Podlutskaya", "Veronica Galvan", "Stacy A. Hussong", "Jonathan J. Halloran" ], "text": "Aging is, by far, the greatest risk factor for most neurodegenerative diseases. In non-diseased conditions, normal aging can also be associated with declines in cognitive function that significantly affect quality of life in the elderly. It was recently shown that inhibition of Mammalian TOR (mTOR) activity in mice by chronic rapamycin treatment extends lifespan, possibly by delaying aging {Harrison, 2009 #4}{Miller, 2011 #168}. Rapamycin (chronic) mTOR C57BL/6 mice (lifespan behavior study) Chronic rapamycin modulates cognitive and non-cognitive behavior across the lifespan in mice 2.24 mg rapamycin per kg body weight/day via rapamycin-supplemented chow (14 mg/kg food), ad libitum, for periods ranging from 8 to 40 weeks not stated not stated not stated" }, { "sid": "LAP2012", "entities": [ "longevity", "mtorc1", "mtorc2" ], "authors": [ "david-m-sabatini", "mathieu-laplante" ], "author_names": [ "David M. Sabatini", "Mathieu Laplante" ], "text": "The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation. Not applicable (review) mTORC1 / mTORC2 Review Comprehensive review of mTOR signaling in growth control and disease (cancer, obesity, diabetes, neurodegeneration)" }, { "sid": "ZAU2026", "entities": [ "tfeb", "rapamycin", "mtorc1" ], "authors": [ "andrea-ballabio", "alex-zaufel", "tarek-moustafa" ], "author_names": [ "Andrea Ballabio", "Alex Zaufel", "Tarek Moustafa" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and hormonal cues to regulate hepatic lipid metabolism with major implications for metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we show that altered hepatic mTORC1-TFEB/TFE3 signaling is associated with coordinated remodeling of bile acid (BA) metabolism during metabolic adaptation. Our data support a model in which cross-talk between mTORC1 and TFEB/TFE3 is associated with divergent regulation of bile acid synthesis and transformation. Liver-specific genetic mTORC1/TFEB-TFE3 manipulation; rapamycin; dietary protein restriction mTORC1-TFEB/TFE3 axis; bile acid synthesis Mouse liver; correlative human MASLD cohort mTORC1-TFEB/TFE3 signalling state is associated with shifts between 12-OH and non-12-OH bile acid species, attenuated by deletion or rapamycin." }, { "sid": "MEN2023", "entities": [ "breast-cancer", "mtorc1", "mtorc2", "4e-bp1" ], "authors": [ "sourav-bandyopadhyay", "hani-goodarzi", "delong-meng", "yu-chi-yang" ], "author_names": [ "Sourav Bandyopadhyay", "Hani Goodarzi", "Delong Meng", "Yu Chi Yang" ], "text": "Activation of the PI3K-mTOR pathway is central to breast cancer pathogenesis including resistance to many targeted therapies. The mTOR kinase forms two distinct complexes, mTORC1 and mTORC2, and understanding which is required for the survival of malignant cells has been limited by tools to selectively and completely impair either subcomplex. To address this, we used RMC-6272, a bi-steric molecule with a rapamycin-like moiety linked to an mTOR active-site inhibitor that displays >25-fold selectivity for mTORC1 over mTORC2 substrates. RMC-6272 (bi-steric mTORC1-selective inhibitor) mTORC1 (4E-BP1), >25-fold selective over mTORC2 Human cell lines; mouse PDX Overcomes hormone- and CDK4/6-inhibitor drug resistance via complete mTORC1 suppression" }, { "sid": "STE2026", "entities": [ "longevity", "rapamycin", "kidney-transplant" ], "authors": [ "darren-e-stewart", "william-e-fitzsimmons" ], "author_names": [ "Darren E Stewart", "William E Fitzsimmons" ], "text": "Rapamycin, an mTOR inhibitor, continues to be investigated for hypothesized physiological, disease prevention, and longevity benefits, but few studies have been conducted in humans. Using US national organ transplant registry data, one of the largest real-world datasets examining chronic rapamycin exposure in humans, we compared the Kaplan-Meier survival age distribution of 4885 kidney transplant recipients prescribed rapamycin compared to 6589 recipients not prescribed rapamycin. Recipients were followed a median of 11 years and 6443 died during the study period." }, { "sid": "HOR2021", "entities": [ "longevity", "rapamycin", "mtor" ], "authors": [ "adam-b-salmon", "steve-horvath", "julie-a-mattison" ], "author_names": [ "Adam B. Salmon", "Steve Horvath", "Julie A. Mattison" ], "text": "Human DNA methylation data have previously been used to develop highly accurate biomarkers of aging (\"epigenetic clocks\"). Subsequent studies demonstrate that similar epigenetic clocks can also be developed for mice and many other mammals. Here, we describe epigenetic clocks for common marmosets (Callithrix jacchus) based on novel DNA methylation data generated from highly conserved mammalian CpGs that were profiled using a custom Infinium array (HorvathMammalMethylChip40). From these, we developed and present here two epigenetic clocks for marmosets that are applicable to whole blood samples. Rapamycin (regimen not stated in abstract) DNA methylation age (epigenetic clock) in blood Common marmoset (Callithrix jacchus) No significant effect of rapamycin on marmoset blood epigenetic age" }, { "sid": "KUB2018", "entities": [ "foxo", "akt-pkb", "mtorc1", "s6k1" ], "authors": [ "hiroyuki-kubota", "shinya-kuroda", "shinsuke-uda" ], "author_names": [ "Hiroyuki Kubota", "Shinya Kuroda", "Shinsuke Uda" ], "text": "Cells respond to various extracellular stimuli through a limited number of signaling pathways. One strategy to process such stimuli is to code the information into the temporal patterns of molecules. Although we showed that insulin selectively regulated molecules depending on its temporal patterns using Fao cells, the in vivo mechanism remains unknown. Here, we show how the insulin-AKT pathway processes the information encoded into the temporal patterns of blood insulin. Insulin delivered in different temporal patterns under clamp Insulin receptor; AKT; S6K; FoxO1/G6Pase; GSK3-beta Rat S6K selectively decodes additional insulin secretion in vivo" }, { "sid": "POL2008", "entities": [], "authors": [ "michael-n-hall", "pazit-polak", "nadine-cybulski", "markus-a-ruegg" ], "author_names": [ "Michael N. Hall", "Pazit Polak", "Nadine Cybulski", "Markus A. Rüegg" ], "text": "raptor is a specific and essential component of mammalian TOR complex 1 (mTORC1), a key regulator of cell growth and metabolism. To investigate a role of adipose mTORC1 in regulation of adipose and whole-body metabolism, we generated mice with an adipose-specific knockout of raptor (raptor(ad-/-)). Compared to control littermates, raptor(ad-/-) mice had substantially less adipose tissue, were protected against diet-induced obesity and hypercholesterolemia, and exhibited improved insulin sensitivity. Genetic – adipose-specific raptor knockout mTORC1 (raptor) Mouse (adipose raptor KO) Adipose raptor loss yields lean mice protected from diet-induced obesity with enhanced mitochondrial respiration" }, { "sid": "KIM2008", "entities": [ "rag-gtpases", "mtorc1", "autophagy" ], "authors": [ "kun-liang-guan", "eunjung-kim" ], "author_names": [ "Kun-Liang Guan", "Eunjung Kim" ], "text": "TORC1 (target of rapamycin complex 1) has a crucial role in the regulation of cell growth and size. A wide range of signals, including amino acids, is known to activate TORC1. Here, we report the identification of Rag GTPases as activators of TORC1 in response to amino acid signals. Knockdown of Rag gene expression suppressed the stimulatory effect of amino acids on TORC1 in Drosophila melanogaster S2 cells. Genetic/biochemical (Rag GTPases) TORC1 / Rag GTPases Mammalian cells (+ Drosophila S2) Rag GTPases activate TORC1 in response to amino-acid signals" }, { "sid": "GUE2006", "entities": [ "rictor", "mlst8", "raptor", "akt-pkb", "mtorc1", "mtorc2" ], "authors": [ "david-m-sabatini", "carson-c-thoreen", "david-a-guertin", "nada-y-kalaany" ], "author_names": [ "David M. Sabatini", "Carson C. Thoreen", "David A. Guertin", "Nada Y. Kalaany" ], "text": "The mTOR kinase controls cell growth, proliferation, and survival through two distinct multiprotein complexes, mTORC1 and mTORC2. mTOR and mLST8 are in both complexes, while raptor and rictor are part of only mTORC1 and mTORC2, respectively. To investigate mTORC1 and mTORC2 function in vivo, we generated mice deficient for raptor, rictor, or mLST8. Like mice null for mTOR, those lacking raptor die early in development. However, mLST8 null embryos survive until e10.5 and resemble embryos missing rictor. Genetic (raptor / rictor / mLST8 knockout mice) mTORC1 vs mTORC2 / Akt-FOXO / PKCα Knockout mice mTORC2 (rictor/mLST8) is required for Akt-FOXO and PKCα signaling but not S6K1; raptor/mTOR-null mice die early" }, { "sid": "OLD2000", "entities": [ "mtor", "insulin", "s6k1" ], "authors": [ "george-thomas", "ernst-hafen", "jacques-montagne" ], "author_names": [ "George Thomas", "Ernst Hafen", "Jacques Montagne" ], "text": "The adaptation of growth in response to nutritional changes is essential for the proper development of all organisms. Here we describe the identification of the Drosophila homolog of the target of rapamycin (TOR), a candidate effector for nutritional sensing. Genetic and biochemical analyses indicate that dTOR impinges on the insulin signaling pathway by autonomously affecting growth through modulating the activity of dS6K. However, in contrast to other components in the insulin signaling pathway, partial loss of dTOR function preferentially reduces growth of the endoreplicating tissues. dTOR loss-of-function alleles dS6K activity; tissue growth Drosophila melanogaster Loss of dTOR -> reduced dS6K activity and reduced growth, mainly in endoreplicating tissues" }, { "sid": "MIC2011", "entities": [ "t-cell-differentiation", "rapamycin", "metformin", "ampk" ], "authors": [ "ryan-d-michalek", "jeffrey-c-rathmell" ], "author_names": [ "Ryan D. Michalek", "Jeffrey C. Rathmell" ], "text": "Stimulated CD4(+) T lymphocytes can differentiate into effector T cell (Teff) or inducible regulatory T cell (Treg) subsets with specific immunological roles. We show that Teff and Treg require distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic. Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Rapamycin (25 nM), metformin (100 uM in vitro, 250 mg/kg daily in vivo), etomoxir (200 uM), glucose withdrawal, Glut1 transgene CD4 T-cell glycolysis versus lipid oxidation, and Teff versus Treg differentiation Mouse Glycolysis supports effector subsets while lipid oxidation and AMPK activation support Treg; mTOR inhibition increases Treg only when lipid oxidation is available" }, { "sid": "MADKOUR2026", "entities": [ "nlrp3" ], "authors": [ "mahmoud-elshal", "ahmed-h-madkour" ], "author_names": [ "Mahmoud Elshal", "Ahmed H. Madkour" ], "text": "Epileptogenesis is a multifactorial process driven by persistent neuroinflammation, oxidative stress and dysregulated intracellular signalling. This study investigated prophylactic carvedilol in the PTZ-induced kindling model. Repeated PTZ administration produced progressive behavioural seizure development, impaired open-field performance, hippocampal neuronal damage, reduced GABA, increased oxidative stress and inflammatory mediators, altered hippocampal NLRP3 expression and changes in PI3K-, AKT- and mTOR-related protein expression. Carvedilol (prophylactic) PI3K/AKT/mTOR; NLRP3 Rat Reduced seizure severity and hippocampal injury; associative (non-causal) changes in PI3K/AKT/mTOR signalling" }, { "sid": "HE2026", "entities": [ "longevity", "akt-pkb", "cellular-senescence", "s6k1" ], "authors": [ "yi-he" ], "author_names": [ "Yi He" ], "text": "Adipose tissue senescence is increasingly recognized as a key driver of systemic aging and age-related functional decline, yet the endocrine regulators that actively promote this process remain poorly defined. Angiopoietin-like protein 8 (ANGPTL8) is a metabolic factor implicated in lipid metabolism and inflammation and has been associated with multiple aging-related disorders. However, its direct role in adipose tissue senescence and organismal aging remains unclear. Angptl8 knockout (mouse lifespan); ANGPTL8 exposure with genetic or pharmacological AKT-mTOR-S6K inhibition in adipocytes; human cohort (observational) ANGPTL8-AKT2-mTOR-S6K axis Mouse; primary adipocytes; human cohort (correlative) ANGPTL8 activates AKT-mTOR-S6K to promote adipocyte senescence; Angptl8 deletion extended mouse lifespan." }, { "sid": "SIL2018", "entities": [ "rapamycin", "mtor" ], "authors": [ "adam-b-salmon", "aubrey-m-sills" ], "author_names": [ "Adam B. Salmon", "Aubrey M. Sills" ], "text": "Interventions to extend lifespan and improve health with increasing age would have significant impact on a growing aged population. There are now several pharmaceutical interventions that extend lifespan in laboratory rodent models with rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR) being the most well studied. In this study, we report on the hematological effects in a cohort of middle-aged common marmosets (Callithrix jacchus) that were enrolled in a study to test the effects of daily rapamycin treatment on aging in this species. Daily oral rapamycin for 9 months Hematological and clinical laboratory markers Common marmoset (Callithrix jacchus) Only minor changes in blood counts after 9 months; lower trough rapamycin in females than males" }, { "sid": "HSI2010", "entities": [ "tumor-growth" ], "authors": [ "davide-ruggero", "kevan-m-shokat", "andrew-c-hsieh" ], "author_names": [ "Davide Ruggero", "Kevan M. Shokat", "Andrew C. Hsieh" ], "text": "We genetically dissect the contribution of the most prominent downstream translational components of mTOR signaling toward Akt-driven lymphomagenesis. While phosphorylation of rpS6 is dispensable for cancer formation, 4EBP-eIF4E exerts significant control over cap-dependent translation, cell growth, cancer initiation, and progression. This effect is mediated at least in part through 4EBP-dependent control of Mcl-1 expression, a key antiapoptotic protein. By using an active site inhibitor of mTOR, PP242, we show a marked therapeutic response in rapamycin-resistant tumors. Genetic dissection (4EBP-eIF4E, rpS6) mTOR / 4EBP-eIF4E Cancer cells; mouse 4EBP-eIF4E (not rpS6) controls cap-dependent translation driving Akt lymphomagenesis – a druggable addiction" }, { "sid": "GIL2026", "entities": [ "longevity", "rapamycin", "mtorc1" ], "authors": [ "brooke-gile", "avik-roy" ], "author_names": [ "Brooke Gile", "Avik Roy" ], "text": "In our ongoing phase II observational pilot trial, the compounded formulation of low-dose rapamycin significantly reduced fatigue-related clinical symptoms in ME/CFS subjects. Although the underlying molecular mechanism remains unclear, exploring metabolic pathways involving circulating blood-borne factors is warranted. Recent studies suggest that increased levels of purines may exacerbate oxidative stress in ME/CFS patients. It is not known if rapamycin modulates purine biosynthesis and improves disease symptoms. Low-dose rapamycin mTORC1 / IMP dehydrogenase / purine biosynthesis / mitochondria Human Reduced fatigue, improved mitochondrial energy metabolism, modulated purine biosynthesis, reduced microglial inflammation" }, { "sid": "GAR2003", "entities": [ "insulin", "rheb" ], "authors": [ "george-thomas", "takahiro-nobukuni", "ernst-hafen", "sara-c-kozma", "johannes-l-hans-bos", "attila-garami" ], "author_names": [ "George Thomas", "Takahiro Nobukuni", "Ernst Hafen", "Sara C. Kozma", "Johannes L. (Hans) Bos", "Attila Garami" ], "text": "Tumor suppressor genes evolved as negative effectors of mitogen and nutrient signaling pathways, such that mutations in these genes can lead to pathological states of growth. Tuberous sclerosis (TSC) is a potentially devastating disease associated with mutations in two tumor suppressor genes, TSC1 and 2, that function as a complex to suppress signaling in the mTOR/S6K/4E-BP pathway. However, the inhibitory target of TSC1/2 and the mechanism by which it acts are unknown. Genetic/biochemical (Rheb, TSC1/2) Rheb / TSC1-TSC2 / mTOR-S6K-4EBP Drosophila & mammalian cells Insulin activates Rheb, a mediator of mTOR/S6K/4E-BP signaling, and this is inhibited by TSC1/2" }, { "sid": "ANC2026", "entities": [ "muscle-growth", "autophagy", "urolithin-a" ], "authors": [ "helen-m-blau", "sara-ancel" ], "author_names": [ "Helen M. Blau", "Sara Ancel" ], "text": "Millions of people worldwide suffer from sarcopenia, a clinically recognized syndrome that is defined as the age-related loss of skeletal muscle mass and strength. Sarcopenia reduces mobility, leads to falls and fractures, and increases the risk of death, posing an ever-increasing health-care and economic burden to society. There are currently no approved therapies for the syndrome, partly owing to its multifactorial aetiology, highlighting the need for therapies with pleiotropic beneficial effects on muscle function. Narrative review of pharmacological strategies for sarcopenia: mTORC1 inhibitors, NAD-related molecules, urolithin A, myostatin inhibitors, SARMs, VEGF/apelin, anti-inflammatory agents, 15-PGDH inhibitors, GLP-1RA combinations Multiple: mTORC1 (autophagy), myostatin, NAD+ metabolism, 15-PGDH Human (review; translational/clinical focus) Synthesizes emerging drug classes to preserve muscle mass/strength in aging; positions mTORC1 inhibition as one of several pleiotropic strategies" }, { "sid": "SIN2013", "entities": [ "t-cell-differentiation", "slc7a5-lat1", "leucine", "mtorc1" ], "authors": [ "doreen-a-cantrell", "linda-v-sinclair" ], "author_names": [ "Doreen A. Cantrell", "Linda V. Sinclair" ], "text": "T lymphocytes must regulate nutrient uptake to meet the metabolic demands of an immune response. Here we show that the intracellular supply of large neutral amino acids (LNAAs) in T cells was regulated by pathogens and the T cell antigen receptor (TCR). T cells responded to antigen by upregulating expression of many amino-acid transporters, but a single System L ('leucine-preferring system') transporter, Slc7a5, mediated uptake of LNAAs in activated T cells. Genetic (Slc7a5, T-cell receptor) Slc7a5 (System L) / leucine / mTORC1 Mouse T cells Antigen-receptor-driven Slc7a5 amino-acid transport coordinates the metabolic reprogramming essential for T-cell differentiation TCR triggering with cognate peptide for 4h or 20h; IL-2 at 20 ng/ml or 1.25 ng/ml for 20h; BCH at 10 mM or 50 mM; rapamycin at 20 nM; CsA at 100 nM; glutamine at 2 mM; leucine at 0.4 mM. minimum of 3 experiments done in triplicates (Fig. 1a,c,d); 6 mice (Fig. 1b); 3 experiments (Fig. 2); 3 mice per group (Fig. 3a); 2 collated experiments (Fig. 3d-f). TCR triggering increased phenylalanine transport (p=0.0147 at 4h, p<0.0001 at 20h); CsA abrogated TCR-induced system L activity (p=0.0242) and Slc7a5 mRNA expression (p=0.0070); Slc7a5 haplo-insufficient T cells showed a 50% reduction in System L transporter activity. Systemic deletion of Slc7a5 causes embryonic lethality, necessitating the use of haplo-insufficient mice." }, { "sid": "PAR2023", "entities": [], "authors": [ "ji-man-park" ], "author_names": [ "Ji-Man Park" ], "text": null }, { "sid": "KRU2010", "entities": [ "tsc1-tsc2", "mtor", "everolimus" ], "authors": [ "david-n-franz", "darcy-a-krueger" ], "author_names": [ "David N. Franz", "Darcy A. Krueger" ], "text": "Neurosurgical resection is the standard treatment for subependymal giant-cell astrocytomas in patients with the tuberous sclerosis complex. An alternative may be the use of everolimus, which inhibits the mammalian target of rapamycin, a protein regulated by gene products involved in the tuberous sclerosis complex. Patients 3 years of age or older with serial growth of subependymal giant-cell astrocytomas were eligible for this open-label study. The primary efficacy end point was the change in volume of subependymal giant-cell astrocytomas between baseline and 6 months. Everolimus mTOR Human – open-label trial (n=28, TSC) Everolimus reduced subependymal giant-cell astrocytoma (SEGA) volume in tuberous sclerosis" }, { "sid": "SAX2016", "entities": [ "arginine" ], "authors": [ "david-m-sabatini", "robert-a-saxton", "lynne-chantranupong", "kevin-e-knockenhauer", "thomas-u-schwartz" ], "author_names": [ "David M. Sabatini", "Robert A. Saxton", "Lynne Chantranupong", "Kevin E. Knockenhauer", "Thomas U. Schwartz" ], "text": "The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physiological effects such as immune cell activation, insulin secretion, and muscle growth, largely mediated through activation of mTORC1 (refs 4, 5, 6, 7). Structural/biochemical (CASTOR1) CASTOR1 / GATOR2 / mTORC1 (arginine) Structure; cells CASTOR1 is a direct arginine sensor upstream of mTORC1; structure reveals the arginine-binding mechanism" }, { "sid": "SAU2003", "entities": [ "insulin", "rheb" ], "authors": [ "bruce-a-edgar", "leslie-j-saucedo" ], "author_names": [ "Bruce A. Edgar", "Leslie J. Saucedo" ], "text": "Insulin signalling is a potent stimulator of cell growth and has been proposed to function, at least in part, through the conserved protein kinase TOR (target of rapamycin). Recent studies suggest that the tuberous sclerosis complex Tsc1-Tsc2 may couple insulin signalling to Tor activity. However, the regulatory mechanism involved remains unclear, and additional components are most probably involved. In a screen for novel regulators of growth, we identified Rheb (Ras homologue enriched in brain), a member of the Ras superfamily of GTP-binding proteins. Genetic (Rheb screen) Rheb / TOR Drosophila Rheb promotes cell growth as a component of the insulin/TOR signalling network" }, { "sid": "WANG2026C", "entities": [ "mtor", "mtorc1" ], "authors": [ "ruizhao-wang", "jian-jiang", "kiryl-d-piatkevich" ], "author_names": [ "Ruizhao Wang", "Jian Jiang", "Kiryl D. Piatkevich" ], "text": "Recording and real-time imaging of promoter activities are critical for deciphering signaling cross-talk, but technologies for simultaneously capturing multiple transient events in living cells are lacking. Here, we design fluorescent protein-based ticker tapes (FPTT) for multiplexed, scalable, longitudinal recording of single-cell physiological activities by integrating multispectral monomeric fluorescent proteins with self-assembling protein fibers. FPTT logged dose-dependent, reversible endogenous cFos transcriptional histories in hippocampal neurons at 3-hour resolution over 8 days. None (tool development: fluorescent protein ticker-tape reporters) mTOR-responsive transcription (and NF-kB, STAT3, NFAT, cAMP) recorded over time HEK293T cells; mouse neurons and liver mTOR reporter activity oscillates with the cell cycle in single cells." }, { "sid": "SUN2026B", "entities": [ "mtor", "deptor", "autophagy", "erk-rsk-mapk" ], "authors": [ "liangbo-sun", "jiqin-lian" ], "author_names": [ "Liangbo Sun", "Jiqin Lian" ], "text": "Eukaryotes initiate autophagy in response to environmental challenges such as nutrient deprivation. However, the mechanisms governing autophagy initiation remain incompletely understood. Here, we demonstrated that OTUB1 phosphorylation plays a key role in starvation-induced autophagy initiation. Specifically, ERK phosphorylates OTUB1 at S118 during starvation. This phosphorylation enables competitive binding of ANXA2 to OTUB1, disrupting its interaction with TRIM29 and enhancing OTUB1 stability. Stabilized OTUB1 upregulated DEPTOR, thereby inhibiting mTOR and inducing autophagy. Starvation/fasting; OTUB1 S118 phosphomutants; Western diet in mice ERK-OTUB1-DEPTOR-mTOR-autophagy axis Cultured cells; mouse (Western diet MASLD model) ERK-phosphorylated OTUB1 stabilises DEPTOR, inhibiting mTOR and initiating autophagy; restoring the axis eased MASLD in mice." }, { "sid": "ROM2016", "entities": [ "caloric-restriction" ], "authors": [ "eric-ravussin", "william-e-kraus", "sergei-v-romashkan" ], "author_names": [ "Eric Ravussin", "William E. Kraus", "Sergei V. Romashkan" ], "text": "The extent to which sustained caloric restriction (CR) in healthy non-obese adults is safe has not been previously investigated. Assess the safety and tolerability of sustained two-year CR intervention in healthy, non-obese adults. A multi-center, randomized controlled trial. Participants were randomized using a 2:1 allocation in favor of 25% CR vs. Ad-Libitum intake (AL). Adverse and serious adverse events (AE, SAE), safety laboratory tests, and other safety parameters were closely monitored. Three participants were withdrawn from the CR intervention because of the safety concerns. Caloric restriction (25%, 2 years) Nutrient-sensing / mTOR (indirect) Human – RCT (CALERIE, n=218, non-obese) Sustained 25% caloric restriction was safe and well tolerated in healthy non-obese adults over 2 years Caloric restriction ~25% (achieved ~480 kcal/day deficit in first 6 months) for 2 years vs ad libitum; multicenter RCT (CALERIE). 218 participants in safety analysis (66 male / 152 female); 30 discontinued (26 CR, 4 AL). Sustained 25% CR was safe and well tolerated over 2 years; most lab abnormalities were small and not significantly different from control. Between-group differences mostly not statistically significant; a few treatment-resistant hematocrit decreases (2 withdrawn); healthy non-obese cohort only." }, { "sid": "CHU2019", "entities": [ "rapamycin", "cellular-senescence", "mtorc1", "skin-aging" ], "authors": [ "christian-sell", "christina-lee-chung" ], "author_names": [ "Christian Sell", "Christina Lee Chung" ], "text": "Aging is a major risk factor for the majority of human diseases, and the development of interventions to reduce the intrinsic rate of aging is expected to reduce the risk for age-related diseases including cardiovascular disease, cancer, and dementia. In the skin, aging manifests itself in photodamage and dermal atrophy, with underlying tissue reduction and impaired barrier function. Topical rapamycin mTORC1 Human – RCT (skin, age >40, n=17 completed) Topical rapamycin reduced senescence markers and signs of aging in human skin Topical rapamycin 10 microM cream vs placebo (DMSO), applied to the hands; no detectable systemic rapamycin (LC/MS LOD 1 ng/ml). 36 enrolled, 17 completed, 13 consented to biopsy, 8 samples analyzable (some analyses n=12). p16 protein reduced (P=0.008); collagen VII protein increased (P=0.0077). p21/tp53 trended down but not significant. Small sample size and high dropout; exploratory; some markers not significant; parametric+non-parametric testing used due to small n." }, { "sid": "WEN2026", "entities": [ "rapamycin", "autophagy", "beclin-1-becn1", "hypoxia" ], "authors": [ "xiaoxiao-zhang" ], "author_names": [ "Xiaoxiao Zhang" ], "text": "Autophagy has been implicated in tissue remodeling, but its role in scleral remodeling during myopia development and in atropine-mediated myopia control remains unclear. We investigated this issue using complementary in vitro and in vivo models. Human scleral fibroblasts (HSFs) were exposed to hypoxia and treated with rapamycin (RAPA) or 3-methyladenine (3-MA). Beclin-1 knockdown and bafilomycin A1 (BafA1)-based LC3B II accumulation assays were used to assess the functional contribution of autophagy and autophagic flux. Rapamycin; 3-methyladenine; Atropine AMPK/mTOR/P70S6K; Beclin-1; LC3B Guinea pig; Human Excess mTOR-regulated scleral autophagy promotes myopia: rapamycin worsened it, 3-MA reduced it; atropine's benefit involved suppressing autophagy" }, { "sid": "SCH2025", "entities": [ "bi-steric-mtorc1-selective-inhibitors", "mtorc1", "mtorc2", "s6k1", "4e-bp1" ], "authors": [ "justin-g-meyerowitz", "howard-a-burris", "yu-chi-yang", "alison-m-schram" ], "author_names": [ "Justin G. Meyerowitz", "Howard A Burris", "Yu Chi Yang", "Alison M. Schram" ], "text": "PI3K/mTOR pathway activation drives oncogenesis and progression of many cancers. RMC-5552 is a bi-steric, mTOR complex 1 (mTORC1)-selective inhibitor that potently inhibits phosphorylation of key mTORC1 substrates eukaryotic initiation factor 4E-binding protein-1 and S6 kinase and exhibits selectivity for mTORC1 over mTORC2. In this study, we report results from a first-in-human, dose-escalation study of RMC-5552 in patients with advanced solid tumors (NCT04774952). RMC-5552 (bi-steric mTORC1-selective inhibitor), 1.6-16mg IV weekly mTORC1 (4E-BP1, S6K1), sparing mTORC2 Human 64% disease control rate (uncontrolled); low (4%) treatment-related hyperglycemia, consistent with mTORC2 sparing" }, { "sid": "JAC2004", "entities": [ "actin-cytoskeleton" ], "authors": [ "michael-n-hall", "estela-jacinto", "robbie-loewith", "markus-a-ruegg" ], "author_names": [ "Michael N. Hall", "Estela Jacinto", "Robbie Loewith", "Markus A. Rüegg" ], "text": "The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of cell growth. In budding yeast, TOR is found in structurally and functionally distinct protein complexes: TORC1 and TORC2. A mammalian counterpart of TORC1 (mTORC1) has been described, but it is not known whether TORC2 is conserved in mammals. Here, we report that a mammalian counterpart of TORC2 (mTORC2) also exists. mTORC2 contains mTOR, mLST8 and mAVO3, but not raptor. Like yeast TORC2, mTORC2 is rapamycin insensitive and seems to function upstream of Rho GTPases to regulate the actin cytoskeleton. Biochemical/genetic (mTORC2/rictor) mTORC2 / actin cytoskeleton Mammalian cells mTORC2 (mTOR-mLST8-rictor) controls the actin cytoskeleton and is rapamycin-insensitive" }, { "sid": "ROD2016", "entities": [ "mtor" ], "authors": [ "kevan-m-shokat", "vanessa-s-rodrik-outmezguine", "neal-rosen", "sabina-cosulich" ], "author_names": [ "Kevan M. Shokat", "Vanessa S. Rodrik-Outmezguine", "Neal Rosen", "Sabina Cosulich" ], "text": "Precision medicines exert selective pressure on tumour cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next-generation therapies to treat the evolving cancer. The PIK3CA-AKT-mTOR pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small-molecule inhibitors that target various nodes in the pathway. New-generation bivalent mTOR inhibitor (RapaLink-type) mTOR (resistance mutations) Cancer cells; mouse A bivalent next-generation inhibitor overcomes mTOR resistance mutations that defeat first- and second-generation drugs" }, { "sid": "TSU2013", "entities": [ "flcn-fnip1-2" ], "authors": [ "david-m-sabatini", "roberto-zoncu", "lynne-chantranupong", "liron-bar-peled", "tim-wang", "choah-kim", "eric-spooner", "zhi-yang-tsun" ], "author_names": [ "David M. Sabatini", "Roberto Zoncu", "Lynne Chantranupong", "Liron Bar-Peled", "Tim Wang", "Choah Kim", "Eric Spooner", "Zhi-Yang Tsun" ], "text": "The mTORC1 kinase is a master growth regulator that senses numerous environmental cues, including amino acids. The Rag GTPases interact with mTORC1 and signal amino acid sufficiency by promoting the translocation of mTORC1 to the lysosomal surface, its site of activation. The Rags are unusual GTPases in that they function as obligate heterodimers, which consist of RagA or B bound to RagC or D. While the loading of RagA/B with GTP initiates amino acid signaling to mTORC1, the role of RagC/D is unknown. Biochemical/genetic (FLCN) FLCN / RagC-RagD / mTORC1 Mammalian cells The folliculin tumor suppressor is a GAP for RagC/D that signals amino-acid levels to mTORC1" }, { "sid": "DEY2008", "entities": [ "tsc1-tsc2", "mtorc1", "hypoxia", "redd1-ddit4", "tumor-growth" ], "authors": [ "m-phillip-deyoung", "leif-w-ellisen" ], "author_names": [ "M. Phillip DeYoung", "Leif W. Ellisen" ], "text": "Hypoxia induces rapid and dramatic changes in cellular metabolism, in part through inhibition of target of rapamycin (TOR) kinase complex 1 (TORC1) activity. Genetic studies have shown the tuberous sclerosis tumor suppressors TSC1/2 and the REDD1 protein to be essential for hypoxia regulation of TORC1 activity in Drosophila and in mammalian cells. The molecular mechanism and physiologic significance of this effect of hypoxia remain unknown. Hypoxia (1% O2); REDD1 and TSC2 knockout and 14-3-3-binding mutants REDD1 -> TSC2/14-3-3 -> mTORC1 Mouse embryonic fibroblasts, human cell lines, nude-mouse xenografts, human tumour samples Hypoxia inhibits mTORC1 by REDD1-driven release of TSC2 from 14-3-3; REDD1 loss promotes tumour growth" }, { "sid": "MAN2016", "entities": [ "lysosome", "v-atpase", "raptor", "leucine", "sestrin2", "mtorc1" ], "authors": [ "roberto-zoncu", "nicholas-t-ktistakis", "maria-manifava" ], "author_names": [ "Roberto Zoncu", "Nicholas T. Ktistakis", "Maria Manifava" ], "text": "Amino acids are essential activators of mTORC1 via a complex containing RAG GTPases, RAGULATOR and the vacuolar ATPase. Sensing of amino acids causes translocation of mTORC1 to lysosomes, an obligate step for activation. To examine the spatial and temporal dynamics of this translocation, we used live imaging of the mTORC1 component RAPTOR and a cell permeant fluorescent analogue of di-leucine methyl ester. Translocation to lysosomes is a transient event, occurring within 2 min of aa addition and peaking within 5 min. Amino acid add-back mTORC1 / RAPTOR lysosomal translocation Human cell line mTORC1 lysosomal translocation is transient (2-5 min) and precedes target phosphorylation" }, { "sid": "SHO2010", "entities": [ "ribosome-biogenesis", "maf1" ], "authors": [ "boris-shor", "ker-yu" ], "author_names": [ "Boris Shor", "Ker Yu" ], "text": null }, { "sid": "LEI2018", "entities": [ "arginine", "slc38a9" ], "authors": [ "tamir-gonen", "hsiang-ting-lei" ], "author_names": [ "Tamir Gonen", "Hsiang-Ting Lei" ], "text": "Recent advances in understanding intracellular amino acid transport and mechanistic target of rapamycin complex 1 (mTORC1) signaling shed light on solute carrier 38, family A member 9 (SLC38A9), a lysosomal transporter responsible for the binding and translocation of several essential amino acids. Here we present the first crystal structure of SLC38A9 from Danio rerio in complex with arginine. As captured in the cytosol-open state, the bound arginine was locked in a transitional state stabilized by transmembrane helix 1 (TM1) of drSLC38A9, which was anchored at the groove between TM5 and TM7. Structural (crystal structure of SLC38A9) SLC38A9 / arginine / mTORC1 Structure; in vitro (Danio rerio) First crystal structure of arginine-bound SLC38A9 (cytosol-open state), the lysosomal amino-acid transporter/sensor for mTORC1" }, { "sid": "BAS2012", "entities": [ "everolimus", "breast-cancer", "mtorc1" ], "authors": [ "gabriel-n-hortobagyi", "martine-j-piccart", "jose-baselga", "mario-campone", "ines-deleu", "michael-gnant", "yoshinori-ito", "fabienne-lebrun", "shinzaburo-noguchi", "alejandra-perez", "kathleen-pritchard", "hope-rugo", "david-lebwohl", "tarek-sahmoud" ], "author_names": [ "Gabriel N. Hortobagyi", "Martine J. Piccart", "José Baselga", "Mario Campone", "Ines Deleu", "Michael Gnant", "Yoshinori Ito", "Fabienne Lebrun", "Shinzaburo Noguchi", "Alejandra Perez", "Kathleen Pritchard", "Hope Rugo", "David Lebwohl", "Tarek Sahmoud" ], "text": "Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity. Everolimus + exemestane mTORC1 Human – phase 3 RCT (BOLERO-2, n=724, HR+ breast cancer) Adding everolimus to exemestane improved progression-free survival in HR+ advanced breast cancer Everolimus 10 mg once daily + exemestane vs placebo + exemestane; oral; international double-blind phase 3, 2:1 randomization (BOLERO-2). 724 women, 189 centers, 24 countries (485 everolimus-combination / 239 control); PK subgroup n=80. Primary endpoint progression-free survival; adding everolimus significantly improved PFS vs exemestane alone (log-rank, stratified). Kaplan-Meier estimates beyond week 36 to be interpreted with caution (few patients at risk, limited follow-up)." }, { "sid": "SHE2019", "entities": [], "authors": [ "david-m-sabatini", "kuang-shen", "kacper-b-rogala", "rick-k-huang" ], "author_names": [ "David M. Sabatini", "Kuang Shen", "Kacper B. Rogala", "Rick K. Huang" ], "text": "mTORC1 controls anabolic and catabolic processes in response to nutrients through the Rag GTPase heterodimer, which is regulated by multiple upstream protein complexes. One such regulator, FLCN-FNIP2, is a GTPase activating protein (GAP) for RagC/D, but despite its important role, how it activates the Rag GTPase heterodimer remains unknown. We used cryo-EM to determine the structure of FLCN-FNIP2 in a complex with the Rag GTPases and Ragulator. FLCN-FNIP2 adopts an extended conformation with two pairs of heterodimerized domains. Structural (cryo-EM) FLCN-FNIP2 / Rag / Ragulator / mTORC1 Cryo-EM structure Cryo-EM structure reveals how FLCN-FNIP2 engages the Rag GTPase heterodimer and Ragulator" }, { "sid": "KAM2000", "entities": [ "ulk1", "rapamycin", "mtor", "autophagy" ], "authors": [ "yoshiaki-kamada", "yoshinori-ohsumi" ], "author_names": [ "Yoshiaki Kamada", "Yoshinori Ohsumi" ], "text": "Autophagy is a membrane trafficking to vacuole/lysosome induced by nutrient starvation. In Saccharomyces cerevisiae, Tor protein, a phosphatidylinositol kinase-related kinase, is involved in the repression of autophagy induction by a largely unknown mechanism. Here, we show that the protein kinase activity of Apg1 is enhanced by starvation or rapamycin treatment. In addition, we have also found that Apg13, which binds to and activates Apg1, is hyperphosphorylated in a Tor-dependent manner, reducing its affinity to Apg1. Nitrogen starvation; rapamycin Tor - Apg13 - Apg1 (ULK1 orthologue) kinase complex Saccharomyces cerevisiae Tor keeps Apg13 hyperphosphorylated, preventing Apg1 activation; starvation or rapamycin raises Apg1 kinase activity and induces autophagy." }, { "sid": "LAI2026", "entities": [ "rapamycin", "immune-function" ], "authors": [ "meiling-lai", "yu-xuan-lyu" ], "author_names": [ "Meiling Lai", "Yu-Xuan Lyu" ], "text": "Canine models are invaluable for translational geroscience, but natural sex-associated immune aging remains under investigated. Here, we characterize the age-associated hematologic and serum cytokine profiles in a controlled cross-sectional cohort of 80 intact laboratory Beagles spanning 1 to 11 years of age. Canine immune aging is heterogeneous and non-linear. While several absolute leukocyte counts declined with age before rising again in geriatric dogs, serum cytokines exhibited distinct, sex-stratified patterns." }, { "sid": "TAR2014", "entities": [ "longevity", "rapamycin", "mtor", "mtorc1" ], "authors": [ "adam-b-salmon", "elizabeth-fernandez", "corinna-ross", "suzette-tardif" ], "author_names": [ "Adam B. Salmon", "Elizabeth Fernandez", "Corinna Ross", "Suzette Tardif" ], "text": "This report is the first description of dosing procedures, pharmacokinetics, biochemical action, and general tolerability of the antiaging drug rapamycin in the common marmoset, a small and short-lived monkey. Eudragit-encapsulated rapamycin was given orally to trained marmosets in a short-term (3 weeks) and a long-term (14 months) study. Circulating trough rapamycin levels (mean = 5.2 ng/mL; 1.93-10.73 ng/mL) achieved at roughly 1.0 mg/kg/day was comparable to those reported in studies of rodents and within the therapeutic range for humans. Oral Eudragit-encapsulated rapamycin, roughly 1.0 mg/kg/day, 3 weeks (short-term) and 14 months (long-term) mTORC1 signalling (phospho-rpS6/total rpS6) in liver and adipose tissue Common marmoset (Callithrix jacchus) Blood levels in the human therapeutic range; reduced mTORC1 signalling in 6 of 8 long-term animals; well tolerated" }, { "sid": "KAE2005", "entities": [ "longevity", "mtor" ], "authors": [ "matt-kaeberlein", "brian-k-kennedy", "stanley-fields" ], "author_names": [ "Matt Kaeberlein", "Brian K. Kennedy", "Stanley Fields" ], "text": "Calorie restriction increases life span in many organisms, including the budding yeast Saccharomyces cerevisiae. From a large-scale analysis of 564 single-gene-deletion strains of yeast, we identified 10 gene deletions that increase replicative life span. Six of these correspond to genes encoding components of the nutrient-responsive TOR and Sch9 pathways. Calorie restriction of tor1D or sch9D cells failed to further increase life span and, like calorie restriction, deletion of either SCH9 or TOR1 increased life span independent of the Sir2 histone deacetylase. Genetic (tor1Δ, sch9Δ) + caloric restriction TOR / Sch9 Yeast (S. cerevisiae) Deleting TOR or Sch9 extends yeast replicative lifespan, overlapping with the caloric-restriction effect" }, { "sid": "SAX2015", "entities": [ "leucine", "sestrin2", "mtorc1" ], "authors": [ "david-m-sabatini", "robert-a-saxton", "lynne-chantranupong", "rachel-l-wolfson", "tim-wang", "michael-e-pacold", "kevin-e-knockenhauer", "thomas-u-schwartz" ], "author_names": [ "David M. Sabatini", "Robert A. Saxton", "Lynne Chantranupong", "Rachel L. Wolfson", "Tim Wang", "Michael E. Pacold", "Kevin E. Knockenhauer", "Thomas U. Schwartz" ], "text": "Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. Structural (crystal structure of Sestrin2-leucine) Sestrin2 / leucine / GATOR2 / mTORC1 Human cell lines (crystal structure) Structure of Sestrin2 bound to leucine reveals the leucine-sensing mechanism for the mTORC1 pathway" }, { "sid": "ARR2016", "entities": [ "longevity", "rapamycin" ], "authors": [ "dudley-w-lamming", "sebastian-i-arriola-apelo", "emma-l-baar", "nicole-e-cummings", "cassidy-p-pumper" ], "author_names": [ "Dudley W. Lamming", "Sebastian I. Arriola Apelo", "Emma L. Baar", "Nicole E. Cummings", "Cassidy P. Pumper" ], "text": "Inhibition of the mTOR (mechanistic target of rapamycin) signaling pathway by the FDA-approved drug rapamycin promotes life span in numerous model organisms and delays age-related disease in mice. However, the utilization of rapamycin as a therapy for age-related diseases will likely prove challenging due to the serious metabolic and immunological side effects of rapamycin in humans. Rapamycin, intermittent (2 mg/kg every 5 days) mTOR Mouse (C57BL/6J) Intermittent rapamycin started at 20 months of age extended female lifespan 2 mg/kg rapamycin every 5 days, starting as late as 20 months of age (route not stated in abstract)." }, { "sid": "SHIMADA2026", "entities": [ "placental-nutrient-sensing", "oxidative-phosphorylation", "mtorc1", "4e-bp1" ], "authors": [ "fredrick-j-rosario", "hiroshi-shimada" ], "author_names": [ "Fredrick J. Rosario", "Hiroshi Shimada" ], "text": "Male fetuses generally grow faster in utero and are heavier at birth than females, whereas perinatal mortality and morbidity are often higher in boys. Placentas were collected from 46 women with uncomplicated pregnancies delivering appropriate-for-gestational-age infants (23 female, 23 male). In homogenates of male placentas, phosphorylation of S6RP (Ser235/236) was increased and total 4E-BP1 protein expression reduced compared with female placentas, indicating enhanced mTORC1 signalling. None (observational comparison by fetal sex) mTORC1; S6RP; 4E-BP1; System A amino acid transport Human Higher mTORC1 activity, amino acid transport and mitochondrial respiratory capacity in male placentas; higher birth-weight-to-placental-weight ratio" }, { "sid": "LEE2010", "entities": [ "age-related-pathology", "sestrin2" ], "authors": [ "andrei-v-budanov", "michael-karin", "jun-hee-lee" ], "author_names": [ "Andrei V. Budanov", "Michael Karin", "Jun Hee Lee" ], "text": "Sestrins are conserved proteins that accumulate in cells exposed to stress, potentiate adenosine monophosphate-activated protein kinase (AMPK), and inhibit activation of target of rapamycin (TOR). We show that the abundance of Drosophila sestrin (dSesn) is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun amino-terminal kinase and transcription factor Forkhead box O (FoxO). dSesn loss of function; rapamycin; AMPK activation Sestrin -> AMPK/TOR feedback loop Drosophila Sestrin loss causes age-related muscle, cardiac and metabolic pathology in flies; rescued by TOR inhibition or AMPK activation" }, { "sid": "CHA2014", "entities": [], "authors": [ "david-m-sabatini", "robert-a-saxton", "lynne-chantranupong", "rachel-l-wolfson", "liron-bar-peled", "steven-p-gygi", "sonia-m-scaria", "jose-m-orozco", "eric-spooner" ], "author_names": [ "David M. Sabatini", "Robert A. Saxton", "Lynne Chantranupong", "Rachel L. Wolfson", "Liron Bar-Peled", "Steven P. Gygi", "Sonia M. Scaria", "Jose M. Orozco", "Eric Spooner" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a major regulator of cell growth that responds to numerous environmental cues. A key input is amino acids, which act through the heterodimeric Rag GTPases (RagA or RagB bound to RagC or RagD) in order to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. GATOR2 is a complex of unknown function that positively regulates mTORC1 signaling by acting upstream of or in parallel to GATOR1, which is a GTPase-activating protein (GAP) for RagA or RagB and an inhibitor of the amino-acid-sensing pathway. Biochemical/genetic (Sestrins) Sestrins / GATOR2 / Rag / mTORC1 Mammalian cells Sestrins bind GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1" }, { "sid": "EHN2008", "entities": [ "tsc1-tsc2", "cognition", "rapamycin", "tuberous-sclerosis-complex" ], "authors": [ "dan-ehninger", "david-j-kwiatkowski", "alcino-j-silva" ], "author_names": [ "Dan Ehninger", "David J. Kwiatkowski", "Alcino J. Silva" ], "text": "Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Rapamycin (in Tsc2+/- mice) mTORC1 / TSC2 Mouse (Tsc2+/-) mTOR inhibition reverses learning and memory deficits in a tuberous sclerosis mouse model" }, { "sid": "KUO1992", "entities": [ "s6k1" ], "authors": [ "john-blenis", "gerald-r-crabtree" ], "author_names": [ "John Blenis", "Gerald R. Crabtree" ], "text": "The macrolide rapamycin induces cell cycle G1 arrest in yeast and in mammalian cells, which suggests that an evolutionarily conserved, rapamycin-sensitive pathway may regulate entry into S phase. In mammals, rapamycin inhibits interleukin-2 receptor-induced S phase entry and subsequent T-cell proliferation, resulting in immunosuppression. Here we show that interleukin-2 selectively stimulates the phosphorylation and activation of p70 S6 kinase but not the erk-encoded MAP kinases and rsk-encoded S6 kinases. Rapamycin p70 S6 kinase (IL-2 signaling) T cells; in vitro Rapamycin selectively inhibits IL-2-induced activation of p70 S6 kinase (basis of immunosuppression)" }, { "sid": "GUE2009", "entities": [ "prostate-cancer", "pten" ], "authors": [ "david-m-sabatini", "david-a-guertin" ], "author_names": [ "David M. Sabatini", "David A. Guertin" ], "text": "mTOR complex 2 (mTORC2) contains the mammalian target of rapamycin (mTOR) kinase and the Rictor regulatory protein and phosphorylates Akt. Whether this function of mTORC2 is critical for cancer progression is unknown. Here, we show that transformed human prostate epithelial cells lacking PTEN require mTORC2 to form tumors when injected into nude mice. Furthermore, we find that Rictor is a haploinsufficient gene and that deleting one copy protects Pten heterozygous mice from prostate cancer. Genetic (Rictor/mTORC2 deletion; Pten loss) mTORC2 (Rictor) / Akt Mouse (prostate) mTORC2 is required for prostate cancer driven by Pten loss; Rictor is haploinsufficient not stated Pten +/- mice (n=9), Pten +/- Rictor +/- mice (n=10), wild-type controls (n=10) for prostate cancer analysis. PC-3 xenografts: shLuc-expressing cells formed tumors of 312 mm 3; shRictor 1 and shRictor 2 cells formed tumors of 10.1 mm 3 (p=0.01) and 39.6 mm 3 (p=0.01). Ki67 positive cells: 2.3% in Pten +/- Rictor +/- vs 10.7% in Pten +/- (p < 0.001). Specific inhibitors of mTORC2 are unavailable, precluding pharmacological testing. Differences in genetic background between Rictor +/- mice and mtor/Raptor/mlst8 heterozygous mice precluded prostate cancer analysis in some cohorts." }, { "sid": "INO2006", "entities": [ "tsc1-tsc2", "rapamycin", "ampk", "tumor-growth" ], "authors": [ "kun-liang-guan", "ken-inoki" ], "author_names": [ "Kun-Liang Guan", "Ken Inoki" ], "text": "Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving beta-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Biochemical/genetic (AMPK, GSK3, TSC2) TSC2 / AMPK / GSK3 / mTOR Mammalian cells AMPK and GSK3 coordinately phosphorylate TSC2 to integrate Wnt and energy signals controlling growth" }, { "sid": "CAN2002", "entities": [ "akt-pkb", "pi3k" ], "authors": [ "lewis-c-cantley" ], "author_names": [ "Lewis C. Cantley" ], "text": "Phosphorylated lipids are produced at cellular membranes during signaling events and contribute to the recruitment and activation of various signaling components. The role of phosphoinositide 3-kinase (PI3K), which catalyzes the production of phosphatidylinositol-3,4,5-trisphosphate, in cell survival pathways; the regulation of gene expression and cell metabolism; and cytoskeletal rearrangements are highlighted. The PI3K pathway is implicated in human diseases including diabetes and cancer, and understanding the intricacies of this pathway may provide new avenues for therapuetic intervention. Not applicable (review) PI3K / PIP3 (upstream of Akt-mTOR) Review Reviews the PI3K pathway in cell survival, metabolism, gene expression and cytoskeletal control" }, { "sid": "CUN2007", "entities": [ "rapamycin", "mitochondrial-biogenesis", "raptor", "pgc-1alpha-yy1", "oxidative-phosphorylation", "mtorc1" ], "authors": [ "pere-puigserver", "vamsi-k-mootha", "john-t-cunningham" ], "author_names": [ "Pere Puigserver", "Vamsi K. Mootha", "John T. Cunningham" ], "text": "Transcriptional complexes that contain peroxisome-proliferator-activated receptor coactivator (PGC)-1alpha control mitochondrial oxidative function to maintain energy homeostasis in response to nutrient and hormonal signals. An important component in the energy and nutrient pathways is mammalian target of rapamycin (mTOR), a kinase that regulates cell growth, size and survival. However, it is unknown whether and how mTOR controls mitochondrial oxidative activities. Here we show that mTOR is necessary for the maintenance of mitochondrial oxidative function. Genetic/pharmacologic (mTOR; rapamycin) mTOR / YY1 / PGC-1α Skeletal muscle cells + tissue mTOR controls mitochondrial oxidative function through a YY1-PGC-1α transcriptional complex" }, { "sid": "YUX2010", "entities": [ "lysosome", "mtorc1", "autophagy" ], "authors": [ "michael-j-lenardo", "li-yu" ], "author_names": [ "Michael J. Lenardo", "Li Yu" ], "text": "Autophagy is an evolutionarily conserved process by which cytoplasmic proteins and organelles are catabolized. During starvation, the protein TOR (target of rapamycin), a nutrient-responsive kinase, is inhibited, and this induces autophagy. In autophagy, double-membrane autophagosomes envelop and sequester intracellular components and then fuse with lysosomes to form autolysosomes, which degrade their contents to regenerate nutrients. Genetic/pharmacologic (mTOR reactivation) mTOR / autophagic lysosome reformation Mammalian cells Reactivation of mTOR terminates autophagy and drives reformation of lysosomes (ALR)" }, { "sid": "GOR2026", "entities": [ "rapamycin", "metformin" ], "authors": [], "author_names": [], "text": "Aging is a systems-level process linking metabolic dysfunction, inflammation, impaired repair, frailty, and multimorbidity, whereas existing pharmacological strategies usually optimize disease-specific endpoints such as weight loss or HbA1c rather than aging-related trajectories. We developed an SBML-compliant quantitative systems pharmacology (QSP) model in which aging is represented as a dynamic, pharmacologically modifiable endpoint. Rapamycin, metformin, SGLT2 inhibitors, GLP-1 receptor agonists (combination therapy, in silico) mTOR/aging pathway (rapamycin arm) within a multi-drug QSP model Human (in silico model calibrated to human trial data) Predicts GLP-1RA+SGLT2i+rapamycin as the optimal combination for aging-related outcomes (frailty, biological age gap), distinct from the best metabolic-outcome combination" }, { "sid": "MAJ2004", "entities": [ "hif-1alpha", "prostate-cancer", "pten" ], "authors": [ "william-r-sellers", "james-brugarolas", "pradip-k-majumder" ], "author_names": [ "William R. Sellers", "James Brugarolas", "Pradip K. Majumder" ], "text": "Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. mTOR inhibition (rapamycin) mTOR / Akt / HIF-1 Mouse (prostate, AKT1 transgenic) mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia via apoptotic and HIF-1-dependent pathways" }, { "sid": "DEL2011", "entities": [ "t-cell-differentiation", "rictor", "immune-function", "mtorc1", "mtorc2", "rheb" ], "authors": [ "jonathan-d-powell", "greg-m-delgoffe", "maureen-r-horton", "kristen-n-pollizzi", "adam-t-waickman" ], "author_names": [ "Jonathan D. Powell", "Greg M. Delgoffe", "Maureen R. Horton", "Kristen N. Pollizzi", "Adam T. Waickman" ], "text": "The kinase mTOR has emerged as an important regulator of the differentiation of helper T cells. Here we demonstrate that differentiation into the T(H)1 and T(H)17 subsets of helper T cells was selectively regulated by signaling from mTOR complex 1 (mTORC1) that was dependent on the small GTPase Rheb. Rheb-deficient T cells failed to generate T(H)1 and T(H)17 responses in vitro and in vivo and did not induce classical experimental autoimmune encephalomyelitis (EAE). However, they retained their ability to become T(H)2 cells. Genetic (Rheb/mTORC1; mTORC2) mTORC1 (Rheb) & mTORC2 Mouse mTORC1 (Rheb-dependent) selectively drives Th1/Th17 differentiation while mTORC2 controls Th2 not stated not stated Nearly 60% (on average) of MOG-immunized T- Rheb −/− mice developed 'non-classical EAE'. not stated" }, { "sid": "JIN2026", "entities": [ "p-glycoprotein-abcb1", "eif4a", "reactive-oxygen-species" ], "authors": [ "peng-jin", "jiayun-he" ], "author_names": [ "Peng Jin", "Jiayun He" ], "text": "Cells face a temporal gap in oxidative stress adaptation, in which acute insults require rapid protein synthesis before transcriptional responses are fully established. Low-dose glucosamine (GlcN) induces a transient intracellular oxidation-sensitive response and activates redox-sensitive PI3K-AKT-mTORC1 signaling, leading to increased P-glycoprotein (P-gp) abundance without a detectable increase in total ABCB1 mRNA. Glucosamine; redox stress mTORC1 / eIF4A / 4E-BP1 Cell line mTOR-eIF4A selectively upregulates P-gp translation under oxidative stress; multidrug resistance" }, { "sid": "BAR2016", "entities": [ "mlst8", "raptor", "mtor" ], "authors": [ "roger-l-williams", "alex-berndt", "christopher-johnson", "domagoj-baretic" ], "author_names": [ "Roger L. Williams", "Alex Berndt", "Christopher Johnson", "Domagoj Baretić" ], "text": "The target of rapamycin (Tor) is a Ser/Thr protein kinase that regulates a range of anabolic and catabolic processes. Tor is present in two complexes, TORC1 and TORC2, in which the Tor-Lst8 heterodimer forms a common sub-complex. We have determined the cryo-electron microscopy (EM) structure of Tor bound to Lst8. Two Tor-Lst8 heterodimers assemble further into a dyad-symmetry dimer mediated by Tor-Tor interactions. Structural (cryo-EM) TOR / Lst8 Cryo-EM structure Tor-Lst8 heterodimers assemble into a dyad-symmetric dimer via Tor-Tor interactions (N-terminal solenoid)" }, { "sid": "PIR2026", "entities": [ "longevity", "rapamycin", "mtorc1" ], "authors": [ "denisa-pirscoveanu", "aurel-popa-wagner" ], "author_names": [ "Denisa Pirscoveanu", "Aurel Popa-Wagner" ], "text": "Interventions targeting conserved aging pathways (including TOR/mTOR signaling) markedly extend lifespan in model organisms, yet efficacy declines with organismal complexity. Synthesizing data from C. elegans, Drosophila, and rodent models, the authors propose that simple organisms are governed by high-leverage pathways, while in mammals aging emerges from distributed, multi-tissue regulatory systems with redundancy, feedback, and competing physiological constraints. TOR/mTOR pathway interventions (rapamycin and analogues) TOR/mTOR signaling; conserved aging pathways Multi-species Lifespan extension via mTOR inhibition declines with organismal complexity; mammals show system-level buffering that limits single-pathway leverage" }, { "sid": "WANG2026B", "entities": [ "rictor", "lung-cancer-nsclc-luad", "pdcd4", "pfkfb3", "mtorc2" ], "authors": [ "hsin-sheng-yang", "qing-wang" ], "author_names": [ "Hsin-Sheng Yang", "Qing Wang" ], "text": "Programmed cell death 4 (Pdcd4) is a tumour suppressor and inhibitor of protein translation with emerging translation-independent functions. Pdcd4 suppresses tumorigenesis by disrupting mTORC2 complex formation through binding Rictor. Deletion mapping and site-directed mutagenesis defined the Rictor-binding domain of Pdcd4 and identified residues R105, K108 and R110 as critical. Co-immunoprecipitation and in vitro kinase assays showed that Pdcd4 binding to Rictor disrupted mTORC2 assembly and inhibited its kinase activity. Pdcd4 overexpression / knockdown; Rictor-binding-deficient mutants Rictor; mTORC2; PFKFB3 Human cell lines; mouse xenograft Disrupted mTORC2 assembly and kinase activity, degraded PFKFB3, suppressed glycolysis and tumour growth" }, { "sid": "KEL2024", "entities": [ "mitophagy", "rapamycin", "p62-sqstm1", "cellular-senescence" ], "authors": [ "viktor-i-korolchuk", "bernadette-carroll", "satomi-miwa", "thomas-von-zglinicki", "penny-lovat", "glyn-nelson", "george-kelly" ], "author_names": [ "Viktor I. Korolchuk", "Bernadette Carroll", "Satomi Miwa", "Thomas von Zglinicki", "Penny Lovat", "Glyn Nelson", "George Kelly" ], "text": "Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Mitophagy inhibition; rapamycin; NAD precursors; p62-targeting small molecule PINK1/Parkin/p62 basal mitophagy Primary human cells (senescent and naturally aged) Basal mitophagy shuts down in senescence; blocking it induces senescence and reactivating it is needed for rapamycin's anti-senescence effect." }, { "sid": "RUS2013", "entities": [ "torin1", "ulk1", "autophagy", "beclin-1-becn1", "vps34-pik3c3" ], "authors": [ "kun-liang-guan", "joungmok-kim", "ryan-c-russell" ], "author_names": [ "Kun-Liang Guan", "Joungmok Kim", "Ryan C. Russell" ], "text": "Autophagy is the primary cellular catabolic program activated in response to nutrient starvation. Initiation of autophagy, particularly by amino-acid withdrawal, requires the ULK kinases. Despite its pivotal role in autophagy initiation, little is known about the mechanisms by which ULK promotes autophagy. Here we describe a molecular mechanism linking ULK to the pro-autophagic lipid kinase VPS34. Following amino-acid starvation or mTOR inhibition, the activated ULK1 phosphorylates Beclin-1 on Ser 14, thereby enhancing the activity of the ATG14L-containing VPS34 complexes. Amino-acid starvation or Torin1; genetic loss of ULK activity (ULK1-/- plus ULK2 knockdown, FIP200-/-); Beclin-1 S14A/S14D knock-down-reconstitution; C. elegans bec-1 S6A transgene ULK1 -> Beclin-1 Ser14 -> ATG14L-VPS34 complex Mouse and human cells; C. elegans mTOR inhibition increased ULK1-dependent Beclin-1 S14 phosphorylation and ATG14L-VPS34 activity; blocking this phosphorylation reduced starvation-induced autophagy" }, { "sid": "TID2026", "entities": [ "mtor" ], "authors": [ "jack-m-parent", "andrew-m-tidball" ], "author_names": [ "Jack M. Parent", "Andrew M. Tidball" ], "text": "Focal cortical dysplasia (FCD) is a common cause of focal epilepsy that typically results from brain mosaic mutations in the mTOR cell signaling pathway. To identify new potential FCD genes, we developed an in vitro CRISPRi screen in human neurons and used FACS enrichment based on the FCD biomarker, phosphorylated S6 ribosomal protein (pS6). Using whole-genome (110,000 gRNAs) and candidate (129 gRNAs) libraries, we discovered 6 new genes in which loss of function significantly increases pS6 levels: LRRC4, EIF3A, TSN, HIP1, PIK3R3, and URI1. CRISPR interference (CRISPRi) knockdown; FACS enrichment on phospho-S6 (pS6); GDNF withdrawal Negative regulators of neuronal mTOR signalling (LRRC4, EIF3A, TSN, HIP1, PIK3R3, URI1) Human iPSC-derived neurons (iNeurons) A genome-wide CRISPRi screen in human iNeurons identifies six genes whose loss raises pS6; two of them (PIK3R3, HIP1) raise phosphorylation throughout the AKT/mTOR/S6 axis, and knockdown of all six makes mTOR signalling resistant to GDNF withdrawal" }, { "sid": "GUE2022", "entities": [ "ribosome-biogenesis", "mtorc1" ], "authors": [ "andreas-milias-argeitis", "paolo-guerra" ], "author_names": [ "Andreas Milias-Argeitis", "Paolo Guerra" ], "text": "Recent studies have revealed that the growth rate of budding yeast and mammalian cells varies during the cell cycle. By linking a multitude of signals to cell growth, the highly conserved target of rapamycin complex 1 (TORC1) and protein kinase A (PKA) pathways are prime candidates for mediating the dynamic coupling between growth and division. However, measurements of TORC1 and PKA activity during the cell cycle are still lacking. None (constant conditions); upstream regulator mutants TORC1 / PKA Yeast TORC1/PKA output to ribosome biogenesis oscillates with the yeast cell cycle under constant conditions" }, { "sid": "LOE2002", "entities": [ "actin-cytoskeleton" ], "authors": [ "michael-n-hall", "estela-jacinto", "robbie-loewith" ], "author_names": [ "Michael N. Hall", "Estela Jacinto", "Robbie Loewith" ], "text": "The target of rapamycin (TOR) proteins in Saccharomyces cerevisiae, TOR1 and TOR2, redundantly regulate growth in a rapamycin-sensitive manner. TOR2 additionally regulates polarization of the actin cytoskeleton in a rapamycin-insensitive manner. We describe two functionally distinct TOR complexes. TOR Complex 1 (TORC1) contains TOR1 or TOR2, KOG1 (YHR186c), and LST8. TORC2 contains TOR2, AVO1 (YOL078w), AVO2 (YMR068w), AVO3 (YER093c), and LST8. Genetic/biochemical (TOR1/TOR2 complexes) TORC1 / TORC2 Yeast (S. cerevisiae) Defines two TOR complexes: TORC1 (rapamycin-sensitive, growth) and TORC2 (rapamycin-insensitive, actin)" }, { "sid": "BIS2008", "entities": [ "mtor" ], "authors": [ "john-j-bissler", "david-n-franz", "francis-x-mccormack", "lisa-young" ], "author_names": [ "John J. Bissler", "David N. Franz", "Francis X. McCormack", "Lisa Young" ], "text": "Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling. We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Sirolimus (rapamycin) mTOR Human – open-label trial (TSC/LAM) Sirolimus reduced angiomyolipoma volume during treatment; tumors regrew after stopping Oral sirolimus, 24-month non-randomized open-label trial (dose titrated to therapeutic trough); full text not retrievable via PMC. ~25 patients with TSC or sporadic LAM (full text unavailable; abstract-level). Sirolimus reduced angiomyolipoma volume (~50%) during treatment; tumors regrew after the drug was stopped. Non-randomized open-label; benefit not durable off-drug; full text not retrievable, so figures from abstract only." }, { "sid": "ZEN2008", "entities": [ "tsc1-tsc2", "rapamycin", "mtorc1", "tuberous-sclerosis-complex" ], "authors": [ "ling-hui-zeng", "michael-wong" ], "author_names": [ "Ling-Hui Zeng", "Michael Wong" ], "text": "Tuberous sclerosis complex (TSC) represents one of the most common genetic causes of epilepsy. TSC gene inactivation leads to hyperactivation of the mammalian target of rapamycin signaling pathway, raising the intriguing possibility that mammalian target of rapamycin inhibitors might be effective in preventing or treating epilepsy in patients with TSC. Mice with conditional inactivation of the Tsc1 gene primarily in glia (Tsc1(GFAP)CKO mice) develop glial proliferation, progressive epilepsy, and premature death. Rapamycin vs vehicle, early (from P14) or late (from 6 weeks) mTORC1 Mouse Prevented (early) or suppressed (late) epilepsy and prolonged survival; reduced phospho-S6, astrogliosis, neuronal disorganisation" }, { "sid": "FER2026", "entities": [ "tfeb", "rag-gtpases", "mtorc1", "tuberous-sclerosis-complex", "flcn-fnip1-2", "tumor-growth", "gator1" ], "authors": [ "andrea-ballabio", "marco-ferniani", "alessia-calcagni", "tuong-huynh" ], "author_names": [ "Andrea Ballabio", "Marco Ferniani", "Alessia Calcagnì", "Tuong Huynh" ], "text": "Birt-Hogg-Dubé (BHD) and Tuberous Sclerosis (TSC) are inherited cancer syndromes associated with kidney cystogenesis and tumorigenesis and caused by mutations of the folliculin (FLCN) and TSC1/2 genes, respectively. We and others previously showed that Transcription Factors EB (TFEB) and E3 (TFE3) are the main drivers of the kidney phenotypes observed in mouse models of these conditions. These transcription factors are also responsible for the feedback hyperactivation of the mechanistic Target of Rapamycin Complex 1 (mTORC1), a known tumorigenic factor. Kidney-specific Depdc5, RagC and Flcn/RagC conditional knockouts mTORC1 vs TFEB/TFE3 in kidney cystogenesis Mouse (kidney) mTORC1 hyperactivation is a key driver of kidney cysts and tumours; constitutive TFEB/TFE3 activity accelerates the pathology." }, { "sid": "RAO2026", "entities": [ "cisplatin", "slc7a5-lat1", "mtor", "leucine", "autophagy" ], "authors": [ "xiaodong-feng", "pengcheng-rao" ], "author_names": [ "Xiaodong Feng", "Pengcheng Rao" ], "text": "Cisplatin-based chemotherapy responses are heterogeneous across cancers. Using genome-wide CRISPR-Cas9 knockout screening, the authors characterized regulators of cisplatin response and uncovered a counterintuitive finding: mTOR inhibition promotes cisplatin tolerance, contradicting the canonical view that PI3K-AKT-mTOR activation confers chemoresistance. Mechanistically, both mTOR suppression and cisplatin treatment converge to activate cytoprotective autophagy, enhancing cancer cell survival under therapeutic stress. mTOR inhibition; SLC7A5 knockout; leucine supplementation SLC7A5; mTOR; autophagy Human cell lines mTOR inhibition increased cisplatin tolerance via cytoprotective autophagy; leucine supplementation restored cisplatin sensitivity" }, { "sid": "SPA2023", "entities": [ "tfeb", "akt-pkb", "mtorc1", "protein-synthesis", "ampk" ], "authors": [ "john-g-albeck", "breanne-sparta" ], "author_names": [ "John G. Albeck", "Breanne Sparta" ], "text": "mTORC1 senses nutrients and growth factors and phosphorylates downstream targets, including the transcription factor TFEB, to coordinate metabolic supply and demand. These functions position mTORC1 as a central controller of cellular homeostasis, but the behavior of this system in individual cells has not been well characterized. Here, we provide measurements necessary to refine quantitative models for mTORC1 as a metabolic controller. Amino acids and insulin, alone, sequential or combined (live-cell stimulation) mTORC1 / TFEB Human cell line mTORC1-TFEB activity changes continuously and fluctuates with nutrient availability in single cells" }, { "sid": "ROC2012", "entities": [ "lysosomal-biogenesis" ], "authors": [ "shawn-m-ferguson", "agnes-roczniak-ferguson" ], "author_names": [ "Shawn M. Ferguson", "Agnes Roczniak-Ferguson" ], "text": "Lysosomes are the major cellular site for clearance of defective organelles and digestion of internalized material. Demand on lysosomal capacity can vary greatly, and lysosomal function must be adjusted to maintain cellular homeostasis. Here, we identified an interaction between the lysosome-localized mechanistic target of rapamycin complex 1 (mTORC1) and the transcription factor TFEB, which promotes lysosome biogenesis. Genetic/pharmacologic (mTORC1/TFEB) mTORC1 / TFEB Mammalian cells mTORC1 controls TFEB to transcriptionally regulate lysosome biogenesis and homeostasis" }, { "sid": "VAL2022", "entities": [ "gator2", "castor1", "sestrin2" ], "authors": [ "david-m-sabatini", "robert-a-saxton", "lynne-chantranupong", "kacper-b-rogala", "max-l-valenstein", "pranav-v-lalgudi", "xin-gu", "edward-j-brignole" ], "author_names": [ "David M. Sabatini", "Robert A. Saxton", "Lynne Chantranupong", "Kacper B. Rogala", "Max L. Valenstein", "Pranav V. Lalgudi", "Xin Gu", "Edward J. Brignole" ], "text": "Mechanistic target of rapamycin complex 1 (mTORC1) controls growth by regulating anabolic and catabolic processes in response to environmental cues, including nutrients. Amino acids signal to mTORC1 through the Rag GTPases, which are regulated by several protein complexes, including GATOR1 and GATOR2. GATOR2, which has five components (WDR24, MIOS, WDR59, SEH1L and SEC13), is required for amino acids to activate mTORC1 and interacts with the leucine and arginine sensors SESN2 and CASTOR1, respectively. None (structural study) GATOR2 complex (with Sestrin2 and CASTOR1 binding sites) Recombinant human protein, cryo-EM Structure of GATOR2 as a two-fold symmetric cage; maps where the leucine and arginine sensors dock" }, { "sid": "MOR2026", "entities": [ "autophagy" ], "authors": [ "tatiana-m-moreno", "caroline-kumsta" ], "author_names": [ "Tatiana M. Moreno", "Caroline Kumsta" ], "text": "Autophagy is widely proposed to decline with age; however, direct evidence across human cell types remains limited. Moreover, it is unclear whether age-associated changes in autophagy-gene transcription are accompanied by corresponding changes in autophagic activity, and whether autophagic activity relates to physiological function during aging. We performed transcriptomic and functional autophagy analyses across subject-matched human cell types from a healthy aging cohort." }, { "sid": "ZHOU2026", "entities": [ "lung-cancer-nsclc-luad", "mrps17", "tet1" ], "authors": [ "nan-zhou" ], "author_names": [ "Nan Zhou" ], "text": "Lung adenocarcinoma (LUAD) poses significant therapeutic challenges. This study investigates the role of mitochondrial ribosomal protein S17 (MRPS17) in LUAD progression, focusing on its interaction with the PI3K-AKT-mTOR signaling pathway. MRPS17 is upregulated in LUAD tissues and associated with poor prognosis. MRPS17 overexpression promoted proliferation, migration and invasion, whereas knockdown induced apoptosis and diminished tumorigenic capability in vitro and in vivo. MRPS17 overexpression / knockdown; TET1 modulation MRPS17; TET1; PI3K-AKT-mTOR Human cell lines; mouse xenograft MRPS17 upregulation activates PI3K-AKT-mTOR and increases tumour aggressiveness; knockdown induces apoptosis and reduces tumour growth" }, { "sid": "SCH2003", "entities": [ "eif4e" ], "authors": [ "david-m-sabatini", "john-blenis", "diane-c-fingar", "stefanie-s-schalm" ], "author_names": [ "David M. Sabatini", "John Blenis", "Diane C. Fingar", "Stefanie S. Schalm" ], "text": "The mammalian target of rapamycin, mTOR, is a serine/threonine kinase that controls cell growth and proliferation via the translation regulators eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). We recently identified a TOR signaling (TOS) motif in the N terminus of S6K1 and the C terminus of 4E-BP1 and demonstrated that in S6K1, the TOS motif is necessary to facilitate mTOR signaling to phosphorylate and activate S6K1. However, it is unclear how the TOS motif in S6K1 and 4E-BP1 mediates mTOR signaling. Biochemical (TOS motif) mTOR / raptor / 4E-BP1 In vitro TOS-motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function" }, { "sid": "MAR2013", "entities": [ "lysosome", "torin1", "tfeb", "rag-gtpases", "mtorc1" ], "authors": [ "rosa-puertollano", "jose-a-martina" ], "author_names": [ "Rosa Puertollano", "José A. Martina" ], "text": "The mTORC1 complex supports cell growth and proliferation in response to energy levels, growth factors, and nutrients. The Rag guanosine triphosphatases (GTPases) activate mTORC1 in response to amino acids by promoting its redistribution to lysosomes. In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression. Interaction of TFEB with active Rag heterodimers promoted recruitment of TFEB to lysosomes, leading to mTORC1-dependent phosphorylation and inhibition of TFEB. siRNA depletion of Raptor, Rags or p18; active/inactive Rag mutants; Torin1; amino-acid starvation and re-feeding; TFEB N-terminal mutants Rag GTPases -> TFEB lysosomal recruitment -> mTORC1-dependent TFEB phosphorylation Human cells Active Rags recruited TFEB to lysosomes, which was needed for mTORC1-dependent TFEB phosphorylation and cytosolic retention; mTORC1 inhibition sent TFEB to the nucleus" }, { "sid": "GAR2009", "entities": [ "sgk1", "atp-competitive-mtor-inhibitors", "mtorc1", "mtorc2", "4e-bp1" ], "authors": [ "dario-r-alessi", "juan-m-garcia-martinez" ], "author_names": [ "Dario R. Alessi", "Juan M. García-Martínez" ], "text": "mTOR (mammalian target of rapamycin) stimulates cell growth by phosphorylating and promoting activation of AGC family kinases such as Akt (protein kinase B), S6K (p70 ribosomal S6 kinase) and SGK (serum and glucocorticoid protein kinase). mTORC1 phosphorylates the hydrophobic motif of S6K, whereas mTORC2 phosphorylates the hydrophobic motif of Akt and SGK. Ku-0063794 (ATP-competitive mTOR inhibitor) mTORC1 & mTORC2 In vitro; cells Ku-0063794 is a specific mTOR inhibitor blocking both complexes (Akt/S6K/SGK signaling)" }, { "sid": "GEI2016", "entities": [ "t-cell-differentiation", "rapamycin", "arginine", "oxidative-phosphorylation" ], "authors": [ "roger-geiger", "antonio-lanzavecchia", "nicola-zamboni" ], "author_names": [ "Roger Geiger", "Antonio Lanzavecchia", "Nicola Zamboni" ], "text": "Metabolic activity is intimately linked to T cell fate and function. Using high-resolution mass spectrometry, we generated dynamic metabolome and proteome profiles of human primary naive T cells following activation. We discovered critical changes in the arginine metabolism that led to a drop in intracellular L-arginine concentration. L-arginine supplementation in vitro (3 to 4 mM) and by oral gavage in mice; arginase inhibition; CRISPR knockout of BAZ1B, PSIP1 and TSN; rapamycin 100 nM as comparator Intracellular L-arginine levels and T-cell metabolic programme, survival and memory phenotype Human and mouse Higher intracellular L-arginine shifted T cells from glycolysis to oxidative phosphorylation and increased survival, memory-like phenotype and anti-tumour activity, without changing mTORC1 readouts" }, { "sid": "CAO2026", "entities": [ "tfeb", "rag-gtpases", "mtorc1", "flcn-fnip1-2" ], "authors": [ "zhi-lie-cao", "wei-ying-chen" ], "author_names": [ "Zhi-Lie Cao", "Wei-Ying Chen" ], "text": "Birt-Hogg-Dube (BHD) syndrome, caused by mutations in the tumor suppressor gene, has traditionally been classified as a classic 'mTORopathy' characterized by global mTORC1 activation. Recent structural and multi-omic studies have fundamentally challenged this view, revealing that FLCN functions as a GAP for RagC/D to govern substrate-selective mTORC1 regulation. none (narrative review of human genetics and mouse mechanistic data) FLCN / RagC-RagD / mTORC1 / MiT-TFE human genetics with mouse mechanistic data (review) Argues that FLCN loss produces substrate-selective rather than global mTORC1 activation, with biallelic loss driving renal tumours via nuclear MiT/TFE and haploinsufficiency sufficing for lung and skin lesions." }, { "sid": "VEZ1975", "entities": [ "rapamycin" ], "authors": [ "surendra-nath-sehgal" ], "author_names": [ "Surendra Nath Sehgal" ], "text": "A streptomycete was isolated from an Easter Island soil sample and found to inhibit Candida albicans, Microsporum gypseum and Trichophyton granulosum. The antibiotic-producing microorganism was characterized and identified as Streptomyces hygroscopicus. The antifungal principle was extracted with organic solvent from the mycelium, isolated in crystalline form and named rapamycin. Rapamycin is mainly active against Candida albicans; minimum inhibitory concentration against ten strains ranged from 0.02 to 0.2 mug/ml. Rapamycin (natural product isolation) Antifungal principle (later FKBP/TOR) Streptomyces hygroscopicus (soil bacterium) Original isolation and characterization of rapamycin as an antifungal antibiotic from Easter Island soil" }, { "sid": "YAN2013", "entities": [ "rapamycin", "mtor", "fkbp12" ], "authors": [ "nikola-p-pavletich", "haijuan-yang", "hyo-j-yang" ], "author_names": [ "Nikola P. Pavletich", "Haijuan Yang", "Hyo J Yang" ], "text": "The mammalian target of rapamycin (mTOR), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to nutrients and growth factors and is frequently deregulated in cancer. Here we report co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 (mLST8) with an ATP transition state mimic and with ATP-site inhibitors. The structures reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. Structural (X-ray crystallography) mTOR / mLST8 X-ray crystallography Co-crystal structures reveal mTOR's intrinsically active kinase and how ATP-site inhibitors bind" }, { "sid": "MCNEILL2026", "entities": [ "autoimmune-cytopenia", "rapamycin" ], "authors": [ "manuel-carcao", "maggie-mcneill" ], "author_names": [ "Manuel Carcao", "Maggie McNeill" ], "text": "[Abstract not available in the PubMed record at time of retrieval, 29 Aug 2026.] Sirolimus mTOR Human Reported effective for paediatric Evans syndrome and secondary autoimmune cytopenias" }, { "sid": "LI2026B", "entities": [ "mtor", "macrophage-polarization", "akt-pkb", "pi3k", "autophagy" ], "authors": [ "zhenhai-wang", "juan-yang" ], "author_names": [ "Zhenhai Wang", "Juan Yang" ], "text": "The persistent intracellular survival of Brucella is a key factor in immune evasion and chronic infection. This study investigated the interplay between macrophage polarization, autophagy and intracellular proliferation of Brucella suis vaccine strain 2 (S2) and the involvement of PI3K/AKT/mTOR signalling in BV2 cells. Following S2 infection, elevated expression of iNOS, Arg1, p-Akt, mTOR and autophagy-related proteins (LC3B-I, LC3B-II, ULK1) was observed with decreased p62. Laser confocal microscopy revealed efficient autophagosome-to-autolysosome conversion. Brucella suis S2 infection; PI3K/Akt/mTOR inhibitors; autophagy modulators PI3K/Akt/mTOR; autophagy (LC3B, ULK1, p62); macrophage polarization Mouse (BV2 cell line) M2 polarization plus autophagy promoted intracellular bacterial replication; pathway inhibition shifted cells to M1 and suppressed autophagy" }, { "sid": "WOL2017", "entities": [ "kicstor" ], "authors": [ "david-m-sabatini", "lynne-chantranupong", "rachel-l-wolfson", "kuang-shen", "kendall-j-condon", "sonia-m-scaria", "gregory-a-wyant", "monther-abu-remaileh", "jose-m-orozco", "xin-gu" ], "author_names": [ "David M. Sabatini", "Lynne Chantranupong", "Rachel L. Wolfson", "Kuang Shen", "Kendall J. Condon", "Sonia M. Scaria", "Gregory A. Wyant", "Monther Abu-Remaileh", "Jose M. Orozco", "Xin Gu" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth that responds to diverse environmental signals and is deregulated in many human diseases, including cancer and epilepsy. Amino acids are a key input to this system, and act through the Rag GTPases to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. Multiple protein complexes regulate the Rag GTPases in response to amino acids, including GATOR1, a GTPase activating protein for RAGA, and GATOR2, a positive regulator of unknown molecular function. Biochemical/genetic (KICSTOR) KICSTOR / GATOR1 / Rag / mTORC1 Mammalian cells KICSTOR recruits GATOR1 to the lysosome and is required for nutrients to regulate mTORC1" }, { "sid": "BET2013", "entities": [ "mam-ermitochondria-contacts" ], "authors": [ "michael-n-hall", "charles-betz", "daniele-stracka" ], "author_names": [ "Michael N. Hall", "Charles Betz", "Daniele Stracka" ], "text": "The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of growth. Mammalian TOR complex 2 (mTORC2) regulates AGC kinase family members and is implicated in various disorders, including cancer and diabetes. Here we report that mTORC2 is localized to the endoplasmic reticulum (ER) subcompartment termed mitochondria-associated ER membrane (MAM). mTORC2 localization to MAM was growth factor-stimulated, and mTORC2 at MAM interacted with the IP3 receptor (IP3R)-Grp75-voltage-dependent anion-selective channel 1 ER-mitochondrial tethering complex. Biochemical/genetic (mTORC2) mTORC2 / Akt / MAM Mammalian cells mTORC2-Akt localizes to mitochondria-associated ER membranes (MAM) to regulate mitochondrial physiology" }, { "sid": "OSH2007", "entities": [ "pras40" ], "authors": [ "joseph-avruch", "kazuyoshi-yonezawa", "kenta-hara", "noriko-oshiro-rapley" ], "author_names": [ "Joseph Avruch", "Kazuyoshi Yonezawa", "Kenta Hara", "Noriko Oshiro-Rapley" ], "text": "The proline-rich Akt substrate of 40 kilodaltons (PRAS40) was identified as a raptor-binding protein that is phosphorylated directly by mammalian target of rapamycin (mTOR) complex 1 (mTORC1) but not mTORC2 in vitro, predominantly at PRAS40 (Ser(183)). The binding of S6K1 and 4E-BP1 to raptor requires a TOR signaling (TOS) motif, which contains an essential Phe followed by four alternating acidic and small hydrophobic amino acids. PRAS40 binding to raptor was severely inhibited by mutation of PRAS40 (Phe(129) to Ala). Biochemical (PRAS40) mTORC1 / PRAS40 Mammalian cells PRAS40 is a raptor-binding physiological mTORC1 substrate (phosphorylated at Ser183)" }, { "sid": "RAV2004", "entities": [ "huntingtons-disease", "mtorc1", "autophagy" ], "authors": [ "brinda-ravikumar", "cahir-okane" ], "author_names": [ "Brinda Ravikumar", "Cahir O'Kane" ], "text": "Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. Rapamycin (mTOR inhibition) mTOR / autophagy Drosophila and mouse Huntington's disease models mTOR inhibition induces autophagy and reduces polyglutamine toxicity in Huntington's disease models" }, { "sid": "HEN2026", "entities": [ "mtor" ], "authors": [ "xian-chang-li", "samson-hennessy-strahs" ], "author_names": [ "Xian Chang Li", "Samson Hennessy-Strahs" ], "text": "Alveolar homeostasis depends on tissue-resident professional phagocytes known as alveolar macrophages (AMs) that catabolize pulmonary surfactant. Pulmonary alveolar proteinosis (PAP) arises from impaired surfactant clearance due to loss or dysfunction of AMs, most commonly from disrupted GM-CSF-dependent AM homeostasis and less frequently from congenital defects in surfactant synthesis or processing. PAP has also been reported as a pulmonary toxicity associated with mTOR inhibitor-based immunosuppressive therapy. Myeloid-specific Mtor genetic deletion; temsirolimus (pharmacologic mTOR inhibitor) mTOR / PPARgamma / Bcl-2 family Mouse (in vivo); GM-CSF-driven AM-like cells (in vitro) mTOR loss (genetic or pharmacologic) depletes alveolar macrophages and causes PAP-like lung pathology; mTOR required for AM survival, phagocytosis and lipid handling" }, { "sid": "ZHOU2026B", "entities": [ "mtor", "corilagin", "akt-pkb", "pi3k", "autophagy", "osteoarthritis", "nf-b" ], "authors": [ "hongbo-you", "ruijia-zhou", "sheng-chen" ], "author_names": [ "Hongbo You", "Ruijia Zhou", "Sheng Chen" ], "text": "Osteoarthritis (OA) is characterized by persistent inflammation, extracellular matrix degradation and impaired autophagy. IL-1β-stimulated primary mouse chondrocytes were used to evaluate Corilagin. Corilagin restored chondrocyte proliferation and increased Aggrecan, collagen II and SOX9 expression while reducing MMP3, MMP13, iNOS and COX2. Mechanistically, Corilagin inhibited PI3K/AKT/mTOR and NF-κB signaling, reduced p65 nuclear translocation and restored autophagic flux (increased Beclin-1 and LC3 II/I, decreased p62). 3-MA partially abolished these protective effects. Corilagin (intra-articular) PI3K/AKT/mTOR; NF-κB; autophagy (Beclin-1, LC3, p62) Mouse Restored autophagic flux, suppressed catabolic and inflammatory markers, protected cartilage in vivo" }, { "sid": "TAO2026", "entities": [ "tsc1-tsc2", "rapamycin", "mtor", "lipid-synthesis", "akt-pkb", "srebp1-srebp2", "s6k1" ], "authors": [ "jiajie-tao", "songlin-li", "sen-zhang", "jiaxiong-he", "shiwen-chen" ], "author_names": [ "Jiajie Tao", "Songlin Li", "Sen Zhang", "Jiaxiong He", "Shiwen Chen" ], "text": "Hepatic glycogen accumulation is a hallmark of glucose intolerance in carnivorous fish, yet the molecular mechanisms governing the partitioning of surplus carbohydrates remain poorly understood. This study integrated physiology and functional assays to elucidate how insulin-dependent mTOR/SREBP1 signaling governs hepatic glucose partitioning and glycogen accumulation. In the present study, we used largemouth bass (poor glucose utilization) and Nile tilapia (efficient glucose utilization) fed diets containing graded carbohydrate levels for 8 weeks. graded dietary carbohydrate; insulin treatment; rapamycin; srebp1, akt1, s6k1 and tsc2 knockdown in primary hepatocytes insulin / PI3K-AKT1-mTOR / SREBP1 lipogenic axis fish (largemouth bass Micropterus salmoides and Nile tilapia), in vivo and primary hepatocytes High-carbohydrate diets suppressed the AKT1/mTOR/SREBP1 axis in largemouth bass and caused hepatic glycogen overload, while insulin restored the axis and shifted partitioning back toward lipogenesis." }, { "sid": "MCC2011", "entities": [ "lymphangioleiomyomatosis", "rapamycin", "mtor", "mtorc1" ], "authors": [ "bruce-c-trapnell", "francis-x-mccormack", "lisa-young" ], "author_names": [ "Bruce C. Trapnell", "Francis X. McCormack", "Lisa Young" ], "text": "Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM. We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. Sirolimus (rapamycin) mTOR Human – RCT (MILES, n=89, women with LAM) Sirolimus stabilized lung function (FEV1) in lymphangioleiomyomatosis during treatment Oral sirolimus, initial 2 mg/day titrated to trough 5-15 ng/ml; 12-month double-blind treatment + 12-month observation off-drug; 1:1 vs placebo (MILES). 111 consented, 89 randomized (43 placebo / 46 sirolimus); women with LAM, FEV1 <=70% predicted. Primary outcome FEV1 slope (mL/month): sirolimus stabilized lung function during treatment while placebo declined; benefit waned after stopping the drug. Interim analysis delayed by site/contracting issues; other health-symptom measures not significantly different; benefit tied to continued dosing." }, { "sid": "BOD2001", "entities": [ "protein-synthesis", "resistance-exercise-mechanical-load" ], "authors": [ "sue-c-bodine", "george-d-yancopoulos", "trevor-n-stitt" ], "author_names": [ "Sue C. Bodine", "George D. Yancopoulos", "Trevor N Stitt" ], "text": "Skeletal muscles adapt to changes in their workload by regulating fibre size by unknown mechanisms. The roles of two signalling pathways implicated in muscle hypertrophy on the basis of findings in vitro, Akt/mTOR (mammalian target of rapamycin) and calcineurin/NFAT (nuclear factor of activated T cells), were investigated in several models of skeletal muscle hypertrophy and atrophy in vivo. The Akt/mTOR pathway was upregulated during hypertrophy and downregulated during muscle atrophy. Genetic/pharmacologic (Akt/mTOR; rapamycin) Akt / mTOR Mouse; muscle Akt/mTOR is necessary and sufficient for skeletal muscle hypertrophy and prevents atrophy in vivo" }, { "sid": "DIB2012", "entities": [ "tbc1d7" ], "authors": [ "brendan-d-manning", "christian-c-dibble", "john-m-asara", "david-j-kwiatkowski", "peter-m-finan", "leon-o-murphy" ], "author_names": [ "Brendan D. Manning", "Christian C. Dibble", "John M. Asara", "David J. Kwiatkowski", "Peter M Finan", "Leon O Murphy" ], "text": "The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. Biochemical/genetic (TBC1D7) TSC1-TSC2-TBC1D7 / Rheb / mTORC1 Mammalian cells TBC1D7 is a third subunit of the TSC1-TSC2 complex that regulates Rheb and mTORC1" }, { "sid": "BIT2016", "entities": [ "longevity", "rapamycin", "mtor" ], "authors": [ "matt-kaeberlein", "alessandro-bitto" ], "author_names": [ "Matt Kaeberlein", "Alessandro Bitto" ], "text": "The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. Rapamycin (transient, 3 months) mTOR Mouse (middle-aged) A 3-month rapamycin course in middle-aged mice, dose- and sex-dependent: the high injected dose (8 mg/kg) raised male life expectancy up to 60% but did NOT extend female lifespan (and shifted female cancers toward aggressive hematopoietic types); a lower dietary dose (126 ppm) raised survival in both sexes. Healthspan (grip, Rotarod) improved after treatment. 8 mg/kg rapamycin via intraperitoneal (i.p.) injections daily for 90 days, starting at 20–21 months of age. Males: N=18 vehicle, N=17 rapamycin; Females: N=20 vehicle, N=20 rapamycin for survival analysis. Male mice: 60% increase in median life expectancy from end of treatment (p=0.02) and 16% increase in overall median lifespan from birth (p=0.03). Female mice: no significant increase in survival (p=0.261), but increased incidence of aggressive hematopoietic cancers (16/16 vs 6/12 controls, p=0.002) and decreased non-hematopoietic neoplasms (1/16 vs 7/12 controls, p=0.004). No data on animals that may have died prior to receipt from NIA for lifespan curves." }, { "sid": "THO2009", "entities": [ "torin1", "atp-competitive-mtor-inhibitors", "rapamycin", "mtorc1", "4e-bp1" ], "authors": [ "david-m-sabatini", "carson-c-thoreen", "nathanael-s-gray", "seong-a-kang", "qingsong-liu" ], "author_names": [ "David M. Sabatini", "Carson C. Thoreen", "Nathanael S. Gray", "Seong A. Kang", "Qingsong Liu" ], "text": "The mammalian target of rapamycin (mTOR) kinase is the catalytic subunit of two functionally distinct complexes, mTORC1 and mTORC2, that coordinately promote cell growth, proliferation, and survival. Rapamycin is a potent allosteric mTORC1 inhibitor with clinical applications as an immunosuppressant and anti-cancer agent. Here we find that Torin1, a highly potent and selective ATP-competitive mTOR inhibitor that directly inhibits both complexes, impairs cell growth and proliferation to a far greater degree than rapamycin. Torin1 (ATP-competitive mTOR inhibitor) mTORC1 (rapamycin-resistant outputs, 4E-BP) Mouse/human cells Torin1 reveals rapamycin-resistant functions of mTORC1 (e.g. 4E-BP1 phosphorylation, autophagy)" }, { "sid": "NAZ2026", "entities": [ "itga2-integrin-alpha-2", "slc7a5-lat1", "breast-cancer", "mtorc1", "autophagy" ], "authors": [ "elena-rainero", "mona-nazemi" ], "author_names": [ "Elena Rainero", "Mona Nazemi" ], "text": "Invasive breast and pancreatic cancer cells thrive within a collagen I-rich, poorly perfused extracellular matrix (ECM) network, necessitating robust metabolic adaptation to endure nutrient deficiency, such as glucose starvation. Here we demonstrate that collagen I is critical for the survival and growth of breast and pancreatic cancer cells. Mechanistically, collagen I promotes alpha2 beta1 integrin-dependent S6 phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) and drives the membrane localisation of the (LAT1)-4F2hc amino acid transporter. collagen I matrix exposure; alpha2beta1 integrin inhibition; LAT1-4F2hc inhibition; glucose starvation mTORC1 / S6 phosphorylation and the LAT1-4F2hc amino acid transporter human breast and pancreatic cancer cell lines in 2D and 3D culture Collagen I raised integrin-dependent mTORC1 activity and membrane LAT1-4F2hc, sustaining amino acid supply and cancer cell survival, and blocking either step reduced growth and invasion." }, { "sid": "LI2026", "entities": [ "mtor" ], "authors": [ "yang-zong" ], "author_names": [ "Yang Zong" ], "text": "Diagnosis of MiT/TFE family translocation renal cell carcinoma is challenging. This study identifies GPR143 as a novel immunohistochemical marker that reliably identifies renal tumors harboring FLCN/TSC/mTOR-TFE pathway alterations, offering a practical diagnostic aid. GPR143 immunohistochemistry MTOR / FLCN / TSC pathway in renal cell carcinoma Human GPR143 overexpression identifies mTOR-pathway-driven renal tumors; positive diagnostic marker" }, { "sid": "LAM2012", "entities": [ "rapamycin", "mtorc2", "insulin-resistance" ], "authors": [ "david-m-sabatini", "dudley-w-lamming", "david-a-guertin", "arlan-richardson", "adam-b-salmon", "joseph-a-baur" ], "author_names": [ "David M. Sabatini", "Dudley W. Lamming", "David A. Guertin", "Arlan Richardson", "Adam B. Salmon", "Joseph A. Baur" ], "text": "Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Rapamycin (chronic) mTORC1 vs mTORC2 Mouse In mice, chronic rapamycin causes insulin resistance via disruption of mTORC2, uncoupled from its longevity effect" }, { "sid": "BAR2013", "entities": [ "gator2", "rag-gtpases", "mtorc1", "gator1" ], "authors": [ "david-m-sabatini", "lynne-chantranupong", "liron-bar-peled", "brian-c-grabiner", "matthew-meyerson", "kathleen-ottina" ], "author_names": [ "David M. Sabatini", "Lynne Chantranupong", "Liron Bar-Peled", "Brian C. Grabiner", "Matthew Meyerson", "Kathleen Ottina" ], "text": "The mTOR complex 1 (mTORC1) pathway promotes cell growth in response to many cues, including amino acids, which act through the Rag guanosine triphosphatases (GTPases) to promote mTORC1 translocation to the lysosomal surface, its site of activation. Although progress has been made in identifying positive regulators of the Rags, it is unknown if negative factors also exist. Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and -2. Biochemical/genetic (GATOR1/GATOR2) GATOR / Rag GTPases / mTORC1 Human cells + cancer genomics GATOR1 is a GAP for RagA/B (negative regulator); GATOR2 acts positively; GATOR1 lost in some cancers" }, { "sid": "FIS2015", "entities": [ "rapamycin", "age-related-pathology" ], "authors": [ "arlan-richardson", "kathleen-e-fischer", "steven-n-austad" ], "author_names": [ "Arlan Richardson", "Kathleen E. Fischer", "Steven N. Austad" ], "text": "Rapamycin, an mTOR inhibitor, has been shown to extend lifespan in a range of model organisms. It has been reported to extend lifespan in multiple strains of mice, administered chronically or acutely early or late in life. The ability of rapamycin to extend health (healthspan) as opposed to life is less well documented. To assess the effects chronic rapamycin treatment on healthspan, enteric rapamycin was given to male and female C57BL/6J mice starting at 4 months of age and continued throughout life. Encapsulated rapamycin in diet, 14 ppm, from 4 months of age for life mTOR Mouse (C57BL/6J, both sexes) Mixed, sex-specific healthspan effects: better female grip strength and male sleep, worse male rotarod, opposite-sex changes in body mass/fat/metabolic rate" }, { "sid": "VAL2025", "entities": [ "gator2", "castor1", "sestrin2" ], "authors": [ "max-l-valenstein", "pranav-v-lalgudi" ], "author_names": [ "Max L. Valenstein", "Pranav V. Lalgudi" ], "text": "None (structural study); sensor-site mutants for validation GATOR2 complex with Sestrin2 and CASTOR1 binding sites; WDR24 beta-propeller Human proteins (cryo-EM); HEK293T cells (mutant validation) Sestrin2 and CASTOR1 occupy distinct sites on GATOR2 and restrict its WDR24 propeller; amino-acid binding changes each sensor's shape and releases it from GATOR2" }, { "sid": "MARCHANT2026", "entities": [ "mtorc1", "insulin-resistance", "gator1" ], "authors": [ "blake-b-rasmussen", "erik-d-marchant", "hanna-kalenta", "jacquelyn-may", "zhao-lai" ], "author_names": [ "Blake B. Rasmussen", "Erik D. Marchant", "Hanna Kalenta", "Jacquelyn May", "Zhao Lai" ], "text": "Aberrant mTORC1 signaling in skeletal muscle has been implicated in aging and insulin resistance, however, it is not known whether chronic mTORC1 activation directly causes glucose intolerance. We tested the hypothesis that constitutive mTORC1 activation in mouse skeletal muscle impairs glucose homeostasis using tamoxifen-inducible, muscle-specific GATOR1 complex knockout. Constitutive mTORC1 activation (GATOR1 muscle-specific KO) mTORC1 / GATOR1 complex Mouse Increased skeletal muscle inflammation without impairment of glucose tolerance" }, { "sid": "CHE2018", "entities": [], "authors": [ "xizi-chen", "yanhui-xu" ], "author_names": [ "Xizi Chen", "Yanhui Xu" ], "text": "Mechanistic target of rapamycin (mTOR) complex 2 (mTORC2) plays an essential role in regulating cell proliferation through phosphorylating AGC protein kinase family members, including AKT, PKC and SGK1. The functional core complex consists of mTOR, mLST8, and two mTORC2-specific components, Rictor and mSin1. Here we investigated the intermolecular interactions within mTORC2 complex and determined its cryo-electron microscopy structure at 4.9 A resolution. The structure reveals a hollow rhombohedral fold with a 2-fold symmetry. The dimerized mTOR serves as a scaffold for the complex assembly. Structural (cryo-EM) mTORC2 (mTOR/mLST8/Rictor/mSin1) Cryo-EM structure Cryo-EM structure of human mTORC2 reveals intermolecular interactions of Rictor and mSin1" }, { "sid": "SET2012", "entities": [ "lysosomal-biogenesis" ], "authors": [ "david-m-sabatini", "roberto-zoncu", "andrea-ballabio", "carmine-settembre", "tuong-huynh", "diego-l-medina" ], "author_names": [ "David M. Sabatini", "Roberto Zoncu", "Andrea Ballabio", "Carmine Settembre", "Tuong Huynh", "Diego L. Medina" ], "text": "The lysosome plays a key role in cellular homeostasis by controlling both cellular clearance and energy production to respond to environmental cues. However, the mechanisms mediating lysosomal adaptation are largely unknown. Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTORC1 inhibits TFEB activity. Genetic/pharmacologic (mTORC1/TFEB) mTORC1 / TFEB Mammalian cells A lysosome-to-nucleus signalling mechanism via mTORC1-TFEB senses and regulates the lysosome" }, { "sid": "RAM2018", "entities": [ "tsc1-tsc2", "rapamycin", "mtor" ], "authors": [ "andrew-c-liu", "john-b-hogenesch", "chidambaram-ramanathan" ], "author_names": [ "Andrew C. Liu", "John B. Hogenesch", "Chidambaram Ramanathan" ], "text": "The circadian clock coordinates physiology and metabolism. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Genetic and pharmacological mTOR inhibition or activation mTOR; core clock proteins (CRY1, BMAL1, CLOCK) Mouse (cells, ex vivo tissue, whole animal) mTOR inhibition lengthens circadian period and dampens amplitude; activation does the opposite" }, { "sid": "ANA2019", "entities": [ "raptor", "rag-gtpases", "mtorc1" ], "authors": [ "david-m-sabatini", "kacper-b-rogala", "roger-l-williams", "madhanagopal-anandapadamanaban", "alex-berndt", "christopher-johnson" ], "author_names": [ "David M. Sabatini", "Kacper B. Rogala", "Roger L. Williams", "Madhanagopal Anandapadamanaban", "Alex Berndt", "Christopher Johnson" ], "text": "The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo-electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagA/RagCnucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Structural (cryo-EM) RagA/RagC / RAPTOR / mTORC1 Cryo-EM structure Structure of RagA/RagC bound to mTORC1 (RAPTOR) explains nucleotide-state-dependent recruitment" }, { "sid": "LON2005", "entities": [ "rheb" ], "authors": [ "joseph-avruch", "kazuyoshi-yonezawa", "xiaomeng-long" ], "author_names": [ "Joseph Avruch", "Kazuyoshi Yonezawa", "Xiaomeng Long" ], "text": "The target of rapamycin (TOR), in complex with the proteins raptor and LST8 (TOR complex 1), phosphorylates the p70S6K and 4E-BP1 to promote mRNA translation. Genetic evidence establishes that TOR complex activity in vivo requires the small GTPase Rheb, and overexpression of Rheb can rescue TOR from inactivation in vivo by amino-acid withdrawal. The Tuberous Sclerosis heterodimer (TSC1/TSC2) functions as a Rheb GTPase activator and inhibits TOR signaling in vivo. Biochemical (Rheb) Rheb / mTORC1 In vitro Rheb binds and directly regulates the mTOR kinase (with TSC1/2 acting as its GAP)" }, { "sid": "JAN2025", "entities": [ "gator2", "castor1" ], "authors": [ "james-h-hurley", "rachel-m-jansen" ], "author_names": [ "James H. Hurley", "Rachel M. Jansen" ], "text": "None (structural study); CASTOR1 and MIOS interface point mutants for validation CASTOR1-GATOR2 interface (MIOS beta-propellers) Human proteins (cryo-EM); HEK293T cells (mutant validation) Arginine binding closes the MIOS-binding surface of CASTOR1, releasing it from GATOR2" }, { "sid": "SHI2014", "entities": [ "lipid-synthesis", "srebp1-srebp2" ], "authors": [ "michael-n-hall", "mitsugu-shimobayashi" ], "author_names": [ "Michael N. Hall", "Mitsugu Shimobayashi" ], "text": "More than 20 years after its discovery, our understanding of target of rapamycin (TOR) signalling continues to grow. Recent global omics studies have revealed physiological roles of mammalian TOR (mTOR) in protein, nucleotide and lipid synthesis. Furthermore, emerging evidence provides new insight into the control of mTOR by other pathways such as Hippo, WNT and Notch signalling. Together, this progress has expanded the list of downstream effectors and upstream regulators of mTOR signalling. Not applicable (review) mTOR network Review Reviews mTOR crosstalk with Hippo/WNT/Notch and its roles in protein, nucleotide and lipid synthesis" }, { "sid": "JOH2013", "entities": [ "longevity", "rapamycin", "mtor", "mtorc1" ], "authors": [ "matt-kaeberlein", "peter-s-rabinovitch", "simon-c-johnson" ], "author_names": [ "Matt Kaeberlein", "Peter S. Rabinovitch", "Simon C. Johnson" ], "text": "Many experts in the biology of ageing believe that pharmacological interventions to slow ageing are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Not applicable (review) mTOR Review Reviews mTOR as a key modulator of ageing and age-related disease across species" }, { "sid": "DRU2009", "entities": [ "muscle-growth", "rapamycin", "mtorc1", "protein-synthesis", "resistance-exercise-mechanical-load" ], "authors": [ "blake-b-rasmussen", "micah-j-drummond" ], "author_names": [ "Blake B. Rasmussen", "Micah J. Drummond" ], "text": "Muscle protein synthesis and mTORC1 signalling are concurrently stimulated following muscle contraction in humans. In an effort to determine whether mTORC1 signalling is essential for regulating muscle protein synthesis in humans, we treated subjects with a potent mTORC1 inhibitor (rapamycin) prior to performing a series of high-intensity muscle contractions. Here we show that rapamycin treatment blocks the early (1-2 h) acute contraction-induced increase ( approximately 40%) in human muscle protein synthesis. Rapamycin (pre-exercise) mTORC1 Human – controlled trial Rapamycin blocks the contraction-induced increase in human skeletal muscle protein synthesis Rapamycin, single oral dose before a bout of high-intensity resistance exercise (exact mg not captured; full text not retrievable via PMC). Small human controlled trial (full text unavailable; abstract-level). Rapamycin blocked the early (1-2 h) ~40% contraction-induced increase in human muscle protein synthesis; downstream mTORC1 signaling (S6K1) blunted. Small sample; full text not retrievable via PMC, so dose/n taken from abstract only." }, { "sid": "PAU2025", "entities": [ "mtor", "pfkfb3" ], "authors": [ "john-g-albeck", "steven-d-cappell", "debasish-paul" ], "author_names": [ "John G. Albeck", "Steven D. Cappell", "Debasish Paul" ], "text": "Mammalian cells entering the cell cycle favour glycolysis to rapidly generate ATP and produce the biosynthetic intermediates that are required for rapid biomass accumulation. Simultaneously, the ubiquitin-ligase anaphase-promoting complex/cyclosome and its coactivator CDH1 (APC/C) remains active, allowing origin licensing and blocking premature DNA replication. Paradoxically, glycolysis is reduced by APC/C through the degradation of key glycolytic enzymes, raising the question of how cells coordinate these mutually exclusive events to ensure proper cell division. Mitogen stimulation; mTOR / phosphatase perturbation mTOR / APC/C-CDH1 / PFKFB3 Human & mouse cells mTOR transiently inactivates APC/C at cell cycle entry, producing a required pulse of glycolysis" }, { "sid": "LIP2015", "entities": [ "mtorc1", "protein-synthesis", "s6k1" ], "authors": [ "john-m-asara", "lara-m-boyle", "fred-c-davis", "jonathan-o-lipton", "ashwin-nathan", "mustafa-sahin", "elizabeth-d-yuan" ], "author_names": [ "John M. Asara", "Lara M. Boyle", "Fred C. Davis", "Jonathan O. Lipton", "Ashwin Nathan", "Mustafa Sahin", "Elizabeth D. Yuan" ], "text": "The circadian timing system synchronizes cellular function by coordinating rhythmic transcription via a transcription-translational feedback loop. How the circadian system regulates gene expression at the translational level remains a mystery. Here, we show that the key circadian transcription factor BMAL1 associates with the translational machinery in the cytosol and promotes protein synthesis. The mTOR-effector kinase, ribosomal S6 protein kinase 1 (S6K1), an important regulator of translation, rhythmically phosphorylates BMAL1 at an evolutionarily conserved site. Genetic and biochemical manipulation of BMAL1 phosphorylation S6K1; BMAL1; translation Mouse S6K1 rhythmically phosphorylates BMAL1; protein synthesis shows BMAL1-dependent circadian oscillation" }, { "sid": "DAN2026", "entities": [ "rapamycin" ], "authors": [ "lufeng-dan" ], "author_names": [ "Lufeng Dan" ], "text": "Metastable phenotypic inheritance is often attributed to epigenetic mechanisms, but reversible genetic alterations can produce similar instability. Here, we investigated the basis of unstable resistance to TORC1 inhibitor (rapamycin plus caffeine) in fission yeast. Six independent, metastable resistant mutants were isolated. Genetic mapping positioned the causal lesion to a single Mendelian locus, identified as gaf1, encoding a GATA transcription factor and a key negative regulator of growth downstream of TORC1. rapamycin plus caffeine selection; gaf1 loss-of-function and wild-type allele restoration TORC1 signalling output via the GATA transcription factor Gaf1 fission yeast (Schizosaccharomyces pombe) Reversible loss-of-function mutations in gaf1 were necessary and sufficient for metastable resistance to TORC1 inhibition, with derepression of translation and metabolic programmes on drug treatment." }, { "sid": "NEF2013", "entities": [ "mtor" ], "authors": [ "dan-ehninger", "frauke-neff", "johannes-beckers", "helmut-fuchs", "valerie-gailus-durner", "marion-horsch", "kristin-moreth", "birgit-rathkolb", "jan-rozman" ], "author_names": [ "Dan Ehninger", "Frauke Neff", "Johannes Beckers", "Helmut Fuchs", "Valérie Gailus-Durner", "Marion Horsch", "Kristin Moreth", "Birgit Rathkolb", "Jan Rozman" ], "text": "Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Rapamycin mTOR Mouse Rapamycin extends lifespan but improves relatively few aging phenotypes – lifespan effect partly separable from aging" }, { "sid": "YANG2026", "entities": [ "rapamycin", "mtor", "autophagy" ], "authors": [ "rui-li", "ge-yang", "ling-zhang", "xiaojie-sun", "yifei-wang" ], "author_names": [ "Rui Li", "Ge Yang", "Ling Zhang", "Xiaojie Sun", "Yifei Wang" ], "text": "Early-life exposure of ICR mice to polypropylene microplastics (PP-MPs) and/or DEHP caused ASD-relevant neurodevelopmental alterations including social interaction deficits, anxiety, and neuronal/synaptic damage in the prefrontal cortex. Proteomic analysis identified the mTOR signaling pathway as a key mechanism. PP-MPs/DEHP exposure activated mTOR signaling with autophagic impairment and dysregulated synaptic plasticity. Rapamycin restored autophagic activity and ameliorated ASD-relevant neurodevelopmental alterations, confirming mTOR-regulated autophagic impairment as the mechanistic basis. Polypropylene microplastics (PP-MPs); DEHP; Rapamycin (rescue) mTOR signaling; autophagy; Shank3; Nlgn1 (synaptic plasticity) Mouse mTOR hyperactivation + autophagy impairment mediates ASD-like neurotoxicity from early-life plastic/plasticizer exposure; mTOR inhibition is protective" }, { "sid": "FOK2014", "entities": [ "mtor" ], "authors": [ "arlan-richardson", "adam-b-salmon", "vivian-diaz", "wilson-c-fok" ], "author_names": [ "Arlan Richardson", "Adam B. Salmon", "Vivian Diaz", "Wilson C. Fok" ], "text": "Rapamycin was found to increase (11% to 16%) the lifespan of male and female C57BL/6J mice most likely by reducing the increase in the hazard for mortality (i.e., the rate of aging) term in the Gompertz mortality analysis. To identify the pathways that could be responsible for rapamycin's longevity effect, we analyzed the transcriptome of liver from 25-month-old male and female mice fed rapamycin starting at 4 months of age. Few changes (<300 transcripts) were observed in transcriptome of rapamycin-fed males; however, a large number of transcripts (>4,500) changed significantly in females. Rapamycin (from 4 months of age) mTOR Mouse (C57BL/6J) Rapamycin increased lifespan 11-16% with major changes in the liver transcriptome 14 ppm encapsulated rapamycin in food, ad libitum, starting at 4 months of age until end of life 175 mice total (40 control males, 45 Rapa males, 45 control females, 45 Rapa females) Rapamycin increased lifespan 16% in females and 11% in males (entire survival curve analysis), and significantly increased mean (14% females, 7% males) and maximum (19% females, 8% males) survival. not stated" }, { "sid": "WAG2014", "entities": [ "mtor" ], "authors": [ "david-m-sabatini", "brian-c-grabiner", "jonathan-e-rosenberg", "nikhil-wagle" ], "author_names": [ "David M. Sabatini", "Brian C. Grabiner", "Jonathan E. Rosenberg", "Nikhil Wagle" ], "text": "Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Everolimus + pazopanib (mTOR inhibition) mTOR (activating mutations) Human (patient, phase I) Activating mTOR mutations underlie an extraordinary response to everolimus in a phase I patient Pazopanib 400 mg daily + everolimus 5 mg daily (MTD; 600 mg + 5 mg gave dose-limiting toxicities); phase I. 9 patients enrolled (5 urothelial, others lung/carcinoid); an exceptional responder analyzed by sequencing. Activating mTOR mutations underlie the extraordinary response to everolimus+pazopanib. 5/9 patients had grade >=3 toxicity (56%, 95% CI 21.2-86.3%); everolimus AUC 41% higher when combined with pazopanib. Inference from a single exceptional responder; basis of mTOR-inhibitor sensitivity incompletely understood; short drug exposure in some." }, { "sid": "KAL2010", "entities": [ "metformin", "rag-gtpases", "mtorc1", "ampk" ], "authors": [ "george-thomas", "benoit-viollet", "sara-c-kozma", "adem-kalender" ], "author_names": [ "George Thomas", "Benoit Viollet", "Sara C. Kozma", "Adem Kalender" ], "text": "Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Metformin and phenformin (biguanides) mTORC1 via Rag GTPases (AMPK- and TSC-independent) Mammalian cells (AMPK-null and TSC1/2-null); preclinical models Biguanides inhibit mTORC1 without AMPK or TSC1/2; the effect requires the Rag GTPases" }, { "sid": "REB2015", "entities": [ "arginine", "slc38a9" ], "authors": [ "giulio-superti-furga", "lukas-a-huber", "taras-stasyk", "manuele-rebsamen" ], "author_names": [ "Giulio Superti-Furga", "Lukas A. Huber", "Taras Stasyk", "Manuele Rebsamen" ], "text": "Cell growth and proliferation are tightly linked to nutrient availability. The mechanistic target of rapamycin complex 1 (mTORC1) integrates the presence of growth factors, energy levels, glucose and amino acids to modulate metabolic status and cellular responses. mTORC1 is activated at the surface of lysosomes by the RAG GTPases and the Ragulator complex through a not fully understood mechanism monitoring amino acid availability in the lysosomal lumen and involving the vacuolar H(+)-ATPase. Biochemical/genetic (SLC38A9) SLC38A9 / Rag-Ragulator / mTORC1 Mammalian cells SLC38A9 is a lysosomal amino-acid (arginine) transporter/sensor component that controls mTORC1" }, { "sid": "WEI2008", "entities": [ "tsc1-tsc2", "rapamycin", "mtor", "macrophage-polarization", "immune-function", "nf-b" ], "authors": [ "thomas-weichhart", "marcus-d-saemann" ], "author_names": [ "Thomas Weichhart", "Marcus D. Säemann" ], "text": "The innate inflammatory immune response must be tightly controlled to avoid damage to the host. Here, we showed that the tuberous sclerosis complex-mammalian target of rapamycin (TSC-mTOR) pathway regulated inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Inhibition of mTOR by rapamycin promoted production of proinflammatory cytokines via the transcription factor NF-kappaB but blocked the release of interleukin-10 via the transcription factor STAT3. Rapamycin (mTOR inhibition) TSC-mTOR / NF-κB Mouse/human monocytes mTOR inhibition promotes pro-inflammatory cytokines via NF-κB – TSC-mTOR regulates the innate inflammatory response" }, { "sid": "ZHA2000", "entities": [ "mtor", "pi3k", "s6k1" ], "authors": [ "thomas-p-neufeld" ], "author_names": [ "Thomas P. Neufeld" ], "text": "The TOR protein kinases (TOR1 and TOR2 in yeast; mTOR/FRAP/RAFT1 in mammals) promote cellular proliferation in response to nutrients and growth factors, but their role in development is poorly understood. Here, we show that the Drosophila TOR homolog dTOR is required cell autonomously for normal growth and proliferation during larval development, and for increases in cellular growth caused by activation of the phosphoinositide 3-kinase (PI3K) signaling pathway. dTOR loss-of-function; PI3K activation; p70S6K overexpression Cell growth and proliferation; p70S6K phosphorylation; viability Drosophila melanogaster; in vitro dTOR required for normal and PI3K-driven growth; S6K overexpression rescues dTOR mutant viability" }, { "sid": "NOR2026", "entities": [ "mtor", "alzheimers-disease" ], "authors": [ "beatrix-m-ueberheide", "ann-charlotte-granholm", "abigail-nordbeck" ], "author_names": [ "Beatrix M. Ueberheide", "Ann-Charlotte Granholm", "Abigail Nordbeck" ], "text": "Down syndrome (DS) is caused by a complete or partial trisomy of chromosome 21, resulting in variable intellectual disabilities and a high risk for early-onset Alzheimer's disease (DS-AD). Dysregulation of the mammalian target of rapamycin (mTOR) and insulin (INS) signaling pathways has been reported in DS. We hypothesized that upstream alterations in these two pathways contribute to hippocampal dysfunction in DS-AD. none (observational post-mortem comparison) mTOR and insulin signalling pathways across hippocampal subfields human post-mortem hippocampus (Down syndrome with Alzheimer's neuropathology versus age-matched neurotypical controls) mTOR pathway signalling differed in specific hippocampal subfields and insulin pathway signalling in dentate granule neurons, reported by the authors as preliminary." }, { "sid": "SCA2020", "entities": [], "authors": [ "michael-n-hall", "timm-maier", "nenad-ban", "daniel-boehringer", "stefan-imseng", "mitsugu-shimobayashi", "alain-scaiola", "edward-stuttfeld" ], "author_names": [ "Michael N. Hall", "Timm Maier", "Nenad Ban", "Daniel Boehringer", "Stefan Imseng", "Mitsugu Shimobayashi", "Alain Scaiola", "Edward Stuttfeld" ], "text": "The protein kinase mammalian target of rapamycin (mTOR) is the central regulator of cell growth. Aberrant mTOR signaling is linked to cancer, diabetes, and neurological disorders. mTOR exerts its functions in two distinct multiprotein complexes, mTORC1 and mTORC2. Here, we report a 3.2-A resolution cryo-EM reconstruction of mTORC2. Structural (cryo-EM) mTORC2 (Rictor/SIN1) Cryo-EM structure 3.2-Å cryo-EM structure of human mTORC2 reveals the entangled Rictor and SIN1 folds" }, { "sid": "WUX2013", "entities": [ "longevity", "mtor", "mtorc1", "mtorc2" ], "authors": [ "toren-finkel", "j-julie-wu" ], "author_names": [ "Toren Finkel", "J. Julie Wu" ], "text": "We analyzed aging parameters using a mechanistic target of rapamycin (mTOR) hypomorphic mouse model. Mice with two hypomorphic alleles are viable but express mTOR at approximately 25% of wild-type levels. These animals demonstrate reduced mTORC1 and mTORC2 activity and exhibit an approximately 20% increase in median survival. While these mice are smaller than wild-type mice, they do not demonstrate any alterations in normalized food intake, glucose homeostasis, or metabolic rate. Consistent with their increased lifespan, the mice exhibited a reduction in a number of aging tissue biomarkers. Genetic (mTOR hypomorph, ~25% expression) mTORC1 & mTORC2 Mouse (mTOR hypomorph) Genetic reduction of mTOR extends median lifespan ~20% with segmental, tissue-specific slowing of aging mTOR protein reduced to approximately 25% of wild type levels males: n=17 (mTOR Δ/Δ), n=10 (WT); females: n=26 (mTOR Δ/Δ), n=24 (WT); combined: n=43 (mTOR Δ/Δ), n=34 (WT) Median survival increased by 22% for males (p=0.02) and 19% for females (p=0.047); overall median survival 30.3 months for mTOR Δ/Δ vs 26.2 months for WT (p=0.0057) Higher euthanasia rate for mTOR Δ/Δ mice due to severe infections (37% vs 17% WT, p<0.01); exacerbated age-dependent decrease in trabecular bone volume and increased age-dependent infections (mouth, eye, skin) in mTOR Δ/Δ mice" }, { "sid": "FER2025", "entities": [ "mtor", "mtorc1", "mtorc2" ], "authors": [ "constantinos-demetriades", "aurelio-a-teleman", "stephanie-a-fernandes", "julian-nuchel", "sabine-wilhelm" ], "author_names": [ "Constantinos Demetriades", "Aurelio A. Teleman", "Stephanie A. Fernandes", "Julian Nüchel", "Sabine Wilhelm" ], "text": "Proper control of mTOR (mechanistic/mammalian target of rapamycin) signaling is relevant for health, disease and ageing. Information from intra- and extra-cellular signaling cues is transmitted to mTOR through an intricate signaling network that impinges on the Rag and Rheb GTPases to regulate its localization and activity. Interestingly, although mTOR is a heavily ubiquitinated protein, the role of this post-translational modification (PTM) in regulating its activation status remains poorly understood. CYLD knockdown/loss of function; cyld-1 RNAi in C. elegans mTOR K63-linked ubiquitination; mTORC1 and mTORC2 activity Human cells; C. elegans; human skin biopsies CYLD loss raised mTORC1/2 activity, protein synthesis and cell size; cyld-1 knockdown reversed lifespan extension of low-TORC1 worms" }, { "sid": "OKI2021", "entities": [ "mtorc1", "tumor-growth" ], "authors": [ "david-t-scadden", "toshihiko-oki" ], "author_names": [ "David T. Scadden", "Toshihiko Oki" ], "text": "Acute myeloid leukemia (AML) is a high remission, high relapse fatal blood cancer. Although mTORC1 is a master regulator of cell proliferation and survival, its inhibitors have not performed well as AML treatments. To uncover the dynamics of mTORC1 activity in vivo, fluorescent probes are developed to track single cell proliferation, apoptosis and mTORC1 activity of AML cells in the bone marrow of live animals and to quantify these activities in the context of microanatomical localization and intra-tumoral heterogeneity. Chemotherapy; timed mTORC1 inhibition mTORC1 (AML cells in vivo) Mouse mTORC1 activity in AML shifts over the course of disease and treatment; timed inhibition works better" }, { "sid": "POW2006", "entities": [ "longevity", "rapamycin", "mtor" ], "authors": [ "matt-kaeberlein", "brian-k-kennedy", "stanley-fields", "r-wilson-powers" ], "author_names": [ "Matt Kaeberlein", "Brian K. Kennedy", "Stanley Fields", "R Wilson Powers" ], "text": "Chronological life span (CLS) in Saccharomyces cerevisiae, defined as the time cells in a stationary phase culture remain viable, has been proposed as a model for the aging of post-mitotic tissues in mammals. We developed a high-throughput assay to determine CLS for approximately 4800 single-gene deletion strains of yeast, and identified long-lived strains carrying mutations in the conserved TOR pathway. Genetic (TOR pathway deletions) TOR / Sch9 Yeast (S. cerevisiae) Decreased TOR pathway signaling extends yeast chronological lifespan" }, { "sid": "SAB1995", "entities": [], "authors": [ "robert-t-abraham" ], "author_names": [ "Robert T. Abraham" ], "text": "The immunosuppressive drug, rapamycin, interferes with an undefined signaling pathway required for the progression of G1-phase T-cells into S phase. Genetic analyses in yeast indicate that binding of rapamycin to its intracellular receptor, FKBP12, generates a toxic complex that inhibits cell growth in G1 phase. These analyses implicated two related proteins, TOR1 and TOR2, as targets of the FKBP12-rapamycin complex in yeast. Biochemical (FKBP12-rapamycin affinity) mTOR (FRAP/RAFT1) / FKBP12 Rat/mouse cells; in vitro Isolation of the mammalian FKBP12-rapamycin target protein (mTOR)" }, { "sid": "ZHO2015", "entities": [ "lysosome", "leucine", "mtorc1" ], "authors": [ "xin-zhou", "jin-zhang" ], "author_names": [ "Xin Zhou", "Jin Zhang" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) senses diverse signals to regulate cell growth and metabolism. It has become increasingly clear that mTORC1 activity is regulated in time and space inside the cell, but direct interrogation of such spatiotemporal regulation is challenging. Here, we describe a genetically encoded mTORC1 activity reporter (TORCAR) that exhibits a change in FRET in response to phosphorylation by mTORC1. Co-imaging mTORC1 activity and calcium dynamics revealed that a growth-factor-induced calcium transient contributes to mTORC1 activity. Genetically encoded FRET reporter (TORCAR) - a measuring tool, not a drug mTORC1 activity (live, subcellular) Mammalian cell lines Real-time, compartment-specific readout of mTORC1 activity; signal-specific spatial patterns" }, { "sid": "SAN2007", "entities": [ "pras40", "raptor", "insulin", "akt-pkb", "mtorc1", "rheb" ], "authors": [ "david-m-sabatini", "yasemin-sancak", "carson-c-thoreen", "seong-a-kang", "timothy-r-peterson", "robert-a-lindquist" ], "author_names": [ "David M. Sabatini", "Yasemin Sancak", "Carson C. Thoreen", "Seong A. Kang", "Timothy R. Peterson", "Robert A Lindquist" ], "text": "The heterotrimeric mTORC1 protein kinase nucleates a signaling network that promotes cell growth in response to insulin and becomes constitutively active in cells missing the TSC1 or TSC2 tumor suppressors. Insulin stimulates the phosphorylation of S6K1, an mTORC1 substrate, but it is not known how mTORC1 kinase activity is regulated. We identify PRAS40 as a raptor-interacting protein that binds to mTORC1 in insulin-deprived cells and whose in vitro interaction with mTORC1 is disrupted by high salt concentrations. Biochemical/genetic (PRAS40) mTORC1 / PRAS40 Human cells (biochemistry) PRAS40 is an insulin-regulated inhibitor of the mTORC1 kinase (raptor-binding)" }, { "sid": "STR2022", "entities": [ "longevity", "rapamycin", "acarbose" ], "authors": [ "randy-strong", "richard-a-miller", "david-e-harrison", "matt-kaeberlein", "adam-b-salmon", "vivian-diaz", "martin-a-javors", "elizabeth-fernandez", "james-f-nelson" ], "author_names": [ "Randy Strong", "Richard A. Miller", "David E. Harrison", "Matt Kaeberlein", "Adam B. Salmon", "Vivian Diaz", "Martin A. Javors", "Elizabeth Fernandez", "James F. Nelson" ], "text": "Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. Rapamycin + acarbose combination; captopril; (R/S)-1,3-butanediol; leucine; PB125; sulindac; syringaresinol mTORC1 (rapamycin); alpha-glucosidase / glucose absorption (acarbose) Mouse Rapamycin + acarbose from 9 months outlived prior rapamycin-only cohorts in males; no added benefit over rapamycin alone in females" }, { "sid": "HSU2011", "entities": [ "grb10" ], "authors": [ "david-m-sabatini", "nathanael-s-gray", "seong-a-kang", "timothy-r-peterson", "peggy-p-hsu", "michael-b-yaffe", "kathleen-ottina" ], "author_names": [ "David M. Sabatini", "Nathanael S. Gray", "Seong A. Kang", "Timothy R. Peterson", "Peggy P. Hsu", "Michael B. Yaffe", "Kathleen Ottina" ], "text": "The mammalian target of rapamycin (mTOR) protein kinase is a master growth promoter that nucleates two complexes, mTORC1 and mTORC2. Despite the diverse processes controlled by mTOR, few substrates are known. We defined the mTOR-regulated phosphoproteome by quantitative mass spectrometry and characterized the primary sequence motif specificity of mTOR using positional scanning peptide libraries. We found that the phosphorylation response to insulin is largely mTOR dependent and that mTOR exhibits a unique preference for proline, hydrophobic, and aromatic residues at the +1 position. Phosphoproteomics (mTOR) mTORC1 / Grb10 / growth-factor signaling Mammalian cells Defines the mTOR phosphoproteome; reveals mTORC1-mediated (Grb10) feedback inhibition of growth-factor signaling" }, { "sid": "INO2003", "entities": [ "tsc1-tsc2", "mtorc1", "ampk" ], "authors": [ "kun-liang-guan", "ken-inoki" ], "author_names": [ "Kun-Liang Guan", "Ken Inoki" ], "text": "Mutations in either the TSC1 or TSC2 tumor suppressor gene are responsible for Tuberous Sclerosis Complex. The gene products of TSC1 and TSC2 form a functional complex and inhibit the phosphorylation of S6K and 4EBP1, two key regulators of translation. Here, we describe that TSC2 is regulated by cellular energy levels and plays an essential role in the cellular energy response pathway. Under energy starvation conditions, the AMP-activated protein kinase (AMPK) phosphorylates TSC2 and enhances its activity. Biochemical/genetic (AMPK/TSC2) TSC2 / AMPK / mTOR Mammalian cells (biochemistry) TSC2 mediates the cellular energy response (via AMPK) to control cell growth and survival" }, { "sid": "POT2002", "entities": [ "tsc1-tsc2", "insulin", "akt-pkb" ], "authors": [ "christopher-j-potter", "tian-xu" ], "author_names": [ "Christopher J. Potter", "Tian Xu" ], "text": "The direct mechanism by which the serine/threonine kinase Akt (also known as protein kinase B (PKB)) regulates cell growth is unknown. Here, we report that Drosophila melanogaster Akt/PKB stimulates growth by phosphorylating the tuberous sclerosis complex 2 (Tsc2) tumour suppressor and inhibiting formation of a Tsc1-Tsc2 complex. We show that Akt/PKB directly phosphorylates Drosophila Tsc2 in vitro at the conserved residues, Ser 924 and Thr 1518. Mutation of these sites renders Tsc2 insensitive to Akt/PKB signalling, increasing the stability of the Tsc1-Tsc2 complex within the cell. Akt/PKB overexpression; Tsc2 S924/T1518 phospho-site mutants Tsc2 phosphorylation; Tsc1-Tsc2 complex; cell size Drosophila melanogaster Akt phosphorylates Tsc2 and disrupts the Tsc1-Tsc2 complex -> increased cell growth" }, { "sid": "SWA2026", "entities": [ "rapamycin" ], "authors": [ "timothy-a-bolger", "akanksha-swarup" ], "author_names": [ "Timothy A. Bolger", "Akanksha Swarup" ], "text": "Medulloblastoma is the most common pediatric brain cancer, but current treatments are largely non-specific, often causing developmental side effects. Genomic sequencing identified the RNA helicase DDX3X as one of the most frequently mutated genes in this cancer and a potential treatment target, yet its role in tumor progression remains elusive. rapamycin (TOR inactivation) in yeast carrying medulloblastoma-associated ded1-mam mutations; 5' UTR reporter assays TORC1-dependent translational control via the RNA helicase Ded1 / DDX3X Saccharomyces cerevisiae with medulloblastoma-relevant reporter assays The mutant grew substantially better than wild type under rapamycin and selectively raised translation of unstructured-5'UTR transcripts after TOR inhibition, rather than raising bulk translation." }, { "sid": "WIL2012", "entities": [ "longevity", "rapamycin", "mtor", "mtorc1" ], "authors": [ "randy-strong", "richard-a-miller", "david-e-harrison", "john-e-wilkinson" ], "author_names": [ "Randy Strong", "Richard A. Miller", "David E. Harrison", "John E Wilkinson" ], "text": "Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age-dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in spontaneous activity, occur more slowly in rapamycin-treated mice, suggesting strongly that rapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease. Rapamycin mTOR Genetically heterogeneous mice Rapamycin slows multiple aspects of aging (heart, liver, tendon, activity), beyond just suppressing cancer 4.7, 14, or 42 ppm rapamycin in food, administered from age 9 months. Genetically heterogeneous mice; young (4 month) and old (20-22 month) control groups, and old mice treated with rapamycin at 4.7, 14, or 42 ppm; N varies by outcome (e.g., 15-80 per group). Rapamycin significantly reduced incidences of liver degeneration (P=0.02), myocardial nuclear abnormalities (P=0.047), endometrial hyperplasia (P=0.05), and adrenal tumors (P=0.04); however, it increased cataract severity (P=0.014 males, P=0.001 females) and testicular degeneration (P<0.001). Histological evaluation of cataracts was limited to a small number of specimens; site-to-site variation was considerable for spontaneous activity; some observed trends did not reach statistical significance." }, { "sid": "HOX2019", "entities": [ "akt-pkb", "pi3k", "mtorc1" ], "authors": [ "brendan-d-manning", "gerta-hoxhaj" ], "author_names": [ "Brendan D. Manning", "Gerta Hoxhaj" ], "text": "The altered metabolic programme of cancer cells facilitates their cell-autonomous proliferation and survival. In normal cells, signal transduction pathways control core cellular functions, including metabolism, to couple the signals from exogenous growth factors, cytokines or hormones to adaptive changes in cell physiology. Not applicable (review) PI3K-AKT (upstream of mTOR) Review Reviews the PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism" }, { "sid": "WYA2017", "entities": [ "leucine", "slc38a9" ], "authors": [ "david-m-sabatini", "rachel-l-wolfson", "gregory-a-wyant", "monther-abu-remaileh", "elizaveta-freinkman", "walter-w-chen" ], "author_names": [ "David M. Sabatini", "Rachel L. Wolfson", "Gregory A. Wyant", "Monther Abu-Remaileh", "Elizaveta Freinkman", "Walter W. Chen" ], "text": "The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins. Biochemical/genetic (SLC38A9) SLC38A9 / mTORC1 (arginine) Mammalian cells SLC38A9 is an arginine sensor that also effluxes essential amino acids from lysosomes, letting cells use protein as a nutrient" }, { "sid": "SPI2010", "entities": [ "rapamycin", "alzheimers-disease", "mtorc1", "autophagy" ], "authors": [ "randy-strong", "arlan-richardson", "natalia-podlutskaya", "veronica-galvan", "jayanta-debnath", "patricia-spilman" ], "author_names": [ "Randy Strong", "Arlan Richardson", "Natalia Podlutskaya", "Veronica Galvan", "Jayanta Debnath", "Patricia Spilman" ], "text": "Reduced TOR signaling has been shown to significantly increase lifespan in a variety of organisms [1], [2], [3], [4]. It was recently demonstrated that long-term treatment with rapamycin, an inhibitor of the mTOR pathway[5], or ablation of the mTOR target p70S6K[6] extends lifespan in mice, possibly by delaying aging. Whether inhibition of the mTOR pathway would delay or prevent age-associated disease such as AD remained to be determined. Rapamycin mTOR / amyloid-β PDAPP transgenic mice (Alzheimer's model) Rapamycin reduces amyloid-β levels and abolishes cognitive deficits in an Alzheimer's mouse model rapamycin-supplemented diet for 13 weeks starting at 4 months of age, identical to the diet that extended lifespan in mice [5] groups of PDAPP mice and littermate non-transgenic controls (total N=124 for cognitive tests, based on F(3,120)) improved learning in rapamycin-fed PDAPP mice at day 4 (P=0.036); memory in rapamycin-fed PDAPP mice was indistinguishable from non-Tg groups; significantly decreased soluble Aβ42 levels in transgenic PDAPP mice (P=0.02) Aβ deposition was not determined" }, { "sid": "FRA2006", "entities": [ "rapamycin", "tuberous-sclerosis-complex" ], "authors": [ "david-n-franz", "kerry-r-crone" ], "author_names": [ "David N. Franz", "Kerry R. Crone" ], "text": "Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the formation of hamartomas in multiple organs. Five to 15% of affected individuals display subependymal giant cell astrocytomas, which can lead to substantial neurological and postoperative morbidity due to the production of hydrocephalus, mass effect, and their typical location adjacent to the foramen of Monro. We sought to see whether therapy with oral rapamycin could affect growth or induce regression in astrocytomas associated with TSC. Oral rapamycin (sirolimus), trough 5-15 ng/ml, 2.5-20 months mTORC1 (via FKBP12) Human Regression of all 5 TSC-associated astrocytomas; regrowth on interruption, re-regression on resumption" }, { "sid": "COT2006", "entities": [ "rapamycin", "mtor", "leucine", "s6k1" ], "authors": [ "george-thomas", "sara-c-kozma", "daniela-cota", "randy-j-seeley" ], "author_names": [ "George Thomas", "Sara C. Kozma", "Daniela Cota", "Randy J. Seeley" ], "text": "The mammalian Target of Rapamycin (mTOR) protein is a serine-threonine kinase that regulates cell-cycle progression and growth by sensing changes in energy status. We demonstrated that mTOR signaling plays a role in the brain mechanisms that respond to nutrient availability, regulating energy balance. In the rat, mTOR signaling is controlled by energy status in specific regions of the hypothalamus and colocalizes with neuropeptide Y and proopiomelanocortin neurons in the arcuate nucleus. Central (icv) leucine; leptin; rapamycin; fasting Hypothalamic mTOR (mTORC1) signalling Rat Central leucine raised hypothalamic mTOR signalling and reduced food intake and body weight; mTOR inhibition blunted leptin anorexia" }, { "sid": "HUANG2026", "entities": [ "pik3ca" ], "authors": [ "congxiu-huang", "xiaoge-sun" ], "author_names": [ "Congxiu Huang", "Xiaoge Sun" ], "text": "Cervical cancer remains a leading cause of cancer-related morbidity and mortality among women worldwide. Although genomic alterations in oncogenic signaling pathways have been implicated in cervical carcinogenesis, the functional impact of recurrent driver mutations remains incompletely understood. Whole-exome sequencing was performed on paired tumor and matched non-tumor tissues from 61 patients to identify recurrent somatic alterations. PIK3CA-E545K mutation AKT/mTOR Human Promotes tumor cell proliferation and invasion" }, { "sid": "ROB2013", "entities": [ "nucleotide-synthesis" ], "authors": [ "michael-n-hall", "aaron-m-robitaille", "mitsugu-shimobayashi", "marion-cornu" ], "author_names": [ "Michael N. Hall", "Aaron M. Robitaille", "Mitsugu Shimobayashi", "Marion Cornu" ], "text": "The Ser-Thr kinase mammalian target of rapamycin (mTOR) controls cell growth and metabolism by stimulating glycolysis and synthesis of proteins and lipids. To further understand the central role of mTOR in cell physiology, we used quantitative phosphoproteomics to identify substrates or downstream effectors of the two mTOR complexes. mTOR controlled the phosphorylation of 335 proteins, including CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). CAD catalyzes the first three steps in de novo pyrimidine synthesis. Quantitative phosphoproteomics mTORC1 / S6K1 / CAD Mammalian cells mTORC1 activates de novo pyrimidine synthesis (CAD phosphorylation), among 335 mTOR-controlled phosphosites" }, { "sid": "MUT2026", "entities": [ "rag-gtpases", "mtorc1" ], "authors": [ "dominic-winter" ], "author_names": [ "Dominic Winter" ], "text": "The subcellular distribution of lysosomes, the main degradative organelles of mammalian cells, responds to metabolic cues in a highly dynamic way. While lysosomal positioning due to amino acid levels is well-characterized, cholesterol-dependent regulation of lysosomal motility is incompletely understood. We explored impaired lysosomal cholesterol export using a mass spectrometry-based multi-OMICs approach, identifying widespread reallocation of resources and signaling pathway modulation. Perturbation of lysosomal cholesterol export (multi-omics) mTOR / LAMTOR1 (Ragulator) Human cell lines Cholesterol perturbation → mTOR-dependent LAMTOR1 (Ser56) phosphorylation controlling lysosomal motility" }, { "sid": "ROM2001", "entities": [ "muscle-growth", "akt-pkb", "pi3k", "mtorc1" ], "authors": [ "sue-c-bodine", "george-d-yancopoulos", "trevor-n-stitt" ], "author_names": [ "Sue C. Bodine", "George D. Yancopoulos", "Trevor N Stitt" ], "text": "Skeletal muscle is composed of multinucleated fibres, formed after the differentiation and fusion of myoblast precursors. Skeletal muscle atrophy and hypertrophy refer to changes in the diameter of these pre-existing muscle fibres. The prevention of atrophy would provide an obvious clinical benefit; insulin-like growth factor 1 (IGF-1) is a promising anti-atrophy agent because of its ability to promote hypertrophy. IGF-1 PI3K/Akt/mTOR & Akt/GSK3 Cultured muscle cells (mouse) IGF-1 drives skeletal myotube hypertrophy via PI3K/Akt/mTOR and PI3K/Akt/GSK3 pathways" }, { "sid": "SUX2017", "entities": [ "rag-gtpases", "mtorc1", "ragulator" ], "authors": [ "roberto-zoncu", "james-h-hurley", "do-jin-kim", "ming-yuan-su" ], "author_names": [ "Roberto Zoncu", "James H. Hurley", "Do Jin Kim", "Ming-Yuan Su" ], "text": "The lysosomal membrane is the locus for sensing cellular nutrient levels, which are transduced to mTORC1 via the Rag GTPases and the Ragulator complex. The crystal structure of the five-subunit human Ragulator at 1.4 A resolution was determined. Lamtor1 wraps around the other four subunits to stabilize the assembly. The Lamtor2:Lamtor3 dimer stacks upon Lamtor4:Lamtor5 to create a platform for Rag binding. Hydrogen-deuterium exchange was used to map the Rag binding site to the outer face of the Lamtor2:Lamtor3 dimer and to the N-terminal intrinsically disordered region of Lamtor1. Structural (crystal/hybrid) Rag GTPases / Ragulator (Lamtor1-5) / mTORC1 Hybrid structure Structure of the RagA/C-Ragulator activation complex; Lamtor1 wraps the subunits to form the Rag-binding platform" }, { "sid": "LEE2024", "entities": [ "longevity", "rapamycin", "mtor", "everolimus", "immune-function" ], "authors": [ "andrea-b-maier", "deborah-j-w-lee" ], "author_names": [ "Andrea B. Maier", "Deborah J W Lee" ], "text": "Rapamycin and its derivatives (rapalogs) are inhibitors of mTOR, a major regulator of the ageing process. We aimed to summarise the effects of rapamycin and its derivatives on the severity of ageing-related physiological changes and disease in adults. A search across five databases yielded 18 400 unique articles, resulting in 19 included studies. Rapamycin and its derivatives improved physiological parameters associated with ageing in the immune, cardiovascular, and integumentary systems of healthy individuals or individuals with ageing-related diseases. Rapamycin and rapalogs (aggregate of 19 studies) mTOR Human – systematic review (19 studies, 5 databases) Improved immune, cardiovascular and skin parameters; no effect on endocrine/muscular/neurological systems" }, { "sid": "ROS2015", "entities": [ "rapamycin", "mtor" ], "authors": [ "adam-b-salmon", "elizabeth-fernandez", "corinna-ross", "suzette-tardif" ], "author_names": [ "Adam B. Salmon", "Elizabeth Fernandez", "Corinna Ross", "Suzette Tardif" ], "text": "Rapamycin has been shown to extend lifespan in rodent models, but the effects on metabolic health and function have been widely debated in both clinical and translational trials. Prior to rapamycin being used as a treatment to extend both lifespan and healthspan in the human population, it is vital to assess the side effects of the treatment on metabolic pathways in animal model systems, including a closely related non-human primate model. Long-term oral encapsulated rapamycin Systemic metabolism (body composition, glucose handling, liver gluconeogenic enzymes) Common marmoset (Callithrix jacchus) Only minor metabolic consequences: no change in weight, lipids or glucose tolerance; small early fat-mass decrease; altered liver G6Pase, PCK and GPI activity" }, { "sid": "ZHAI2026", "entities": [ "pungenin", "mtor", "akt-pkb" ], "authors": [ "gang-li", "wencai-zhai", "lei-zhang", "jun-yang" ], "author_names": [ "Gang Li", "Wencai Zhai", "Lei Zhang", "Jun Yang" ], "text": "Androgenetic alopecia (AGA) is characterized by progressive miniaturization of hair follicles driven by dihydrotestosterone (DHT)-mediated androgen receptor signalling. Pungenin, a phenolic glucoside, was investigated in DHT-induced AGA model mice. In primary mouse hair follicle cells exposed to DHT, pungenin mitigated cellular injury, restored morphology and viability, and significantly reduced type II 5alpha-reductase expression. Topical pungenin markedly accelerated hair regeneration by histological analysis and serum biochemistry. Pungenin (topical) PI3K/AKT/FoxO/mTOR; SRD5A2 Mouse Accelerated hair regeneration, restored follicle cell viability, reduced 5α-reductase expression" }, { "sid": "HAFEZ2026", "entities": [ "melittin" ], "authors": [ "amany-a-e-ahmed", "saeed-a-hafez" ], "author_names": [ "Amany A E Ahmed", "Saeed A Hafez" ], "text": "Melittin, the main component in bee venom, exhibits valuable anti-inflammatory and immunomodulatory properties in various diseases; meanwhile, its effect on psoriasis has not been explored yet. Mice were divided into 5 groups: Control, Imiquimod (IMQ), methotrexate (MTX, 1 mg/kg), melittin (40 mg/kg), or melittin (80 mg/kg). All groups except the control received topical IMQ for seven days. Melittin PI3K/Akt/mTOR Mouse Reduces psoriatic inflammation via mTOR suppression and autophagy activation" }, { "sid": "CUI2023", "entities": [ "tfeb", "raptor", "rag-gtpases", "mtorc1", "flcn-fnip1-2", "ragulator" ], "authors": [ "andrea-ballabio", "james-h-hurley", "alessandra-esposito", "gennaro-napolitano", "zhicheng-cui", "jlenia-monfregola", "lukas-a-huber", "mariana-de-araujo" ], "author_names": [ "Andrea Ballabio", "James H. Hurley", "Alessandra Esposito", "Gennaro Napolitano", "Zhicheng Cui", "Jlenia Monfregola", "Lukas A. Huber", "Mariana de Araujo" ], "text": "The transcription factor TFEB is a master regulator of lysosomal biogenesis and autophagy. The phosphorylation of TFEB by the mechanistic target of rapamycin complex 1 (mTORC1) is unique in its mTORC1 substrate recruitment mechanism, which is strictly dependent on the amino acid-mediated activation of the RagC GTPase activating protein FLCN. TFEB lacks the TOR signalling motif responsible for the recruitment of other mTORC1 substrates. We used cryogenic-electron microscopy to determine the structure of TFEB as presented to mTORC1 for phosphorylation, which we refer to as the 'megacomplex'. Structural (cryo-EM, reconstituted complex) mTORC1-TFEB-Rag-Ragulator megacomplex Human proteins, cell-free reconstitution Structure of TFEB captured between two Rag-Ragulator complexes for mTORC1-mediated phosphorylation; non-canonical Rag dimer grips TFEB's N-terminal helix via a RagC-GDP-dependent clamp" }, { "sid": "MOE2025", "entities": [ "longevity", "muscle-growth", "rapamycin", "mtor" ], "authors": [ "sajad-zalzala", "mauricio-moel", "girish-harinath" ], "author_names": [ "Sajad Zalzala", "Mauricio Moel", "Girish Harinath" ], "text": "This 48-week decentralized, double-blinded, randomized, placebo-controlled trial (NCT04488601) evaluated the long-term safety of intermittent low-dose rapamycin in a healthy, normative-aging human cohort. Participants received placebo, 5 mg or 10 mg compounded rapamycin weekly. The primary outcome measure was visceral adiposity (by DXA scan), secondary outcomes were blood biomarkers, and lean tissue and bone mineral content (by DXA scan). Established surveys were utilized to evaluate health and well-being. Safety was assessed through adverse events and blood biomarker monitoring. Intermittent low-dose rapamycin (5/10 mg weekly, 48 wk) mTOR Human – RCT (PEARL, ages 50-85, n=114 completed) Intermittent low-dose rapamycin was safe over 1 year; some healthspan gains (e.g. lean tissue in women at 10 mg) Rapamycin (compounded), 5 mg/week or 10 mg/week orally, 48 weeks; randomized double-blind placebo-controlled. Note: compounded effective dose ~66% lower than the advertised dose. 114 completed: 40 at 5 mg/wk, 35 at 10 mg/wk, 39 placebo. Low female enrollment (35.1%). Primary endpoint (visceral adipose tissue) NOT met. Secondary: decreased bone mineral density (OR 0.24, 95% CI 0.06-0.93, p=0.04); increased lean tissue (esp. women at 10 mg); small HbA1c rise in 5 mg males (p=0.010). Overall safe/well tolerated over 1 year. Small n -> wide 95% CIs / underpowered; low female enrollment; compounded-dose uncertainty; minor changes in RBC / BUN / HbA1c; human gerotherapeutic data still limited." }, { "sid": "EIS2009", "entities": [ "longevity", "spermidine", "autophagy" ], "authors": [ "tobias-eisenberg", "frank-madeo", "sabrina-buttner", "didac-carmona-gutierrez", "sabrina-schroeder", "christoph-magnes", "christoph-ruckenstuhl", "nektarios-tavernarakis", "guido-kroemer" ], "author_names": [ "Tobias Eisenberg", "Frank Madeo", "Sabrina Büttner", "Didac Carmona-Gutierrez", "Sabrina Schroeder", "Christoph Magnes", "Christoph Ruckenstuhl", "Nektarios Tavernarakis", "Guido Kroemer" ], "text": "Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death. Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. In addition, spermidine administration potently inhibited oxidative stress in ageing mice. spermidine administration; depletion of endogenous polyamines; autophagy gene disruption autophagy, via histone acetyltransferase inhibition and histone H3 deacetylation yeast, Drosophila, C. elegans, human immune cells, and ageing mice for oxidative stress only Spermidine extended lifespan in yeast, flies and worms and raised autophagy, and the longevity benefit was lost when autophagy was disabled." }, { "sid": "FLY2013", "entities": [ "cardiac-aging", "longevity", "rapamycin", "mtor", "mtorc1" ], "authors": [ "randy-strong", "brian-k-kennedy", "pankaj-kapahi", "simon-melov", "james-m-flynn" ], "author_names": [ "Randy Strong", "Brian K. Kennedy", "Pankaj Kapahi", "Simon Melov", "James M. Flynn" ], "text": "Rapamycin has been shown to extend lifespan in numerous model organisms including mice, with the most dramatic longevity effects reported in females. However, little is known about the functional ramifications of this longevity-enhancing paradigm in mammalian tissues. We treated 24-month-old female C57BL/6J mice with rapamycin for 3 months and determined health outcomes via a variety of noninvasive measures of cardiovascular, skeletal, and metabolic health for individual mice. Rapamycin (3 months, late life) mTOR Aged (24-month) female mice Late-life rapamycin reverses age-related cardiac dysfunction in aged mice oral delivery of microencapsulated rapamycin diet at 14 parts per million (ppm) for 3 months N = 18 for each group (treated vs. nontreated) Significant systemic reduction in 4 cytokines (G-CSF, LIX, IL-17, IL-7) linked to inflammation (n=10 per group, P<0.05) Under- or overestimation of body composition in energy expenditure (EE) calculation is a known pitfall of indirect calorimetry" }, { "sid": "ZHO2009", "entities": [ "cognition", "rapamycin", "pten", "mtorc1" ], "authors": [ "luis-f-parada", "jing-zhou" ], "author_names": [ "Luis F. Parada", "Jing Zhou" ], "text": "PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a lipid phosphatase that counteracts the function of phosphatidylinositol-3 kinase (PI3K). Loss of function of PTEN results in constitutive activation of AKT and downstream effectors and correlates with many human cancers, as well as various brain disorders, including macrocephaly, seizures, Lhermitte-Duclos disease, and autism. We previously generated a conditional Pten knock-out mouse line with Pten loss in limited postmitotic neurons in the cortex and hippocampus. mTORC1 inhibition (rapamycin) mTORC1 / PTEN-Akt Mouse (neural Pten KO) mTORC1 inhibition prevents and reverses neuronal hypertrophy in Pten-null brain and ameliorates a subset of PTEN-associated abnormal behaviours" }, { "sid": "FOR2010", "entities": [ "metformin", "lkb1-stk11", "ampk" ], "authors": [ "benoit-viollet", "marc-foretz" ], "author_names": [ "Benoit Viollet", "Marc Foretz" ], "text": "Metformin is widely used to treat hyperglycemia in individuals with type 2 diabetes. Recently the LKB1/AMP-activated protein kinase (LKB1/AMPK) pathway was proposed to mediate the action of metformin on hepatic gluconeogenesis. However, the molecular mechanism by which this pathway operates had remained elusive. Surprisingly, here we have found that in mice lacking AMPK in the liver, blood glucose levels were comparable to those in wild-type mice, and the hypoglycemic effect of metformin was maintained. Metformin in AMPK-null / LKB1-null mouse liver Hepatic energy state (AMPK-independent) Mouse Metformin suppresses hepatic gluconeogenesis without AMPK or LKB1, via reduced hepatic energy charge" }, { "sid": "FRE2016", "entities": [ "everolimus", "tuberous-sclerosis-complex" ], "authors": [ "david-n-franz", "jacqueline-a-french", "petrus-j-de-vries", "paolo-curatolo" ], "author_names": [ "David N. Franz", "Jacqueline A. French", "Petrus J. de Vries", "Paolo Curatolo" ], "text": "Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used for various benign tumours associated with tuberous sclerosis complex. We assessed the efficacy and safety of two trough exposure concentrations of everolimus, 3-7 ng/mL (low exposure) and 9-15 ng/mL (high exposure), compared with placebo as adjunctive therapy for treatment-resistant focal-onset seizures in tuberous sclerosis complex. Adjunctive everolimus at trough 3-7 or 9-15 ng/mL vs placebo mTORC1 (via FKBP12) Human Seizure frequency reduced, dose-dependently (responder rate 15.1% placebo, 28.2% low, 40.0% high exposure)" }, { "sid": "VEL2003", "entities": [ "longevity", "mtor" ], "authors": [ "tibor-vellai" ], "author_names": [ "Tibor Vellai" ], "text": "Genetic (RNAi of let-363/CeTOR) TOR (CeTOR) C. elegans RNAi of C. elegans TOR roughly doubles adult lifespan, acting largely parallel to insulin/IGF-1-DAF-16" }, { "sid": "JAC2026", "entities": [ "longevity", "rapamycin", "mtor" ], "authors": [ "robin-j-mockett", "lauren-n-jackson" ], "author_names": [ "Robin J. Mockett", "Lauren N. Jackson" ], "text": "Rapamycin supplementation has been reported to extend life spans in numerous species, including Drosophila melanogaster, but a recent study in this laboratory revealed a marked life-shortening effect in y w male flies. The experiments reported here were performed to characterize conditions under which rapamycin could extend or shorten life spans in five fly strains. On a cornmeal/torula yeast-based medium, rapamycin extended life in one experiment, had no effect in six and was harmful in 19. Rapamycin (dietary supplementation, varying concentration and food medium) TOR/mTOR pathway (rapamycin-FKBP12-TOR) Drosophila melanogaster (5 strains, incl. y w and Dahomey) Diet-dependent bidirectional effect on adult lifespan (beneficial on nutrient-rich medium, harmful on cornmeal/torula medium); developmental toxicity at high doses" }, { "sid": "NAZ2013", "entities": [], "authors": [ "jorn-dengjel", "francesco-cecconi", "francesca-nazio" ], "author_names": [ "Jörn Dengjel", "Francesco Cecconi", "Francesca Nazio" ], "text": "Autophagy is important in the basal or stress-induced clearance of bulk cytosol, damaged organelles, pathogens and selected proteins by specific vesicles, the autophagosomes. Following mTOR (mammalian target of rapamycin) inhibition, autophagosome formation is primed by the ULK1 and the beclin-1-Vps34-AMBRA1 complexes, which are linked together by a scaffold platform, the exocyst. Although several regulative steps have been described along this pathway, few targets of mTOR are known, and the cross-talk between ULK1 and beclin 1 complexes is still not fully understood. Genetic/biochemical (mTOR/ULK1/AMBRA1/TRAF6) mTOR / ULK1 / AMBRA1 / TRAF6 Mammalian cells mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function via AMBRA1-TRAF6" }, { "sid": "SAX2026", "entities": [ "everolimus", "tuberous-sclerosis-complex" ], "authors": [ "julian-r-sampson", "petrus-j-de-vries", "anurag-saxena" ], "author_names": [ "Julian R. Sampson", "Petrus J. de Vries", "Anurag Saxena" ], "text": "Mammalian target of rapamycin (mTOR) inhibitors are effective treatments for tumours and epilepsy in tuberous sclerosis complex (TSC). This study aimed to determine the effects of the mTOR inhibitor everolimus and a placebo on neuropsychological functioning in TSC. Individuals with TSC aged 16-60 years and IQ>60 who scored <=5th percentile in one or more of 10 memory or executive function variables were randomised 2:1 to 24 weeks everolimus or placebo and retested at baseline and 4, 12, 24 and 36 weeks. Everolimus (mTOR inhibitor) vs placebo, 24 weeks, randomised 2:1 mTOR (mTORC1) Human (TSC patients, aged 16-60 years) No clear benefit of everolimus over placebo on neuropsychological function; both arms showed large responder rates (87% vs 75%), likely reflecting practice/placebo effects rather than a true drug effect" }, { "sid": "RAUCH2026", "entities": [ "tnks2-tankyrase-2" ], "authors": [ "peter-bai", "boglarka-rauch" ], "author_names": [ "Peter Bai", "Boglarka Rauch" ], "text": "Although tankyrases (TNKSs) were originally described as enzymes safeguarding genome integrity, TNKSs are also associated with metabolism and are involved in the differentiation of multiple cell lineages including adipocytes. Here we aimed to understand the role of TNKSs specifically in adipocyte differentiation. We found that the deletion of TNKS1 or TNKS2 decreased the rate of adipocyte differentiation. TNKS2 knockout / NV-5138 (autophagy activator) AMPK/mTORC1 Cell line Reduces adipocyte differentiation rate; AMPK activation suppresses mTORC1" }, { "sid": "KAP2004", "entities": [ "tsc1-tsc2", "longevity", "mtorc1" ], "authors": [ "pankaj-kapahi", "seymour-benzer" ], "author_names": [ "Pankaj Kapahi", "Seymour Benzer" ], "text": "In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. Genetic (TOR pathway modulation) TOR Drosophila melanogaster Reducing TOR pathway activity extends fly lifespan, overlapping with dietary restriction" }, { "sid": "MAR2026B", "entities": [ "rapamycin", "mtorc1", "gator1" ], "authors": [ "blake-b-rasmussen", "adam-b-salmon", "erik-d-marchant", "hanna-kalenta", "jacquelyn-may", "zhao-lai" ], "author_names": [ "Blake B. Rasmussen", "Adam B. Salmon", "Erik D. Marchant", "Hanna Kalenta", "Jacquelyn May", "Zhao Lai" ], "text": "mTORC1 activity is increased in muscle with aging and is implicated as a potential driver of age-related declines in muscle health. While pharmacological inhibition of mTORC1 improves lifespan and healthspan, it remains unclear whether chronic activation of mTORC1 is sufficient to accelerate aging in skeletal muscle. We aimed to address this question using an inducible model of muscle-specific knockout of Depdc5, which encodes the protein DEP domain containing 5 (DEPDC5), a negative regulator of mTORC1." }, { "sid": "WAN2015", "entities": [ "arginine", "slc38a9" ], "authors": [ "david-m-sabatini", "roberto-zoncu", "lynne-chantranupong", "rachel-l-wolfson", "liron-bar-peled", "kuang-shen", "shuyu-wang", "gregory-a-wyant", "tim-wang", "elizabeth-d-yuan", "choah-kim", "zhi-yang-tsun" ], "author_names": [ "David M. Sabatini", "Roberto Zoncu", "Lynne Chantranupong", "Rachel L. Wolfson", "Liron Bar-Peled", "Kuang Shen", "Shuyu Wang", "Gregory A. Wyant", "Tim Wang", "Elizabeth D. Yuan", "Choah Kim", "Zhi-Yang Tsun" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Biochemical/genetic (SLC38A9) SLC38A9 / Rag-Ragulator / mTORC1 Mammalian cells SLC38A9 signals arginine sufficiency to mTORC1 at the lysosomal surface" }, { "sid": "SHIM2026", "entities": [ "muscle-growth", "leucine", "sestrin2", "mtorc1", "protein-synthesis" ], "authors": [ "hyeon-soo-kim", "jae-ho-shim" ], "author_names": [ "Hyeon Soo Kim", "Jae Ho Shim" ], "text": "Sarcopenia, the age-related loss of skeletal muscle mass and function, lacks FDA-approved pharmacotherapy. The mechanistic target of rapamycin complex 1 (mTORC1), activated by leucine via Sestrin2, is the master regulator of muscle protein synthesis, but L-leucine suffers from rapid catabolism and poor bioavailability. Here, we report D-leucine methyl ester hydrochloride (DLMEH), a metabolically stabilized prodrug incorporating D-stereoisomer conversion, methyl esterification, and hydrochloride salt formation. D-leucine methyl ester hydrochloride (DLMEH) versus L-leucine; Sestrin2 siRNA knockdown; rapamycin co-treatment Sestrin2-dependent mTORC1 activation and muscle protein synthesis Rat (in vivo); human primary myotubes DLMEH bound Sestrin2 with leucine-equivalent affinity and raised mTORC1-dependent protein synthesis, preserving muscle mass, grip strength and endurance in the rat atrophy model." }, { "sid": "SHE2018B", "entities": [ "arginine", "rag-gtpases", "slc38a9", "ragulator" ], "authors": [ "david-m-sabatini", "kuang-shen" ], "author_names": [ "David M. Sabatini", "Kuang Shen" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) growth pathway detects nutrients through a variety of sensors and regulators that converge on the Rag GTPases, which form heterodimers consisting of RagA or RagB tightly bound to RagC or RagD and control the subcellular localization of mTORC1. The Rag heterodimer uses a unique \"locking\" mechanism to stabilize its active (RagA(GTP)-RagC(GDP)) or inactive (RagA(GDP)-RagC(GTP)) nucleotide states. Biochemical nucleotide-exchange assays (Ragulator, SLC38A9) Ragulator / SLC38A9 / Rag GTPases / mTORC1 Purified proteins; human cells (HEK293) Ragulator releases GTP from RagC and arginine-bound SLC38A9 loads RagA with GTP; together they activate the Rag heterodimer" }, { "sid": "CAR2008", "entities": [ "erk-rsk-mapk" ], "authors": [ "lewis-c-cantley", "george-thomas", "pier-paolo-pandolfi", "sara-c-kozma", "arkaitz-carracedo", "jose-baselga" ], "author_names": [ "Lewis C. Cantley", "George Thomas", "Pier Paolo Pandolfi", "Sara C. Kozma", "Arkaitz Carracedo", "José Baselga" ], "text": "Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule-dependent increase in activation of the MAPK pathway. mTOR inhibition (rapamycin/rapalogs) mTORC1 / MAPK / PI3K Human (patient tumour biopsies on RAD001); mouse; human cells mTORC1 inhibition activates the MAPK pathway through a PI3K-dependent feedback loop (a resistance mechanism)" }, { "sid": "CHA2016", "entities": [ "arginine", "gator2", "castor1", "mtorc1" ], "authors": [ "david-m-sabatini", "robert-a-saxton", "lynne-chantranupong", "kuang-shen", "j-wade-harper", "steven-p-gygi", "sonia-m-scaria", "gregory-a-wyant", "tim-wang" ], "author_names": [ "David M. Sabatini", "Robert A. Saxton", "Lynne Chantranupong", "Kuang Shen", "J. Wade Harper", "Steven P. Gygi", "Sonia M. Scaria", "Gregory A. Wyant", "Tim Wang" ], "text": "Amino acids signal to the mTOR complex I (mTORC1) growth pathway through the Rag GTPases. Multiple distinct complexes regulate the Rags, including GATOR1, a GTPase activating protein (GAP), and GATOR2, a positive regulator of unknown molecular function. Arginine stimulation of cells activates mTORC1, but how it is sensed is not well understood. Recently, SLC38A9 was identified as a putative lysosomal arginine sensor required for arginine to activate mTORC1 but how arginine deprivation represses mTORC1 is unknown. Biochemical/genetic (CASTOR1/2) CASTOR / GATOR2 / mTORC1 (arginine) Human cells (biochemistry) The CASTOR proteins are direct arginine sensors for the mTORC1 pathway" }, { "sid": "DIB2015", "entities": [ "pi3k" ], "authors": [ "lewis-c-cantley", "christian-c-dibble" ], "author_names": [ "Lewis C. Cantley", "Christian C. Dibble" ], "text": "The class I phosphoinositide 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling network directs cellular metabolism and growth. Not applicable (review) PI3K / mTORC1 Review Reviews how PI3K signaling activates mTORC1" }, { "sid": "NOL2026", "entities": [ "longevity", "rapamycin", "mtor" ], "authors": [ "lyvia-neves-rebello-alves-nolasco", "iuri-drumond-louro" ], "author_names": [ "Lyvia Neves Rebello Alves Nolasco", "Iúri Drumond Louro" ], "text": "Rapamycin is a macrolide compound originally identified for its antifungal activity and subsequently recognized as a potent inhibitor of the mechanistic target of rapamycin (mTOR), a conserved signaling kinase that integrates nutrient availability, growth factor signals, and cellular stress responses to regulate cell growth and metabolism. This review examines rapamycin across biological and medical fields, covering its discovery, chemical and pharmacological properties, and the central role of mTOR as its primary molecular target. none (narrative review of rapamycin and rapalogs) mTOR signalling not applicable (review spanning preclinical and clinical literature) Argues that mTOR inhibition is a unifying strategy across chronic disease and healthspan, while setting out the limitations and adverse effects of the approach." }, { "sid": "DAB2026", "entities": [ "foxo", "akt-pkb", "mtorc1" ], "authors": [ "agnieszka-dabkowska", "malgorzata-firczuk" ], "author_names": [ "Agnieszka Dąbkowska", "Malgorzata Firczuk" ], "text": "B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by impaired B-cell maturation and poor prognosis in relapsed/refractory (R/R) cases. While CD20-targeted immunotherapies offer clinical benefit, their efficacy is limited by low and heterogeneous CD20 expression on BCP-ALL cells. In this study, we demonstrate that overexpression of wild-type IKZF1, a tumor suppressor frequently mutated in high-risk BCP-ALL, upregulates CD20 and promotes leukemic B cell maturation. mTORC1 inhibitors; wild-type IKZF1 overexpression; anti-CD20 monoclonal antibody combination mTORC1, with CD20 induction via the AKT-FOXO1 axis human BCP-ALL cell lines, patient-derived models and in vivo models mTORC1 inhibition raised CD20 and promoted B-lineage maturation, improving anti-CD20 antibody efficacy including in IKZF1-deleted models." }, { "sid": "SHI1998", "entities": [ "rapamycin", "5top-mrna", "s6k1" ], "authors": [ "george-thomas", "sara-c-kozma", "mario-pende" ], "author_names": [ "George Thomas", "Sara C. Kozma", "Mario Pende" ], "text": "Recent studies have shown that the p70(s6k)/p85(s6k) signaling pathway plays a critical role in cell growth by modulating the translation of a family of mRNAs termed 5'TOPs, which encode components of the protein synthetic apparatus. Here we demonstrate that homozygous disruption of the p70(s6k)/p85(s6k) gene does not affect viability or fertility of mice, but that it has a significant effect on animal growth, especially during embryogenesis. Surprisingly, S6 phosphorylation in liver or in fibroblasts from p70(s6k)/p85(s6k)-deficient mice proceeds normally in response to mitogen stimulation. Germline S6K1 (p70/p85 S6K) knockout; rapamycin in knockout fibroblasts Body size; S6 phosphorylation; 5'TOP mRNA translation; S6K2 expression Mouse Loss of S6K1 reduces body size, especially embryonic growth, while S6 phosphorylation and rapamycin-sensitive 5'TOP translation persist via S6K2" }, { "sid": "DIB2013", "entities": [ "mtorc1" ], "authors": [ "brendan-d-manning", "christian-c-dibble" ], "author_names": [ "Brendan D. Manning", "Christian C. Dibble" ], "text": "Flux through metabolic pathways is inherently sensitive to the levels of specific substrates and products, but cellular metabolism is also managed by integrated control mechanisms that sense the nutrient and energy status of a cell or organism. The mechanistic target of rapamycin complex 1 (mTORC1), a protein kinase complex ubiquitous to eukaryotic cells, has emerged as a critical signalling node that links nutrient sensing to the coordinated regulation of cellular metabolism. Not applicable (review) mTORC1 Review Reviews how mTORC1 integrates signals to coordinate nutrient input with biosynthetic output" }, { "sid": "ULL2026", "entities": [ "tfeb", "p62-sqstm1", "mtorc1", "autophagy", "flcn-fnip1-2" ], "authors": [ "helene-knvelsrud", "halvor-ullern" ], "author_names": [ "Helene Knævelsrud", "Halvor Ullern" ], "text": "Birt-Hogg-Dubé syndrome (BHD) is an autosomal, dominant condition caused by FLCN mutation and characterized by enhanced risk for kidney tumors. Previous studies have shown constitutive nuclear localization of the transcription factor TFEB and simultaneous hyperactivation of canonical MTORC1 signaling in the absence of FLCN. Here we assess the impact on autophagy under the situation of combined anabolic and catabolic activation. FLCN gene loss (patient-derived model; no pharmacological intervention) FLCN / mTORC1 / TFEB / SQSTM1 (p62) Human (BHD patient-derived kidney cancer cell line; Norwegian patient tumor cohort) FLCN loss decouples SQSTM1/p62 accumulation from bulk autophagy flux despite mTORC1 hyperactivation and nuclear TFEB" }, { "sid": "KAH2000", "entities": [ "rapamycin", "mtor", "kidney-transplant" ], "authors": [ "barry-d-kahan" ], "author_names": [ "Barry D. Kahan" ], "text": "Acute rejection episodes after renal transplantation are an important clinical challenge, despite use of multidrug immunosuppressive regimens. We did a prospective, multicentre, randomised, double-blind trial to investigate the impact of the addition of sirolimus, compared with azathioprine, to a cyclosporin and prednisone regimen. 719 recipients of primary HLA-mismatched cadaveric or living-donor renal allografts who displayed initial graft function were randomly assigned, after transplantation, sirolimus 2 mg daily (n=284) or 5 mg daily (n=274), or azathioprine (n=161). Sirolimus (vs azathioprine; + cyclosporine/prednisone) mTOR Human – phase III RCT (n=719, renal transplant) Adding sirolimus reduced acute renal allograft rejection compared with azathioprine" }, { "sid": "ROB2012", "entities": [], "authors": [ "david-m-sabatini", "dudley-w-lamming", "t-keith-blackwell", "stacey-robida-stubbs" ], "author_names": [ "David M. Sabatini", "Dudley W. Lamming", "T. Keith Blackwell", "Stacey Robida-Stubbs" ], "text": "The TOR kinase, which is present in the functionally distinct complexes TORC1 and TORC2, is essential for growth but associated with disease and aging. Elucidation of how TOR influences life span will identify mechanisms of fundamental importance in aging and TOR functions. Here we show that when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity. SKN-1 also upregulates TORC1 pathway gene expression in a feedback loop. Rapamycin triggers a similar protective response in C. Genetic + rapamycin (TORC1 inhibition) TORC1 / SKN-1(Nrf) / DAF-16(FoxO) C. elegans Genetic TORC1 inhibition extends lifespan via SKN-1/Nrf and DAF-16/FoxO; rapamycin's effect needs SKN-1 but not DAF-16 not stated not stated not stated not stated" }, { "sid": "MIL2011", "entities": [ "longevity", "rapamycin", "mtor", "simvastatin", "resveratrol" ], "authors": [ "randy-strong", "richard-a-miller", "david-e-harrison", "clinton-astle", "kevin-flurkey", "nancy-l-nadon", "zelton-dave-sharp" ], "author_names": [ "Randy Strong", "Richard A. Miller", "David E. Harrison", "Clinton Astle", "Kevin Flurkey", "Nancy L. Nadon", "Zelton Dave Sharp" ], "text": "Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. Median survival was extended by an average of 10% in males and 18% in females. Rapamycin attenuated age-associated decline in spontaneous activity in males but not in females. Causes of death were similar in control and rapamycin-treated mice. Resveratrol (at 300 and 1200 ppm food) and simvastatin (12 and 120 ppm) did not have significant effects on survival in male or female mice. Rapamycin (vs resveratrol, simvastatin) mTOR Mouse (genetically heterogeneous, ITP, 3 sites) Rapamycin from 9 months extended lifespan (males +10%, females +18%); resveratrol and simvastatin did not" }, { "sid": "SEL2009", "entities": [ "longevity", "mtorc1", "s6k1" ], "authors": [ "george-thomas", "linda-partridge", "dominic-j-withers", "sara-c-kozma", "colin-selman" ], "author_names": [ "George Thomas", "Linda Partridge", "Dominic J. Withers", "Sara C. Kozma", "Colin Selman" ], "text": "Caloric restriction (CR) protects against aging and disease, but the mechanisms by which this affects mammalian life span are unclear. We show in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. Genetic (S6K1 knockout) S6K1 / mTOR Mouse (S6K1 KO) S6K1 deletion extends lifespan in female mice only (+19% median, not significant in males) and improves healthspan measures not stated not stated Median lifespan in S6K1 -/- mice increased by 80 days (from 862 to 942 days) or 9% relative to WT mice (X 2 = 10.52, p < 0.001) for both sexes combined. Female S6K1 -/- mice median lifespan increased by 153 days (19%) (p < 0.001), while male S6K1 -/- mice showed no effect (p > 0.05). not stated" }, { "sid": "RUV2005", "entities": [ "rapamycin", "5top-mrna", "insulin", "protein-synthesis" ], "authors": [ "oded-meyuhas", "igor-ruvinsky" ], "author_names": [ "Oded Meyuhas", "Igor Ruvinsky" ], "text": "The regulated phosphorylation of ribosomal protein (rp) S6 has attracted much attention since its discovery in 1974, yet its physiological role has remained obscure. To directly address this issue, we have established viable and fertile knock-in mice, whose rpS6 contains alanine substitutions at all five phosphorylatable serine residues (rpS6(P-/-)). Here we show that contrary to the widely accepted model, this mutation does not affect the translational control of TOP mRNAs. Knock-in of non-phosphorylatable rpS6 (five Ser->Ala) 5'TOP translation; protein synthesis; cell size; beta-cell size; glucose tolerance Mouse Loss of rpS6 phosphorylation reduces cell and beta-cell size and impairs glucose tolerance without affecting 5'TOP translation" }, { "sid": "YAO2011", "entities": [ "everolimus", "pancreatic-neuroendocrine-tumor", "mtorc1" ], "authors": [ "kjell-oberg", "jaume-capdevila", "james-c-yao", "david-lebwohl" ], "author_names": [ "Kjell Öberg", "Jaume Capdevila", "James C. Yao", "David Lebwohl" ], "text": "Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. Everolimus mTORC1 Human – phase 3 RCT (RADIANT-3, n=410) Everolimus prolonged progression-free survival in advanced pancreatic neuroendocrine tumors Everolimus 10 mg once daily vs placebo; oral; international multicenter double-blind phase 3 (RADIANT-3). 410 patients, 82 centers, 18 countries (target 392) with advanced pancreatic neuroendocrine tumors. Everolimus prolonged progression-free survival vs placebo (primary endpoint). Confirmed objective responses 5% (everolimus) vs 2% (placebo). Noninfectious pneumonitis / interstitial lung disease in 7 patients (5 drug-related, ~2%); other cancer therapies debated as comparators." }, { "sid": "LAW2018", "entities": [], "authors": [ "roberto-zoncu", "rosalie-e-lawrence", "james-h-hurley", "ofer-moldavski", "do-jin-kim" ], "author_names": [ "Roberto Zoncu", "Rosalie E. Lawrence", "James H. Hurley", "Ofer Moldavski", "Do Jin Kim" ], "text": "A key step in nutrient sensing is activation of the master growth regulator, mTORC1 kinase, on the lysosomal membrane. Nutrients enable mTORC1 scaffolding by a complex composed of the Rag GTPases (Rags) and Ragulator, but the underlying mechanism of mTORC1 capture is poorly understood. Combining dynamic imaging in cells and reconstituted systems, we uncover an affinity switch that controls mTORC1 lifetime and activation at the lysosome. Biochemical/imaging (Rag-Ragulator) Rag GTPases / Ragulator / mTORC1 Mammalian cells A nutrient-induced affinity switch controls mTORC1 capture and lifetime on the Rag-Ragulator lysosomal scaffold" }, { "sid": "MAT2017", "entities": [ "longevity", "caloric-restriction" ], "authors": [ "david-b-allison", "julie-a-mattison", "rozalyn-m-anderson", "rafael-de-cabo" ], "author_names": [ "David B. Allison", "Julie A. Mattison", "Rozalyn M. Anderson", "Rafael de Cabo" ], "text": "Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species but its impact in nonhuman primates has been controversial. In the late 1980s two parallel studies were initiated to determine the effect of CR in rhesus monkeys. The University of Wisconsin study reported a significant positive impact of CR on survival, but the National Institute on Aging study detected no significant survival effect. Caloric restriction Nutrient-sensing / mTOR (indirect) Rhesus macaque (2 independent cohorts) Caloric restriction improved health and (in the Wisconsin cohort) survival in rhesus monkeys CR monkeys received 30% less food than height-, age- and sex-matched control monkeys (NIA); CR was implemented on a per-individual basis after establishing baseline food intake (UW). NIA study: 121 monkeys; UW study: 76 monkeys. UW study: statistically significant effect of CR in increasing survival (Cox regression P =0.017); NIA study: no significant impact of CR on survival. Fundamental differences in study design and implementation between NIA and UW studies (e.g., age of onset, genetic origin, diet composition, feeding practices); NIA study's wide age of onset precluded grouping for analysis; UW study likely lacked statistical power for longevity." }, { "sid": "YIP2010", "entities": [ "rapamycin", "mlst8", "raptor", "fkbp12", "mtorc1" ], "authors": [ "david-m-sabatini", "seong-a-kang", "calvin-k-yip" ], "author_names": [ "David M. Sabatini", "Seong A. Kang", "Calvin K. Yip" ], "text": "The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth in response to the nutrient and energy status of the cell, and its deregulation is common in human cancers. Little is known about the overall architecture and subunit organization of this essential signaling complex. We have determined the three-dimensional (3D) structure of the fully assembled human mTORC1 by cryo-electron microscopy (cryo-EM). Our analyses reveal that mTORC1 is an obligate dimer with an overall rhomboid shape and a central cavity. FKBP12-rapamycin or Torin1 on purified mTORC1; Raptor-free mTOR preparations mTORC1 (mTOR-Raptor dimer) Human (protein purified from HEK-293T cells) FKBP12-rapamycin bound mTORC1 and, over time, disassembled it; S6K1 phosphorylation fell quickly, 4E-BP1 phosphorylation only after prolonged exposure" }, { "sid": "WAN2026", "entities": [ "longevity", "5top-mrna", "mtorc1", "protein-synthesis", "4e-bp1" ], "authors": [ "zongzhao-zhai" ], "author_names": [ "Zongzhao Zhai" ], "text": "Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes that are crucial for physiological homeostasis and ageing. mTORC1 preferentially regulates the translation of 5'-terminal oligopyrimidine (TOP) motif-containing mRNAs (which encode mainly ribosomal proteins) through the 4E-BP translational repressor; however, this function of mTORC1 is resistant to rapamycin inhibition. genetic ablation of Lsp2 in Drosophila; essential amino acid feeding; rapamycin comparison mTORC1 output to TOP-motif mRNA translation via 4E-BP Drosophila melanogaster Loss of Lsp2 selectively reduced TOP mRNA translation in a 4E-BP-dependent way and robustly extended lifespan without impairing reproduction." }, { "sid": "YAN2026", "entities": [ "slc15a3", "mtorc1" ], "authors": [ "hani-goodarzi" ], "author_names": [ "Hani Goodarzi" ], "text": "Antimetabolites, chemotherapy targeting nucleotide biosynthesis, are among the oldest and most widely used cancer treatments, yet resistance remains a daunting barrier, especially in the fight against B cell lymphomas. However, the underlying mechanisms of this resistance have long remained elusive. Using an innovative, integrated omics approach, we unexpectedly identified that the accumulation of dipeptides and upregulation of the dipeptide transporter SLC15A3 underlie resistance to nucleotide deficiency in a Myc-driven large B cell lymphoma mouse model. SLC15A3 inhibition; mTORC1 inhibition mTORC1; SLC15A3 dipeptide transporter; nutrient sensing Mouse; human lymphoma cell lines SLC15A3 imports dipeptides to activate mTORC1, conferring antimetabolite chemoresistance; silencing SLC15A3 restores 6MP sensitivity and resistant lymphomas become selectively rapamycin-sensitive" }, { "sid": "GIN1999", "entities": [ "eif4e", "mtor", "4e-bp1" ], "authors": [ "nahum-sonenberg", "steven-p-gygi", "robert-t-abraham", "anne-claude-gingras" ], "author_names": [ "Nahum Sonenberg", "Steven P. Gygi", "Robert T. Abraham", "Anne-Claude Gingras" ], "text": "The multisubunit eukaryotic translation initiation factor (eIF) 4F recruits 40S ribosomal subunits to the 5' end of mRNA. The eIF4F subunit eIF4E interacts directly with the mRNA 5' cap structure. Assembly of the eIF4F complex is inhibited by a family of repressor polypeptides, the eIF4E-binding proteins (4E-BPs). Binding of the 4E-BPs to eIF4E is regulated by phosphorylation: Hypophosphorylated 4E-BP isoforms interact strongly with eIF4E, whereas hyperphosphorylated isoforms do not. Biochemical (mTOR / 4E-BP1) mTOR / 4E-BP1 / eIF4E Mammalian cells; in vitro 4E-BP1 phosphorylation follows a two-step mechanism that regulates its binding to eIF4E" }, { "sid": "BEN2016", "entities": [ "nucleotide-synthesis" ], "authors": [ "brendan-d-manning", "gerta-hoxhaj", "issam-ben-sahra", "john-m-asara" ], "author_names": [ "Brendan D. Manning", "Gerta Hoxhaj", "Issam Ben-Sahra", "John M. Asara" ], "text": "In response to growth signals, mechanistic target of rapamycin complex 1 (mTORC1) stimulates anabolic processes underlying cell growth. We found that mTORC1 increases metabolic flux through the de novo purine synthesis pathway in various mouse and human cells, thereby influencing the nucleotide pool available for nucleic acid synthesis. Genetic/pharmacologic (mTORC1) mTORC1 / ATF4 / mitochondrial folate (THF) cycle Mammalian cells mTORC1 induces de novo purine synthesis through control of the mitochondrial tetrahydrofolate cycle" }, { "sid": "DUR2026", "entities": [ "growth-hormone-igf-1-axis", "longevity", "insulin-resistance" ], "authors": [ "john-j-kopchick", "darlene-e-berryman", "edward-o-list", "silvana-duran-ortiz", "yuji-ikeno" ], "author_names": [ "John J. Kopchick", "Darlene E. Berryman", "Edward O. List", "Silvana Duran-Ortiz", "Yuji Ikeno" ], "text": "Suppression of growth hormone (GH) signaling is known to be effective to extend lifespan in mammals, yet most models rely on congenital disruption of the GH/insulin-like growth factor-1 (IGF-1) axis. Whether modulation of this pathway later in life can still influence aging and the underlying cellular mechanisms remains incompletely understood. To address this, we ablated the growth hormone receptor (Ghr) at 12-months of age in mice (12mGHRKO), using a tamoxifen-inducible model. Tamoxifen-inducible whole-body Ghr knockout initiated at 12 months of age Growth hormone receptor (GHR) / GH-IGF-1 axis; hepatic GH-STAT5 signalling Mouse (12mGHRKO, both sexes) Extended lifespan in both sexes from a midlife start; improved insulin sensitivity, neuromuscular and bone ageing in males; feminised male hepatic transcriptome" }, { "sid": "LV2026S", "entities": [ "tsc1-tsc2", "mtor", "usp7" ], "authors": [ "shiqi-lv", "xiaoyan-zhang" ], "author_names": [ "Shiqi Lv", "Xiaoyan Zhang" ], "text": "Ubiquitin-specific protease 7 (USP7) is a deubiquitinase implicated in tumor progression; its role in renal fibrosis was unclear. USP7 was significantly upregulated in kidneys of patients with chronic kidney disease (CKD), correlating with fibrotic lesions and renal dysfunction. Genetic depletion and pharmacological blockade of USP7 significantly attenuated fibroblast activation and extracellular matrix deposition in unilateral ureteral obstruction and unilateral renal ischemia-reperfusion injury mouse models. Genetic (USP7 knockdown) and pharmacological USP7 inhibition USP7 -> KDM5B -> TSC1 -> mTOR axis Mouse (UUO, unilateral renal I/R injury models); human CKD kidney tissue (correlative) USP7 depletion/inhibition restores TSC1 expression, suppresses mTOR activation, and attenuates fibroblast activation and renal fibrosis" }, { "sid": "MEI2008", "entities": [ "tsc1-tsc2", "rapamycin", "everolimus", "mtorc1", "tuberous-sclerosis-complex" ], "authors": [ "david-j-kwiatkowski", "lynsey-meikle" ], "author_names": [ "David J. Kwiatkowski", "Lynsey Meikle" ], "text": "Tuberous sclerosis (TSC) is a hamartoma syndrome attributable to mutations in either TSC1 or TSC2 in which brain involvement causes epilepsy, mental retardation, and autism. We have reported recently a mouse neuronal model of TSC in which Tsc1 is ablated in most neurons during cortical development. We have tested rapamycin and RAD001, both mammalian target of rapamycin mTORC1 inhibitors, as potential therapeutic agents in this model. Median survival is improved from 33 d to more than 100 d; behavior, phenotype, and weight gain are all also markedly improved. Rapamycin / RAD001 (mTORC1 inhibition) mTORC1 / Akt Mouse (Tsc1 neuronal KO) mTOR inhibitors improve survival and function in a neuronal model of tuberous sclerosis" }, { "sid": "DEM2026", "entities": [ "mtorc1", "protein-synthesis", "ampk" ], "authors": [ "simon-raffel", "aykut-demir", "nicola-zamboni" ], "author_names": [ "Simon Raffel", "Aykut Demir", "Nicola Zamboni" ], "text": "Targeting metabolic dependencies of leukemic stem cells (LSC) may open avenues to improve outcomes of patients suffering from acute myeloid leukemia (AML). LSCs rely heavily on an active tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation whereas healthy hematopoietic stem and progenitor cells (HSPCs) possess more metabolic flexibility. Here, we identify the TCA cycle enzyme isocitrate dehydrogenase 3 (IDH3) as a critical and selective regulator of LSC maintenance. IDH3A knockdown (shRNA); BCL2 inhibition with venetoclax IDH3A-citrate-AMPK-mTORC1 axis Human AML patient samples, bone marrow organoids, xenograft mice IDH3A loss raised intracellular citrate, activated AMPK and suppressed mTORC1 and translation, sensitising leukemic stem cells to venetoclax." }, { "sid": "GRA2014", "entities": [ "mtor" ], "authors": [ "david-m-sabatini", "kuang-shen", "brian-c-grabiner", "kivanc-birsoy" ], "author_names": [ "David M. Sabatini", "Kuang Shen", "Brian C. Grabiner", "Kivanç Birsoy" ], "text": "Genes encoding components of the PI3K-AKT-mTOR signaling axis are frequently mutated in cancer, but few mutations have been characterized in MTOR, the gene encoding the mTOR kinase. Using publicly available tumor genome sequencing data, we generated a comprehensive catalog of mTOR pathway mutations in cancer, identifying 33 MTOR mutations that confer pathway hyperactivation. The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types, with one cluster particularly prominent in kidney cancer. Genomics (MTOR mutations) mTOR (hyperactivating mutations) Cancer cell panels Catalogs 33 hyperactivating cancer-associated MTOR mutations (6 clusters) that can predict rapamycin sensitivity" }, { "sid": "SONH2026", "entities": [ "mitophagy", "ulk1", "mtor", "autophagy", "ampk", "urolithin-a" ], "authors": [ "hangyul-song", "chang-myung-oh" ], "author_names": [ "Hangyul Song", "Chang-Myung Oh" ], "text": "In a two-hit HFpEF mouse model (high-fat diet + L-NAME), urolithin A (UA) alleviated diastolic dysfunction, cardiac hypertrophy, and fibrosis. UA activated AMPK signaling while inhibiting mTOR, promoting ULK1-dependent autophagy initiation and restoring impaired mitophagic flux. Multi-omics revealed UA remodels the gut microbiome-ceramide axis, reducing circulating ceramide accumulation and lipotoxic stress. Single-nucleus transcriptomics in human iPSC-derived cardiomyocytes confirmed attenuation of fibrosis-related cellular programming. Urolithin A (gut microbiome-derived compound) AMPK / mTOR / ULK1 / mitophagy / ceramide axis Mouse Improved diastolic function, reduced cardiac hypertrophy and fibrosis via mitophagy restoration; reduced ceramide accumulation" }, { "sid": "LANDOAS2026", "entities": [ "lung-transplant", "everolimus" ], "authors": [ "pierrick-bedouch", "agathe-landoas" ], "author_names": [ "Pierrick Bedouch", "Agathe Landoas" ], "text": "Everolimus has been incorporated into the immunosuppressive management of lung transplant patients. Due to its anti-proliferative properties it is being studied in the context of chronic lung allograft dysfunction (CLAD). A retrospective single-centre observational study of lung transplant patients between January 2000 and August 2021 treated with everolimus during follow-up. The timing of everolimus introduction was identified as a risk factor for CLAD (OR 1.069, 95% CI 1.017-1.123), as was the number of everolimus discontinuations (OR 12.660, 95% CI 1.025-156.329). Everolimus mTOR Human Early introduction and fewer interruptions associated with lower CLAD risk; lung function stability maintained" }, { "sid": "TIW2026", "entities": [ "akt-pkb", "mtorc1", "protein-synthesis", "tumor-growth" ], "authors": [ "ashutosh-tiwari", "anindya-bagchi" ], "author_names": [ "Ashutosh Tiwari", "Anindya Bagchi" ], "text": "Depletion of the circPVT1-encoded micropeptide (FFX) AKT-mTORC1 signalling and cap-dependent translation, sustaining MYC Human MYC-amplified cancer cell lines; mouse xenografts The micropeptide sustains AKT-mTORC1 signalling and cap-dependent translation; depleting it lowered MYC protein and impaired xenograft tumour growth." }, { "sid": "MAR2026", "entities": [ "everolimus", "breast-cancer", "mtorc1" ], "authors": [ "diogo-martins-branco", "evandro-de-azambuja" ], "author_names": [ "Diogo Martins-Branco", "Evandro de Azambuja" ], "text": "Multicentre, international, retrospective quasi-experimental study (n=207 women with ER+/HER2- advanced breast cancer after CDK4/6 inhibitor progression). Everolimus + endocrine therapy (n=150) vs endocrine therapy alone (n=57). Median real-world PFS: 5.0 vs 4.3 months (adjusted HR 0.68, 95% CI 0.47-0.99). Time to everolimus failure: 4.2 months. No significant differences in time to chemotherapy or overall survival. Safety profile consistent with prior reports. Median follow-up 31.8 months. Everolimus (mTOR inhibitor) + endocrine therapy mTORC1 Human Modest PFS improvement (HR 0.68) in post-CDK4/6i ER+ breast cancer; no OS benefit demonstrated" }, { "sid": "AYL2015", "entities": [ "rapamycin", "mlst8", "raptor", "fkbp12", "mtorc1" ], "authors": [ "michael-n-hall", "timm-maier", "nenad-ban", "christopher-aylett", "daniel-boehringer", "stefan-imseng", "evelyn-sauer" ], "author_names": [ "Michael N. Hall", "Timm Maier", "Nenad Ban", "Christopher Aylett", "Daniel Boehringer", "Stefan Imseng", "Evelyn Sauer" ], "text": "Target of rapamycin (TOR), a conserved protein kinase and central controller of cell growth, functions in two structurally and functionally distinct complexes: TORC1 and TORC2. Dysregulation of mammalian TOR (mTOR) signaling is implicated in pathologies that include diabetes, cancer, and neurodegeneration. We resolved the architecture of human mTORC1 (mTOR with subunits Raptor and mLST8) bound to FK506 binding protein (FKBP)-rapamycin, by combining cryo-electron microscopy at 5.9 angstrom resolution with crystallographic studies of Chaetomium thermophilum Raptor at 4.3 angstrom resolution. Structural (cryo-EM) mTORC1 (mTOR/Raptor/mLST8/FKBP-rapamycin) Cryo-EM structure Resolves the architecture of human mTORC1 bound to FKBP-rapamycin" }, { "sid": "LASSILA2026", "entities": [ "pxr-nr1i2", "mtor", "akt-pkb" ], "authors": [ "outi-kummu", "jukka-hakkola", "piia-lassila" ], "author_names": [ "Outi Kummu", "Jukka Hakkola", "Piia Lassila" ], "text": "Pregnane X receptor (PXR) is a master xenobiotic nuclear receptor. Activation of PXR has been linked to liver growth in mice, usually via interaction with YAP, but this adaptive response had not been observed in humans. The authors investigated the effect of the human PXR agonist rifampicin on liver size in a controlled clinical trial in healthy volunteers. One-week rifampicin treatment caused a 2.7% mean increase in liver volume-to-body weight ratio without affecting liver fat content (n=16). Rifampicin (human); pregnenolone-16α-carbonitrile (mouse) PXR; AKT-MTOR; YAP Human; mouse 2.7% increase in liver volume-to-body-weight ratio in humans; PXR-driven hepatomegaly and improved glucose tolerance in male mice via AKT-MTOR" }, { "sid": "BAN2014", "entities": [ "longevity", "metformin" ], "authors": [ "christian-bannister", "craig-currie" ], "author_names": [ "Christian Bannister", "Craig Currie" ], "text": "Clinical and observational studies have shown an increased risk of cardiovascular events and death associated with sulphonylureas versus metformin. However, it has never been determined whether this was due to the beneficial effects of metformin or detrimental effects of sulphonylureas. The objective of this study was therefore to compare all-cause mortality in diabetic patients treated first-line with either sulphonylurea or metformin monotherapy with that in matched individuals without diabetes. Metformin (vs sulphonylurea) monotherapy AMPK / mTOR (indirect) Human – retrospective cohort (n=180,926) Metformin-treated diabetics had lower all-cause mortality than sulphonylurea users and even matched non-diabetic controls" }, { "sid": "KAR2017", "entities": [], "authors": [ "robbie-loewith", "christiane-berger-schaffitzel", "manikandan-karuppasamy" ], "author_names": [ "Robbie Loewith", "Christiane Berger-Schaffitzel", "Manikandan Karuppasamy" ], "text": "The target of rapamycin (TOR) kinase assembles into two distinct multiprotein complexes, conserved across eukaryote evolution. In contrast to TOR complex 1 (TORC1), TORC2 kinase activity is not inhibited by the macrolide rapamycin. Here, we present the structure of Saccharomyces cerevisiae TORC2 determined by electron cryo-microscopy. TORC2 contains six subunits assembling into a 1.4 MDa rhombohedron. Tor2 and Lst8 form the common core of both TOR complexes. Structural (cryo-EM) TORC2 (Tor2/Lst8/Avo) Cryo-EM structure (S. cerevisiae) Cryo-EM structure of yeast TORC2, a 1.4-MDa rhombohedron of six subunits" }, { "sid": "BAB2025", "entities": [ "leucine-bcaa-restriction", "alzheimers-disease" ], "authors": [ "dudley-w-lamming", "reji-babygirija", "bailey-a-knopf" ], "author_names": [ "Dudley W. Lamming", "Reji Babygirija", "Bailey A. Knopf" ], "text": "Dietary protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Each BCAA has distinct physiological and molecular effects, and while restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the role of each individual BCAA on AD is unknown. Dietary (restriction of individual BCAAs: Leu/Ile/Val) BCAAs / mTORC1 Mouse (3xTg Alzheimer's model) Individual BCAAs have distinct, sex-specific effects on Alzheimer's progression; restricting any BCAA improved short-term memory in males (isoleucine strongest), while valine restriction gave the largest cognitive benefit in females Diets with 67% reduction of isoleucine, leucine, or valine, started at 6 months of age; duration was 9 months for body composition, 3 months for metabolic tests. 3xTg and NTg mice of both sexes; n=5-14 per diet group per sex, varying by experiment. ValR diet significantly increased energy expenditure in 3xTg females (p<0.05); IleR increased energy expenditure in 3xTg males (p<0.05) and improved glucose tolerance in both sexes (p<0.05). not stated" }, { "sid": "CHE2008", "entities": [ "tsc1-tsc2", "mtorc1", "reactive-oxygen-species" ], "authors": [ "kun-liang-guan", "chong-chen", "pan-zheng", "yu-liu" ], "author_names": [ "Kun-Liang Guan", "Chong Chen", "Pan Zheng", "Yu Liu" ], "text": "The tuberous sclerosis complex (TSC)-mammalian target of rapamycin (mTOR) pathway is a key regulator of cellular metabolism. We used conditional deletion of Tsc1 to address how quiescence is associated with the function of hematopoietic stem cells (HSCs). We demonstrate that Tsc1 deletion in the HSCs drives them from quiescence into rapid cycling, with increased mitochondrial biogenesis and elevated levels of reactive oxygen species (ROS). Genetic (Tsc1 conditional knockout) TSC-mTOR / mitochondrial biogenesis / ROS Mouse (conditional Tsc1 KO) TSC-mTOR maintains hematopoietic stem cell quiescence and function by repressing mitochondrial biogenesis and ROS Mice (6 wk old) treated with polyinosine-polycytidine (pIpC) every other day for 2 wk to induce Tsc1 deletion. Variable, e.g., n=3 to n=10 mice per group depending on the experiment. Tsc1 deletion reduced quiescent LT-HSCs from ~70% to <15% and increased BrdU incorporation nearly fourfold (from 13% to ~60%); resulted in an ~50% reduction in white blood cell counts (P = 0.001). It is unlikely that the HSCs in the spleen are fully functional because HSCs have reduced self-renewal when their niche in BM is disrupted." }, { "sid": "FAC2008", "entities": [ "sin1-mapkap1", "rictor", "mtor", "akt-pkb", "mtorc2" ], "authors": [ "estela-jacinto", "bing-su", "valeria-facchinetti" ], "author_names": [ "Estela Jacinto", "Bing Su", "Valeria Facchinetti" ], "text": "The target of rapamycin (TOR), as part of the rapamycin-sensitive TOR complex 1 (TORC1), regulates various aspects of protein synthesis. Whether TOR functions in this process as part of TORC2 remains to be elucidated. Here, we demonstrate that mTOR, SIN1 and rictor, components of mammalian (m)TORC2, are required for phosphorylation of Akt and conventional protein kinase C (PKC) at the turn motif (TM) site. This TORC2 function is growth factor independent and conserved from yeast to mammals. Genetic loss of mTOR, SIN1 or rictor (mTORC2 disruption) Akt and conventional PKC turn-motif phosphorylation, folding and stability Mouse cells, human cells, yeast Loss of mTORC2 abolishes Akt/PKC turn-motif phosphorylation and destabilises newly synthesised Akt and PKC" }, { "sid": "DEM2014", "entities": [ "lysosome", "tsc1-tsc2", "rag-gtpases", "mtorc1", "rheb" ], "authors": [ "constantinos-demetriades", "aurelio-a-teleman" ], "author_names": [ "Constantinos Demetriades", "Aurelio A. Teleman" ], "text": "TOR complex 1 (TORC1) is a potent anabolic regulator of cellular growth and metabolism. When cells have sufficient amino acids, TORC1 is active due to its lysosomal localization mediated via the Rag GTPases. Upon amino acid removal, the Rag GTPases release TORC1, causing it to become cytoplasmic and inactive. We show here that, upon amino acid removal, the Rag GTPases also recruit TSC2 to the lysosome, where it can act on Rheb. Only when both the Rag GTPases and Rheb are inactive is TORC1 fully released from the lysosome. Biochemical/genetic (Rag / TSC2) TORC1 / Rag GTPases / TSC2 Mammalian cells Upon amino-acid starvation the Rag GTPases recruit TSC2 to the lysosome to inactivate TORC1" }, { "sid": "PEREZ2026", "entities": [ "longevity" ], "authors": [ "alejandro-ocampo", "kevin-perez" ], "author_names": [ "Alejandro Ocampo", "Kevin Perez" ], "text": "We develop an integrated, high-throughput platform to evaluate pharmacological lifespan-extending interventions across five model organisms spanning unicellular to mammalian biology including yeast, nematodes, fruit flies, killifish, and mice. By combining automated imaging, miniaturized assays, and deep-learning-based death detection, we evaluate over 400 compounds across thousands of conditions. In S. cerevisiae, a miniaturized PI/flow cytometry CLS assay enables scalable screening and identifies key assay confounders, while in C. elegans and D. >400 small-molecule compounds screened for lifespan extension Conserved longevity pathways (cross-species geroprotector screen) Yeast, C. elegans, D. melanogaster, killifish, mouse Cross-species screening identifies multi-species geroprotectors and reveals convergence on conserved longevity pathways" }, { "sid": "SAN2010", "entities": [ "lysosome", "rag-gtpases", "mtorc1", "rheb", "ragulator" ], "authors": [ "david-m-sabatini", "roberto-zoncu", "yasemin-sancak", "liron-bar-peled", "andrew-l-markhard" ], "author_names": [ "David M. Sabatini", "Roberto Zoncu", "Yasemin Sancak", "Liron Bar-Peled", "Andrew L. Markhard" ], "text": "The mTORC1 kinase promotes growth in response to growth factors, energy levels, and amino acids, and its activity is often deregulated in disease. The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb. We show that amino acids induce the movement of mTORC1 to lysosomal membranes, where the Rag proteins reside. Biochemical/genetic (Ragulator-Rag) Ragulator / Rag / mTORC1 / Rheb Human cells + Drosophila The Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids" }, { "sid": "ZON2011", "entities": [ "lysosome", "v-atpase", "rag-gtpases", "mtorc1", "ragulator" ], "authors": [ "david-m-sabatini", "roberto-zoncu", "yasemin-sancak", "liron-bar-peled", "shuyu-wang", "alejo-efeyan" ], "author_names": [ "David M. Sabatini", "Roberto Zoncu", "Yasemin Sancak", "Liron Bar-Peled", "Shuyu Wang", "Alejo Efeyan" ], "text": "The mTOR complex 1 (mTORC1) protein kinase is a master growth regulator that is stimulated by amino acids. Amino acids activate the Rag guanosine triphosphatases (GTPases), which promote the translocation of mTORC1 to the lysosomal surface, the site of mTORC1 activation. We found that the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1. The v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome. Biochemical/genetic (v-ATPase) v-ATPase / Rag-Ragulator / mTORC1 Human cells + cell-free reconstitution mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase" }, { "sid": "ZHANG2026C", "entities": [ "erbb3-her3", "breast-cancer", "akt-pkb", "pi3k" ], "authors": [ "jingyue-zhang" ], "author_names": [ "Jingyue Zhang" ], "text": "The Xingxiao Pill (XXP) is a traditional Chinese medicine formula used in tumour therapy. XXP exhibited proliferation-inhibiting activity against eight breast cancer cell lines and both proliferation-inhibiting and apoptosis-promoting activity against 4T1 cells in vitro and in a 4T1 subcutaneous tumour model in vivo. XXP induced mitochondrial apoptosis via the cytochrome C/caspase-9/caspase-3/PARP cascade. Xingxiao Pill (TCM formula); cinnamic acid; palmitic acid ErbB3/PI3K/AKT/mTOR; amino acid metabolism Mouse Inhibited proliferation and induced caspase-mediated apoptosis; reduced AKT/mTOR phosphorylation" }, { "sid": "ROG2019", "entities": [ "raptor", "rag-gtpases", "mtorc1", "rheb", "ragulator" ], "authors": [ "david-m-sabatini", "kacper-b-rogala", "monther-abu-remaileh", "nouf-n-laqtom", "xin-gu", "edward-j-brignole" ], "author_names": [ "David M. Sabatini", "Kacper B. Rogala", "Monther Abu-Remaileh", "Nouf N. Laqtom", "Xin Gu", "Edward J. Brignole" ], "text": "The mTORC1 (mechanistic target of rapamycin complex 1) protein kinase regulates growth in response to nutrients and growth factors. Nutrients promote its translocation to the lysosomal surface, where its Raptor subunit interacts with the Rag guanosine triphosphatase (GTPase)-Ragulator complex. Nutrients switch the heterodimeric Rag GTPases among four different nucleotide-binding states, only one of which (RagA/B GTP-RagC/D GDP) permits mTORC1 association. Structural (cryo-EM, reconstituted complex) + mutagenesis mTORC1 / Raptor / Rag-Ragulator Human proteins, cell-free reconstitution 3.2 A structure showing how Raptor reads the nucleotide state of RagA and RagC to dock mTORC1 on the lysosome; docking-disrupting mutations block mTORC1 lysosomal localization and signalling" }, { "sid": "WOLF2017", "entities": [ "samtor", "castor1", "sestrin2", "mtorc1", "slc38a9" ], "authors": [ "david-m-sabatini", "rachel-l-wolfson" ], "author_names": [ "David M. Sabatini", "Rachel L. Wolfson" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that responds to a diverse set of environmental inputs, including amino acids. Over the past 10 years, a number of proteins have been identified that help transmit amino acid availability to mTORC1. However, amino acid sensors for this pathway have only recently been discovered. Here, we review these recent advances and highlight the variety of unexplored questions that emerge from the identification of these sensors. Not applicable (review) mTORC1 amino-acid sensors Review Reviews the recently discovered amino-acid sensors for the mTORC1 pathway" }, { "sid": "LIX2010", "entities": [ "mtor" ], "authors": [ "ronald-s-duman", "nanxin-li" ], "author_names": [ "Ronald S. Duman", "Nanxin Li" ], "text": "The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. Ketamine (NMDA-receptor antagonist) mTOR Rat mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists (ketamine) Ketamine 5-10 mg/kg (systemic); Ro 25-6981 10 mg/kg (systemic); Rapamycin, U0126, LY294002 (ICV infusion) not stated Ketamine (5-10 mg/kg) rapidly activated mTOR signaling, increased synaptic proteins (PSD95, GluR1, synapsin I), increased spine density, significantly increased EPSC frequency and amplitude, and produced rapid antidepressant effects in FST, LH, and NSFT. These effects were blocked by rapamycin. Ro 25-6981 (10 mg/kg) showed similar effects. The mechanisms underlying the induction of mTOR signaling are unclear. Ketamine is a psychotomimetic drug with abuse potential, and a more selective agent would be desirable for clinical antidepressant use." }, { "sid": "POW2011", "entities": [ "mtor" ], "authors": [ "jonathan-d-powell", "maureen-r-horton" ], "author_names": [ "Jonathan D. Powell", "Maureen R. Horton" ], "text": "mTOR is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental cues in the form of growth factors, amino acids, and energy. In the study of the immune system, mTOR is emerging as a critical regulator of immune function because of its role in sensing and integrating cues from the immune microenvironment. With the greater appreciation of cellular metabolism as an important regulator of immune cell function, mTOR is proving to be a vital link between immune function and metabolism. Not applicable (review) mTOR (immune) Review Reviews mTOR as a central regulator of immune responses" }, { "sid": "BUD2008", "entities": [ "tsc1-tsc2", "sestrin2", "mtorc1", "ampk" ], "authors": [ "andrei-v-budanov", "michael-karin" ], "author_names": [ "Andrei V. Budanov", "Michael Karin" ], "text": "The tumor suppressor p53 is activated upon genotoxic and oxidative stress and in turn inhibits cell proliferation and growth through induction of specific target genes. Cell growth is positively regulated by mTOR, whose activity is inhibited by the TSC1:TSC2 complex. Although genotoxic stress has been suggested to inhibit mTOR via p53-mediated activation of mTOR inhibitors, the precise mechanism of this link was unknown. Sestrin1/2 overexpression and knockdown; genotoxic stress; Sesn2 knockout mice p53 -> Sestrin1/2 -> AMPK -> TSC2 -> mTOR Human and mouse cells; mice Sestrins activate AMPK toward TSC2 and inhibit mTOR after DNA damage" }, { "sid": "ZIN2011", "entities": [ "akt-pkb", "pi3k", "mtorc2" ], "authors": [ "michael-n-hall", "vittoria-zinzalla", "daniele-stracka" ], "author_names": [ "Michael N. Hall", "Vittoria Zinzalla", "Daniele Stracka" ], "text": "The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of growth. Mammalian TOR complex 2 (mTORC2) regulates AGC kinase family members and is implicated in various disorders, including cancer and diabetes. Here, we investigated the upstream regulation of mTORC2. A genetic screen in yeast and subsequent studies in mammalian cells revealed that ribosomes, but not protein synthesis, are required for mTORC2 signaling. Genetic/biochemical (mTORC2 / ribosome) mTORC2 / ribosome / Akt Mammalian cells mTORC2 is activated by direct association with the ribosome (PI3K-dependent)" }, { "sid": "TAN2026", "entities": [ "renal-cell-carcinoma-rcc", "everolimus", "temsirolimus", "s6k1" ], "authors": [ "haojie-huang", "bo-tang" ], "author_names": [ "Haojie Huang", "Bo Tang" ], "text": "mTOR inhibitors including everolimus and temsirolimus have been approved by US FDA for treatment of clear cell renal cell carcinoma (ccRCC) in clinic. However, resistance to these drugs has been inevitable and the underlying mechanism remains poorly understood. Histone modifier ZMYND8 paradoxically acts as a transcription coactivator or corepressor. SPOP or NEK7 inhibition, including a NEK7-targeting PROTAC combined with everolimus SPOP-ZMYND8-ZHX2-NEK7 axis driving p70S6K activation Human ccRCC cell lines; mouse xenografts SPOP-driven ZMYND8 ubiquitination induces NEK7, which activates p70S6K independently of mTOR and confers mTOR-inhibitor resistance; NEK7 degradation restored everolimus sensitivity." }, { "sid": "YIL2012", "entities": [ "tsc1-tsc2", "rapamycin", "caloric-restriction", "mtorc1", "rheb" ], "authors": [ "david-m-sabatini", "dudley-w-lamming", "shomit-sengupta", "omer-h-yilmaz", "kivanc-birsoy" ], "author_names": [ "David M. Sabatini", "Dudley W. Lamming", "Shomit Sengupta", "Ömer H. Yilmaz", "Kivanç Birsoy" ], "text": "How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie restriction (60% of ad libitum); rapamycin; inducible Rheb overexpression; Tsc1 or Rictor deletion; Bst1 knockdown mTORC1 in Paneth cells Mouse Lower Paneth-cell mTORC1 (by CR or rapamycin) increases intestinal stem-cell number and function via Bst1/cADPR; forced mTORC1 activity blocks it" }, { "sid": "PEN2017", "entities": [ "kicstor" ], "authors": [ "ming-o-li", "min-peng" ], "author_names": [ "Ming O. Li", "Min Peng" ], "text": "Mechanistic target of rapamycin complex 1 (TORC1) integrates nutrient signals to control cell growth and organismal homeostasis across eukaryotes. The evolutionarily conserved GATOR complex regulates mTORC1 signalling through Rag GTPases, and GATOR1 displays GTPase activating protein (GAP) activity for RAGA and RAGB (RAGA/B) and GATOR2 has been proposed to be an inhibitor of GATOR1. Furthermore, the metazoan-specific SESN proteins function as guanine nucleotide dissociation inhibitors (GDIs) for RAGA/B, and interact with GATOR2 with unknown effects. Genetic/biochemical (SZT2 / KICSTOR) SZT2 / GATOR / Rag / mTORC1 Mammalian cells SZT2 dictates GATOR control of mTORC1 signalling" }, { "sid": "NIC2023", "entities": [ "lipid-synthesis", "mtorc1", "malonyl-coa" ], "authors": [ "constantinos-demetriades", "aurelio-a-teleman", "claudio-de-virgilio", "stephanie-a-fernandes", "peter-gollwitzer", "julian-nuchel", "laura-brohee", "gianluca-figlia", "raffaele-nicastro" ], "author_names": [ "Constantinos Demetriades", "Aurelio A. Teleman", "Claudio De Virgilio", "Stephanie A. Fernandes", "Peter Gollwitzer", "Julian Nüchel", "Laura Brohée", "Gianluca Figlia", "Raffaele Nicastro" ], "text": "Cell growth is regulated by the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which functions both as a nutrient sensor and a master controller of virtually all biosynthetic pathways. This ensures that cells are metabolically active only when conditions are optimal for growth. Notably, although mTORC1 is known to regulate fatty acid biosynthesis, how and whether the cellular lipid biosynthetic capacity signals back to fine-tune mTORC1 activity remains poorly understood. FASN downregulation/inhibition; malonyl-CoA mTOR catalytic pocket (mTORC1) Yeast and mammalian cells Malonyl-CoA binds the mTOR ATP-binding pocket as a competitive inhibitor, so reduced fatty-acid synthesis capacity dampens mTORC1 activity." }, { "sid": "TRI2026", "entities": [ "longevity", "mtor", "cellular-senescence", "senescence-associated-secretory-phenotype-sasp" ], "authors": [ "hitesha-trivedi", "sohel-shaikh" ], "author_names": [ "Hitesha Trivedi", "Sohel Shaikh" ], "text": "Cellular senescence, a key feature of ageing, involves irreversible cell cycle arrest and the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP) factors, which contribute to tissue degeneration and age-related diseases. Targeting senescent cells with senolytics, senomorphics and anti-ageing therapies marks a major shift in translational geroscience, with the potential to delay or reverse age-related conditions. A systematic review and narrative synthesis was conducted in accordance with PRISMA 2020 guidelines." }, { "sid": "TSA2012", "entities": [ "tsc1-tsc2", "rapamycin", "mtorc1", "tuberous-sclerosis-complex" ], "authors": [ "mustafa-sahin", "peter-t-tsai" ], "author_names": [ "Mustafa Sahin", "Peter T. Tsai" ], "text": "Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Purkinje-cell-specific Tsc1 deletion; rapamycin TSC1/TSC2 -> mTORC1 Mouse Tsc1 loss in Purkinje cells caused autism-like behaviour and reduced PC excitability; rapamycin prevented the deficits" }, { "sid": "SHA2004", "entities": [ "tsc1-tsc2", "insulin", "irs-1-irs-2", "s6k1", "rheb", "insulin-resistance" ], "authors": [ "tony-hunter", "o-jameel-shah" ], "author_names": [ "Tony Hunter", "O. Jameel Shah" ], "text": "Tuberous sclerosis is a largely benign tumor syndrome derived from the acquisition of somatic lesions in genes encoding the tumor suppressor products, TSC1 or TSC2. Loss of function of the TSC1-TSC2 complex, which acts as a Rheb GAP, yields constitutive, unrestrained signaling from the cell growth machinery comprised of Rheb, mTOR, and S6K. We demonstrate herein that constitutive activation of the Rheb/mTOR/S6K cassette, whether by genetic deletion of TSC1 or TSC2 or by ectopic expression of Rheb, is sufficient to induce insulin resistance. TSC1 or TSC2 deletion; ectopic Rheb expression Rheb/mTOR/S6K -> IRS1/IRS2 Mammalian cells Constitutive Rheb/mTOR/S6K signalling depletes IRS1/2, causing cellular insulin resistance and weaker survival signalling" }, { "sid": "TAN2024", "entities": [ "rapamycin", "mtorc1" ], "authors": [], "author_names": [], "text": "Aim: Hyperphosphorylated tau plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Whether mammalian target of rapamycin (mTOR) directly interacts with the Tau protein at Ser214, Ser356 and Thr231 is not clear. This study aimed to investigate whether mTOR-regulated tau phosphorylation disrupts mitochondrial dynamics and function and whether rapamycin, an mTOR inhibitor, can modulate tau phosphorylation levels and attenuate AD-related alterations. Rapamycin (mTOR inhibition) mTOR / Tau (Ser214/Ser356/Thr231) Mouse (tauopathy, Tau3E CA3) Targeting mTOR restores tau-induced metabolic, mitochondrial and cognitive deficits in a tauopathy model" }, { "sid": "HUD2007", "entities": [ "renal-cell-carcinoma-rcc", "mtor", "temsirolimus" ], "authors": [ "robert-j-motzer", "gary-hudes" ], "author_names": [ "Robert J. Motzer", "Gary Hudes" ], "text": "Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. Temsirolimus (± interferon alfa) mTOR Human – phase III RCT (n=626, poor-prognosis RCC) Temsirolimus improved overall survival vs interferon alfa in poor-prognosis metastatic renal-cell carcinoma" }, { "sid": "CAR2017", "entities": [ "cellular-senescence", "mtorc1" ], "authors": [ "viktor-i-korolchuk", "bernadette-carroll", "thomas-von-zglinicki", "penny-lovat", "glyn-nelson" ], "author_names": [ "Viktor I. Korolchuk", "Bernadette Carroll", "Thomas von Zglinicki", "Penny Lovat", "Glyn Nelson" ], "text": "Mammalian target of rapamycin complex 1 (mTORC1) and cell senescence are intimately linked to each other and to organismal aging. Inhibition of mTORC1 is the best-known intervention to extend lifespan, and recent evidence suggests that clearance of senescent cells can also improve health and lifespan. Enhanced mTORC1 activity drives characteristic phenotypes of senescence, although the underlying mechanisms responsible for increased activity are not well understood. Senescence induction (oxidative stress, replicative exhaustion, oncogene activation); serum and amino-acid starvation; correction of membrane depolarisation and cilia defects mTORC1 growth-factor and amino-acid sensing inputs Human fibroblasts Senescent human fibroblasts keep mTORC1 constitutively active and starvation-resistant, and restoring pathway sensitivity killed the cells, suggesting persistent mTORC1 signalling supports senescent-cell survival." }, { "sid": "THO2012", "entities": [ "eif4e", "mtorc1", "4e-bp1" ], "authors": [ "david-m-sabatini", "carson-c-thoreen", "lynne-chantranupong", "nathanael-s-gray", "tim-wang" ], "author_names": [ "David M. Sabatini", "Carson C. Thoreen", "Lynne Chantranupong", "Nathanael S. Gray", "Tim Wang" ], "text": "The mTOR complex 1 (mTORC1) kinase nucleates a pathway that promotes cell growth and proliferation and is the target of rapamycin, a drug with many clinical uses. mTORC1 regulates messenger RNA translation, but the overall translational program is poorly defined and no unifying model exists to explain how mTORC1 differentially controls the translation of specific mRNAs. Here we use high-resolution transcriptome-scale ribosome profiling to monitor translation in mouse cells acutely treated with the mTOR inhibitor Torin 1, which, unlike rapamycin, fully inhibits mTORC1 (ref. 2). Ribosome profiling (Torin1) mTORC1 / 4E-BP / TOP mRNAs Mouse cells Proposes a unifying model: mTORC1 controls translation of TOP mRNAs via 4E-BP" }, { "sid": "WUL2006", "entities": [ "mtorc1", "mtorc2" ], "authors": [ "michael-n-hall", "robbie-loewith", "stephan-wullschleger" ], "author_names": [ "Michael N. Hall", "Robbie Loewith", "Stephan Wullschleger" ], "text": "The target of rapamycin (TOR) is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues. Here, highlighting contributions from studies in model organisms, we review mammalian TOR complexes and the signaling branches they mediate. TOR is part of two distinct multiprotein complexes, TOR complex 1 (TORC1), which is sensitive to rapamycin, and TORC2, which is not. Not applicable (review) TORC1 / TORC2 Review Reviews TOR complexes and the signaling branches they mediate in growth and metabolism" }, { "sid": "URF2017", "entities": [ "longevity", "rapamycin", "mtor" ], "authors": [ "matt-kaeberlein", "kate-e-creevy", "silvan-r-urfer" ], "author_names": [ "Matt Kaeberlein", "Kate E. Creevy", "Silvan R. Urfer" ], "text": "Age is the single greatest risk factor for most causes of morbidity and mortality in humans and their companion animals. As opposed to other model organisms used to study aging, dogs share the human environment, are subject to similar risk factors, receive comparable medical care, and develop many of the same age-related diseases humans do. In this study, 24 middle-aged healthy dogs received either placebo or a non-immunosuppressive dose of rapamycin for 10 weeks. Rapamycin (short-term) mTOR Companion dogs (client-owned RCT, n=24) Short-term rapamycin was well tolerated in middle-aged dogs, with signs of improved cardiac function" }, { "sid": "JUN2015", "entities": [ "slc38a9" ], "authors": [ "christian-behrends", "jennifer-jung" ], "author_names": [ "Christian Behrends", "Jennifer Jung" ], "text": "The serine/threonine kinase mTORC1 regulates cellular homeostasis in response to many cues, such as nutrient status and energy level. Amino acids induce mTORC1 activation on lysosomes via the small Rag GTPases and the Ragulator complex, thereby controlling protein translation and cell growth. Here, we identify the human 11-pass transmembrane protein SLC38A9 as a novel component of the Rag-Ragulator complex. SLC38A9 localizes with Rag-Ragulator complex components on lysosomes and associates with Rag GTPases in an amino acid-sensitive and nucleotide binding state-dependent manner. Biochemical/genetic (SLC38A9) SLC38A9 / Rag-Ragulator / mTORC1 Mammalian cells SLC38A9 is a lysosomal component of the Rag-Ragulator that mediates amino-acid-dependent mTORC1 activation" }, { "sid": "HOW2017", "entities": [ "tsc1-tsc2", "metformin", "mtorc1", "ampk" ], "authors": [ "brendan-d-manning", "reuben-j-shaw", "gerta-hoxhaj", "jessica-j-howell", "george-talbott", "marc-turner" ], "author_names": [ "Brendan D. Manning", "Reuben J. Shaw", "Gerta Hoxhaj", "Jessica J. Howell", "George Talbott", "Marc Turner" ], "text": "Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion. Metformin (dose-dependent) AMPK / TSC / Rag / mTORC1 Mouse liver + primary hepatocytes Metformin inhibits hepatic mTORC1 via dose-dependent AMPK- and TSC-complex-dependent mechanisms" }, { "sid": "GOL2022", "entities": [ "lysosome", "tfeb", "rag-gtpases", "mtorc1", "ragulator" ], "authors": [ "constantinos-demetriades", "peter-gollwitzer", "sabine-wilhelm" ], "author_names": [ "Constantinos Demetriades", "Peter Gollwitzer", "Sabine Wilhelm" ], "text": "Amino acid availability controls mTORC1 activity via a heterodimeric Rag GTPase complex that functions as a scaffold at the lysosomal surface, bringing together mTORC1 with its activators and effectors. Mammalian cells express four Rag proteins (RagA-D) that form dimers composed of RagA/B bound to RagC/D. Traditionally, the Rag paralogue pairs (RagA/B and RagC/D) are referred to as functionally redundant, with the four dimer combinations used interchangeably in most studies. Cell lines engineered to express single Rag heterodimers; amino-acid withdrawal Rag GTPase paralogues (RagA/B, RagC/D), mTORC1 substrate selection, TFEB/TFE3 Human cell lines RagD promotes phosphorylation of lysosomal substrates TFEB/TFE3 through tighter LAMTOR binding, while RagB-expressing cells keep mTORC1 lysosomal and active even during starvation." }, { "sid": "HAN2025", "entities": [ "longevity", "rapamycin", "mtor" ], "authors": [ "jacob-m-hands", "bradley-rosen" ], "author_names": [ "Jacob M Hands", "Bradley Rosen" ], "text": "Low dose rapamycin therapy has been proposed as a longevity candidate in healthy aging adults. We present a review of the evidence for low dose rapamycin and rapalog therapies in healthy human adults and model the findings of one cohort study using the PhenoAge model. Despite the preclinical evidence supporting the use of sirolimus to enhance mean and maximal lifespan, the data in humans have yet to establish that rapamycin, or its analogues, is a proven seno-therapeutic that can delay aging in healthy older adults. Not applicable (narrative review + PhenoAge modeling) mTOR Narrative review (+ modeling of one cohort) Reviews the limited human evidence for off-label low-dose rapamycin in healthy adults; benefit not yet established" }, { "sid": "KAN2013", "entities": [ "torin1", "ulk1", "rapamycin", "mtorc1", "s6k1", "4e-bp1" ], "authors": [ "david-m-sabatini", "seong-a-kang", "benjamin-e-turk", "michael-b-yaffe" ], "author_names": [ "David M. Sabatini", "Seong A. Kang", "Benjamin E. Turk", "Michael B. Yaffe" ], "text": "The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs life span in model organisms. A persistent mystery is why the phosphorylation of many bona fide mTORC1 substrates is resistant to rapamycin. We find that the in vitro kinase activity of mTORC1 toward peptides encompassing established phosphorylation sites varies widely and correlates strongly with the resistance of the sites to rapamycin, as well as to nutrient and growth factor starvation within cells. Rapamycin; Torin1; amino-acid and growth-factor starvation; point mutations around phosphorylation sites mTORC1 substrate sites (S6K1, 4E-BP1, ULK1 and others) Human and mouse cell lines; in vitro Site-intrinsic substrate quality predicts which mTORC1 outputs are rapamycin- and starvation-resistant" }, { "sid": "BRO1994", "entities": [], "authors": [ "stuart-l-schreiber", "eric-j-brown" ], "author_names": [ "Stuart L. Schreiber", "Eric J. Brown" ], "text": "The structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways. FKBP12-rapamycin inhibits progression through the G1 phase of the cell cycle in osteosarcoma, liver and T cells as well as in yeast, and interferes with mitogenic signalling pathways that are involved in G1 progression, namely with activation of the protein p70S6k (refs 5, 11-13) and cyclin-dependent kinases. Biochemical (FKBP12-rapamycin complex) mTOR (FRAP) / FKBP12 Bovine brain; in vitro Identifies the mammalian FKBP12-rapamycin target protein that controls G1 cell-cycle progression" }, { "sid": "DAL2016", "entities": [ "ulk1", "leucine", "pi3k", "mtorc1", "autophagy", "ampk", "mtorc2" ], "authors": [ "piero-dalle-pezze", "daryl-p-shanley", "annika-g-sonntag", "kathrin-thedieck", "alexander-m-heberle" ], "author_names": [ "Piero Dalle Pezze", "Daryl P. Shanley", "Annika G. Sonntag", "Kathrin Thedieck", "Alexander M Heberle" ], "text": "Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we here combine a computational-experimental approach with text mining-enhanced quantitative proteomics. Amino acid withdrawal and re-addition AMPK; PI3K; mTORC2; mTORC1; ULK1 Human cell lines Amino acids acutely co-activate AMPK and mTOR; AMPK sustains autophagy under amino acid sufficiency" }, { "sid": "SHE2018", "entities": [ "rag-gtpases", "mtorc1", "gator1" ], "authors": [ "david-m-sabatini", "lynne-chantranupong", "kuang-shen", "kendall-j-condon", "max-l-valenstein", "edward-j-brignole", "rick-k-huang" ], "author_names": [ "David M. Sabatini", "Lynne Chantranupong", "Kuang Shen", "Kendall J. Condon", "Max L. Valenstein", "Edward J. Brignole", "Rick K. Huang" ], "text": "Nutrients, such as amino acids and glucose, signal through the Rag GTPases to activate mTORC1. The GATOR1 protein complex-comprising DEPDC5, NPRL2 and NPRL3-regulates the Rag GTPases as a GTPase-activating protein (GAP) for RAGA; loss of GATOR1 desensitizes mTORC1 signalling to nutrient starvation. GATOR1 components have no sequence homology to other proteins, so the function of GATOR1 at the molecular level is currently unknown. Here we used cryo-electron microscopy to solve structures of GATOR1 and GATOR1-Rag GTPases complexes. Structural (cryo-EM) GATOR1 (DEPDC5/NPRL2/NPRL3) / RagA / mTORC1 Cryo-EM structure Cryo-EM structures of GATOR1 and GATOR1-Rag reveal its GAP activity and inhibitory-clamp mechanism" }, { "sid": "FIN2002", "entities": [ "eif4e", "mtor", "pi3k", "s6k1", "4e-bp1" ], "authors": [ "john-blenis", "diane-c-fingar" ], "author_names": [ "John Blenis", "Diane C. Fingar" ], "text": "The coordinated action of cell cycle progression and cell growth (an increase in cell size and cell mass) is critical for sustained cellular proliferation, yet the biochemical signals that control cell growth are poorly defined, particularly in mammalian systems. We find that cell growth and cell cycle progression are separable processes in mammalian cells and that growth to appropriate cell size requires mTOR- and PI3K-dependent signals. Genetic/pharmacologic (mTOR/S6K1/4EBP1) mTOR / S6K1 / 4EBP1-eIF4E Mammalian cells Mammalian cell size is controlled by mTOR through its downstream targets S6K1 and 4EBP1/eIF4E" }, { "sid": "ALS2026", "entities": [ "growth-hormone-igf-1-axis", "longevity" ], "authors": [ "patrick-c-phillips", "rose-s-al-saadi" ], "author_names": [ "Patrick C. Phillips", "Rose S. Al-Saadi" ], "text": "Males and females are known to have dramatically different health and lifespan trajectories, but the underlying basis for these differences is yet to be fully elucidated. In the nematode model system, most aging studies have been conducted with hermaphrodites, and little is known about male-specific responses to pro-longevity mutations. Several previous studies have used the auxin-inducible degron system to degrade the DAF-2/IGF-1 receptor in hermaphrodites, finding that both ubiquitous and tissue-specific degradation can extend lifespan. Auxin-inducible degron degradation of the DAF-2/IGF-1 receptor, ubiquitous or germline-specific Insulin/IGF-1 receptor signalling (DAF-2) Caenorhabditis elegans, males Ubiquitous DAF-2 degradation raised male median lifespan by more than 440% and prolonged late-life reproductive function, while germline-specific degradation shortened male lifespan." }, { "sid": "MAY2004", "entities": [ "tif-ia-rrn3", "ribosome-biogenesis" ], "authors": [ "christine-mayer", "ingrid-grummt" ], "author_names": [ "Christine Mayer", "Ingrid Grummt" ], "text": null }, { "sid": "GUIB2026", "entities": [ "rapamycin" ], "authors": [ "antoine-fraissenon", "laurent-guibaud" ], "author_names": [ "Antoine Fraissenon", "Laurent Guibaud" ], "text": "Maternal sirolimus therapy has emerged as a potential prenatal treatment for extensive fetal lymphatic malformations, particularly when associated with the risk of neonatal airway compromise. Data on prenatal indications, pharmacokinetics, and outcomes remain limited. We aimed to describe patient selection, treatment management, maternal and fetal safety, and early outcomes. Between December 2023 and May 2025, 15 fetuses with extensive cystic or mixed vascular anomalies suggestive of lymphatic malformations were referred to a national reference center. Maternal sirolimus (rapamycin) during pregnancy, dose-adjusted to maternal trough levels mTOR Human (pregnant women and fetuses, n=6) Partial or marked regression of extensive fetal lymphatic malformation occurred in five of six newborns, with transplacental drug transfer and mild maternal side effects." }, { "sid": "KIM2002", "entities": [ "raptor", "mtor", "mtorc1", "s6k1" ], "authors": [ "david-m-sabatini", "do-hyung-kim", "dos-d-sarbassov", "siraj-m-ali", "hediye-erdjument-bromage", "paul-tempst", "robert-r-latek" ], "author_names": [ "David M. Sabatini", "Do-Hyung Kim", "Dos D. Sarbassov", "Siraj M. Ali", "Hediye Erdjument-Bromage", "Paul Tempst", "Robert R. Latek" ], "text": "mTOR/RAFT1/FRAP is the target of the immunosuppressive drug rapamycin and the central component of a nutrient- and hormone-sensitive signaling pathway that regulates cell growth. We report that mTOR forms a stoichiometric complex with raptor, an evolutionarily conserved protein with at least two roles in the mTOR pathway. Raptor has a positive role in nutrient-stimulated signaling to the downstream effector S6K1, maintenance of cell size, and mTOR protein expression. The association of raptor with mTOR also negatively regulates the mTOR kinase activity. Biochemical/genetic (raptor) mTOR / raptor Human/rodent cell lines (biochemistry) mTOR forms a nutrient-sensitive complex with raptor that signals to the cell-growth machinery" }, { "sid": "CHO1996", "entities": [ "rapamycin", "mtor", "fkbp12" ], "authors": [ "stuart-l-schreiber", "jon-clardy" ], "author_names": [ "Stuart L. Schreiber", "Jon Clardy" ], "text": "Rapamycin, a potent immunosuppressive agent, binds two proteins: the FK506-binding protein (FKBP12) and the FKBP-rapamycin-associated protein (FRAP). A crystal structure of the ternary complex of human FKBP12, rapamycin, and the FKBP12-rapamycin-binding (FRB) domain of human FRAP at a resolution of 2.7 angstroms revealed the two proteins bound together as a result of the ability of rapamycin to occupy two different hydrophobic binding pockets simultaneously. The structure shows extensive interactions between rapamycin and both proteins, but fewer interactions between the proteins. Structural (X-ray crystallography) FKBP12 / rapamycin / FRAP (FRB domain) X-ray crystallography 2.7-Å ternary structure of FKBP12-rapamycin bound to the FRB domain of human FRAP/mTOR" }, { "sid": "ZON2010", "entities": [ "mtorc1", "mtorc2" ], "authors": [ "david-m-sabatini", "roberto-zoncu", "alejo-efeyan" ], "author_names": [ "David M. Sabatini", "Roberto Zoncu", "Alejo Efeyan" ], "text": "In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. Not applicable (review) mTORC1 / mTORC2 Review Reviews TOR signaling from growth-signal integration to cancer, diabetes and ageing" }, { "sid": "PET2011", "entities": [ "lipid-synthesis", "srebp1-srebp2" ], "authors": [ "david-m-sabatini", "david-a-guertin", "seong-a-kang", "timothy-r-peterson" ], "author_names": [ "David M. Sabatini", "David A. Guertin", "Seong A. Kang", "Timothy R. Peterson" ], "text": "The nutrient- and growth factor-responsive kinase mTOR complex 1 (mTORC1) regulates many processes that control growth, including protein synthesis, autophagy, and lipogenesis. Through unknown mechanisms, mTORC1 promotes the function of SREBP, a master regulator of lipo- and sterolgenic gene transcription. Here, we demonstrate that mTORC1 regulates SREBP by controlling the nuclear entry of lipin 1, a phosphatidic acid phosphatase. Genetic/pharmacologic (mTORC1/lipin1) mTORC1 / lipin1 / SREBP Mammalian cells mTORC1 controls lipin1 nuclear entry to regulate the SREBP lipogenic transcription program" }, { "sid": "DEL2009", "entities": [ "t-cell-differentiation", "mtor", "mtorc1", "mtorc2" ], "authors": [ "jonathan-d-powell", "greg-m-delgoffe", "sara-c-kozma" ], "author_names": [ "Jonathan D. Powell", "Greg M. Delgoffe", "Sara C. Kozma" ], "text": "Effector T cell differentiation requires the simultaneous integration of multiple, and sometimes opposing, cytokine signals. We demonstrated mTOR's role in dictating the outcome of T cell fate. mTOR-deficient T cells displayed normal activation and IL-2 production upon initial stimulation. However, such cells failed to differentiate into T helper 1 (Th1), Th2, or Th17 effector cells. The inability to differentiate was associated with decreased STAT transcription factor activation and failure to upregulate lineage-specific transcription factors. Genetic (mTOR-deficient T cells) mTOR Mouse (T cells) mTOR is required for effector T-cell differentiation; its loss biases cells toward the regulatory T-cell lineage" }, { "sid": "ALE2010", "entities": [ "tsc1-tsc2", "mtorc1", "lkb1-stk11", "reactive-oxygen-species", "ampk" ], "authors": [ "kun-liang-guan", "ken-inoki", "angela-alexander", "cheryl-lyn-walker" ], "author_names": [ "Kun-Liang Guan", "Ken Inoki", "Angela Alexander", "Cheryl Lyn Walker" ], "text": "Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. ROS exposure; ATM deficiency; rapamycin ATM -> LKB1/AMPK -> TSC2 -> mTORC1 Cell lines; Atm-deficient mice ROS-activated ATM represses mTORC1 and induces autophagy; rapamycin rescues lymphomagenesis in Atm-null mice" }, { "sid": "CHR2009", "entities": [ "atp-competitive-mtor-inhibitors" ], "authors": [ "martin-pass", "christine-m-chresta" ], "author_names": [ "Martin Pass", "Christine M. Chresta" ], "text": "The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, with an IC50 of 0.8 nmol/L. AZD8055 (ATP-competitive mTOR inhibitor) mTORC1 & mTORC2 Cancer cells; xenograft AZD8055 is a potent, selective, orally bioavailable ATP-competitive mTOR inhibitor with antitumor activity" }, { "sid": "BAR2023", "entities": [ "cardiac-aging", "longevity", "rapamycin", "mtor" ], "authors": [ "matt-kaeberlein", "kate-e-creevy", "brian-g-barnett" ], "author_names": [ "Matt Kaeberlein", "Kate E. Creevy", "Brian G. Barnett" ], "text": "Geroscience studies of low-dose rapamycin in laboratory species have identified numerous benefits, including reversing age-related cardiac dysfunction. Cardiovascular benefits have been observed in dogs with 10 weeks of treatment, raising questions about possible benefits and adverse effects of long-term use of low-dose rapamycin. The objectives of this study were to assess the impact of 6 months of low-dose rapamycin on echocardiographic indices of cardiac function in healthy dogs and to document the occurrence of adverse events. Rapamycin 0.025 mg/kg three times per week for 6 months vs placebo mTOR Companion dogs (client-owned RCT, n=17) Well tolerated for 6 months, but no measurable change in heart function versus placebo (small trial)" }, { "sid": "BON2012", "entities": [ "lars-leucyl-trna-synthetase", "leucine", "rag-gtpases", "mtorc1" ], "authors": [ "claudio-de-virgilio", "gregory-bonfils" ], "author_names": [ "Claudio De Virgilio", "Grégory Bonfils" ], "text": "The target of rapamycin complex 1 (TORC1) is an essential regulator of eukaryotic cell growth that responds to growth factors, energy levels, and amino acids. The mechanisms through which the preeminent amino acid leucine signals to the TORC1-regulatory Rag GTPases, which activate TORC1 within the yeast EGO complex (EGOC) or the structurally related mammalian Rag-Ragulator complex, remain elusive. We find that the leucyl-tRNA synthetase (LeuRS) Cdc60 interacts with the Rag GTPase Gtr1 of the EGOC in a leucine-dependent manner. Leucine availability; Cdc60 (LeuRS) mutants affecting tRNA(Leu) editing Cdc60-Gtr1 interaction; TORC1 activity Saccharomyces cerevisiae Leucine promotes LeuRS (Cdc60) binding to Gtr1, which activates TORC1; tRNA editing by Cdc60 disrupts this" }, { "sid": "GAR2008", "entities": [ "sgk1" ], "authors": [ "dario-r-alessi", "juan-m-garcia-martinez" ], "author_names": [ "Dario R. Alessi", "Juan M. García-Martínez" ], "text": "SGK1 (serum- and glucocorticoid-induced protein kinase 1) is a member of the AGC (protein kinase A/protein kinase G/protein kinase C) family of protein kinases and is activated by agonists including growth factors. SGK1 regulates diverse effects of extracellular agonists by phosphorylating regulatory proteins that control cellular processes such as ion transport and growth. Genetic/biochemical (mTORC2/SGK1) mTORC2 / SGK1 Mammalian cells mTORC2 controls the hydrophobic-motif phosphorylation and activation of SGK1" }, { "sid": "PYO2013", "entities": [ "longevity", "atg5", "autophagy" ], "authors": [ "yong-keun-jung", "jong-ok-pyo" ], "author_names": [ "Yong-Keun Jung", "Jong-Ok Pyo" ], "text": "Autophagy has been implicated in the ageing process, but whether autophagy activation extends lifespan in mammals is unknown. Here we show that ubiquitous overexpression of Atg5, a protein essential for autophagosome formation, extends median lifespan of mice by 17.2%. We demonstrate that moderate overexpression of Atg5 in mice enhances autophagy, and that Atg5 transgenic mice showed anti-ageing phenotypes, including leanness, increased insulin sensitivity and improved motor function. Genetic (Atg5 overexpression) Autophagy (Atg5) Mouse (Atg5-overexpressing transgenic) Ubiquitous Atg5 overexpression enhances autophagy and extends median mouse lifespan by ~17% Atg5 cDNA inserted into pCAGGS vector driven by cytomegalovirus enhancer and chicken β-actin promoter, expressed ubiquitously in transgenic mice. n=65 for WT mice and n=70 for Atg5 Tg mice (line 25, combined sex); n=25 for WT and n=30 for other Atg5 Tg lines (43, 47, 471). Median lifespan of Atg5 Tg mice (line 25) was 119 days (~17%) longer than WT (P <0.001); maximum lifespan was 900±34 days for Atg5 Tg vs 781±22 days for WT (P <0.01). not stated" }, { "sid": "NOB2005", "entities": [ "raptor", "mtor", "pi3k", "mtorc1", "vps34-pik3c3" ], "authors": [ "maya-p-byfield", "jonathan-m-backer", "takahiro-nobukuni", "johannes-l-hans-bos" ], "author_names": [ "Maya P. Byfield", "Jonathan M. Backer", "Takahiro Nobukuni", "Johannes L. (Hans) Bos" ], "text": "During the evolution of metazoans and the rise of systemic hormonal regulation, the insulin-controlled class 1 phosphatidylinositol 3OH-kinase (PI3K) pathway was merged with the primordial amino acid-driven mammalian target of rapamycin (mTOR) pathway to control the growth and development of the organism. Insulin regulates mTOR function through a recently described canonical signaling pathway, which is initiated by the activation of class 1 PI3K. However, how the amino acid input is integrated with that of the insulin signaling pathway is unclear. Amino acid stimulation; hVps34 knockdown and pharmacological PI3K inhibition Class 3 PI3K (hVps34) -> mTOR/raptor Human cell lines Amino acids signal to mTOR/raptor through hVps34, a route separate from insulin and class 1 PI3K" }, { "sid": "ABU2017", "entities": [ "lysosome", "torin1", "v-atpase", "mtor" ], "authors": [ "monther-abu-remaileh", "sze-ham-chan", "elizaveta-freinkman", "choah-kim", "nouf-n-laqtom" ], "author_names": [ "Monther Abu-Remaileh", "Sze Ham Chan", "Elizaveta Freinkman", "Choah Kim", "Nouf N. Laqtom" ], "text": "The lysosome degrades and recycles macromolecules, signals to the cytosol and nucleus, and is implicated in many diseases. Here, we describe a method for the rapid isolation of mammalian lysosomes and use it to quantitatively profile lysosomal metabolites under various cell states. Under nutrient-replete conditions, many lysosomal amino acids are in rapid exchange with those in the cytosol. v-ATPase inhibition; mTOR inhibition; nutrient starvation Lysosomal amino-acid efflux, mTOR pathway Human HEK293 cells Inhibiting mTOR strongly reduced lysosomal efflux of most essential amino acids, converting the lysosome into a depot for them." }, { "sid": "MEL2003", "entities": [ "longevity", "autophagy" ], "authors": [ "beth-levine", "alicia-melendez" ], "author_names": [ "Beth Levine", "Alicia Meléndez" ], "text": "Both dauer formation (a stage of developmental arrest) and adult life-span in Caenorhabditis elegans are negatively regulated by insulin-like signaling, but little is known about cellular pathways that mediate these processes. Autophagy, through the sequestration and delivery of cargo to the lysosomes, is the major route for degrading long-lived proteins and cytoplasmic organelles in eukaryotic cells. Using nematodes with a loss-of-function mutation in the insulin-like signaling pathway, we show that bec-1, the C. Genetic (autophagy-gene RNAi) Autophagy / insulin-IGF (daf-2) C. elegans Autophagy genes are essential for dauer development and for lifespan extension in insulin/IGF (daf-2) mutants" }, { "sid": "PRI1992", "entities": [ "s6k1" ], "authors": [ "joseph-avruch", "barbara-e-bierer" ], "author_names": [ "Joseph Avruch", "Barbara E. Bierer" ], "text": "The immunosuppressant rapamycin inhibited proliferation of the H4IIEC hepatoma cell line. Rapamycin, but not its structural analog FK506, also inhibited the basal and insulin-stimulated activity of the p70 ribosomal protein S6 kinase. By contrast, insulin stimulation of the p85 Rsk S6 kinase and mitogen-activated protein (MAP) kinase activity were unaffected by drug. Rapamycin (vs FK506) p70 S6 kinase Mammalian cells; in vitro Rapamycin (not FK506) inhibits basal and insulin-stimulated p70 S6 kinase activity" }, { "sid": "MEN2014", "entities": [ "energy-cellular-stress" ], "authors": [ "brendan-d-manning", "lewis-c-cantley", "alexander-j-valvezan", "christian-c-dibble", "sue-menon", "gerta-hoxhaj", "george-talbott" ], "author_names": [ "Brendan D. Manning", "Lewis C. Cantley", "Alexander J. Valvezan", "Christian C. Dibble", "Sue Menon", "Gerta Hoxhaj", "George Talbott" ], "text": "mTORC1 promotes cell growth in response to nutrients and growth factors. Insulin activates mTORC1 through the PI3K-Akt pathway, which inhibits the TSC1-TSC2-TBC1D7 complex (the TSC complex) to turn on Rheb, an essential activator of mTORC1. However, the mechanistic basis of how this pathway integrates with nutrient-sensing pathways is unknown. We demonstrate that insulin stimulates acute dissociation of the TSC complex from the lysosomal surface, where subpopulations of Rheb and mTORC1 reside. Genetic/biochemical (TSC complex/Rheb) TSC complex / Rheb / mTORC1 Mammalian cells Insulin drives lysosomal dissociation of the TSC complex, integrating insulin and nutrient regulation of mTORC1" }, { "sid": "SEN2010", "entities": [ "tsc1-tsc2", "raptor", "mtorc1" ], "authors": [ "david-m-sabatini", "timothy-r-peterson", "mathieu-laplante", "shomit-sengupta" ], "author_names": [ "David M. Sabatini", "Timothy R. Peterson", "Mathieu Laplante", "Shomit Sengupta" ], "text": "The multi-component mechanistic target of rapamycin complex 1 (mTORC1) kinase is the central node of a mammalian pathway that coordinates cell growth with the availability of nutrients, energy and growth factors. Progress has been made in the identification of mTORC1 pathway components and in understanding their functions in cells, but there is relatively little known about the role of the pathway in vivo. Specifically, we have little knowledge regarding the role mTORC1 has in liver physiology. Genetic (raptor liver knockout) mTORC1 / PPARα / ketogenesis Mouse/cells mTORC1 controls fasting-induced ketogenesis (via PPARα); this control is blunted with ageing" }, { "sid": "VAN2007", "entities": [ "pras40" ], "authors": [ "do-hyung-kim", "emilie-vander-haar" ], "author_names": [ "Do-Hyung Kim", "Emilie Vander Haar" ], "text": "Insulin stimulates protein synthesis and cell growth by activation of the protein kinases Akt (also known as protein kinase B, PKB) and mammalian target of rapamycin (mTOR). It was reported that Akt activates mTOR by phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2). However, in recent studies the physiological requirement of Akt phosphorylation of TSC2 for mTOR activation has been questioned. Here, we identify PRAS40 (proline-rich Akt/PKB substrate 40 kDa) as a novel mTOR binding partner that mediates Akt signals to mTOR. Biochemical/genetic (PRAS40/Akt) mTORC1 / PRAS40 / Akt Mammalian cells Insulin signals to mTOR via Akt phosphorylation of PRAS40, relieving its inhibition of mTORC1" }, { "sid": "FAN2026", "entities": [ "ribosome-biogenesis", "5top-mrna", "mtorc1", "protein-synthesis" ], "authors": [ "marikki-laiho", "rachel-green", "wenjun-fan" ], "author_names": [ "Marikki Laiho", "Rachel Green", "Wenjun Fan" ], "text": "Ribosome biogenesis is a resource-consuming process that facilitates rapid growth and feeds uncontrolled, cancerous traits. Constraining ribosome biogenesis and protein translation has become a tenable therapeutic strategy for cancer. Yet, we do not know how cells that rely on high metabolic activity adapt and sustain their growth when deprived of their translational capacity. Conversely, stem cells and treatment-resistant cells persist under low metabolic states challenging their eradication. These are critical questions in cancer therapies. Functional genomics/CRISPR screens under RNA Pol I inhibition; mTOR inactivation (genetic/pharmacologic) mTORC1 / ribosome biogenesis / 5'TOP mRNA translation Human cancer cell lines mTOR inactivation redistributes limited ribosomes from 5'TOP mRNAs to survival-essential transcripts, enabling adaptive survival ('translational fitness') under ribosome biogenesis deficiency" }, { "sid": "GIN2026", "entities": [ "akt-pkb", "mtorc1", "irs-1-irs-2", "s6k1" ], "authors": [ "miriam-ginzberg", "ran-kafri" ], "author_names": [ "Miriam Ginzberg", "Ran Kafri" ], "text": "Direct measurement of feedback regulation remains difficult because it usually relies on pathway perturbations and prior knowledge of circuit topology. We introduce AoF (Assay of Feedback), a single-cell imaging framework that combines fixed-cell measurements of a target (together with DNA and Geminin as cell-cycle ordering markers) with ergodic rate analysis to reconstruct target dynamics in steady-state proliferating populations and quantify how a target's inferred rate of change depends on its own level. None (observational imaging assay); mTORC1/S6K1 inhibition used in supporting biochemistry AKT phosphorylation; mTORC1-S6K1-IRS1 negative feedback Cultured mammalian cells Reveals cell-cycle-localized negative feedback on AKT at G1/S, attributed to mTORC1/S6K1-IRS1" }, { "sid": "CON2021", "entities": [ "mitochondrial-dysfunction" ], "authors": [ "david-m-sabatini", "kendall-j-condon", "jose-m-orozco" ], "author_names": [ "David M. Sabatini", "Kendall J. Condon", "Jose M. Orozco" ], "text": "In mammalian cells, nutrients and growth factors signal through an array of upstream proteins to regulate the mTORC1 growth control pathway. Because the full complement of these proteins has not been systematically identified, we developed a FACS-based CRISPR-Cas9 genetic screening strategy to pinpoint genes that regulate mTORC1 activity. Along with almost all known positive components of the mTORC1 pathway, we identified many genes that impact mTORC1 activity. Genome-wide CRISPR-Cas9 screen mTORC1 (mitochondrial-dysfunction sensing) CRISPR screen; cells CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction" }, { "sid": "HAR1998", "entities": [ "mtor", "s6k1", "4e-bp1" ], "authors": [ "joseph-avruch", "kazuyoshi-yonezawa", "kenta-hara" ], "author_names": [ "Joseph Avruch", "Kazuyoshi Yonezawa", "Kenta Hara" ], "text": "The present study identifies the operation of a signal tranduction pathway in mammalian cells that provides a checkpoint control, linking amino acid sufficiency to the control of peptide chain initiation. Withdrawal of amino acids from the nutrient medium of CHO-IR cells results in a rapid deactivation of p70 S6 kinase and dephosphorylation of eIF-4E BP1, which become unresponsive to all agonists. Readdition of the amino acid mixture quickly restores the phosphorylation and responsiveness of p70 and eIF-4E BP1 to insulin. Biochemical (amino-acid withdrawal) mTOR / p70 S6K / 4E-BP1 CHO cells; in vitro Amino-acid sufficiency and mTOR regulate p70 S6K and 4E-BP1 through a common effector mechanism" }, { "sid": "GAO2026B", "entities": [ "everolimus", "renal-angiomyolipoma", "tuberous-sclerosis-complex" ], "authors": [ "ke-gao", "jianxin-ni" ], "author_names": [ "Ke Gao", "Jianxin Ni" ], "text": "Renal angiomyolipomas associated with tuberous sclerosis complex (TSC-RAML) may lead to progressive renal damage and hemorrhage. Everolimus is recommended as first-line therapy, but predictors of treatment response and optimal dosing strategies remain unclear. In this multicenter prospective cohort study across multiple centers in China, 183 consecutive patients with TSC-RAML were enrolled, with three prespecified analytical subsets: standard-dose everolimus efficacy, CT-based tumor fat-composition analysis, and exploratory dose-comparison analysis. Everolimus, standard-dose vs low-dose; CT-based tumor fat composition analysis mTOR (via everolimus) Human (TSC-RAML patients, n=183, multicenter China cohort) Everolimus reduces TSC-associated renal angiomyolipoma tumor volume, more effectively in fat-poor lesions; no significant difference between low and standard dose in an exploratory, non-randomised subset, with less oral mucositis on the low dose" }, { "sid": "PEA2009", "entities": [ "t-cell-differentiation", "rapamycin", "metformin", "ampk" ], "authors": [ "russell-g-jones", "erika-l-pearce", "yongwon-choi" ], "author_names": [ "Russell G. Jones", "Erika L. Pearce", "Yongwon Choi" ], "text": "CD8 T cells, which have a crucial role in immunity to infection and cancer, are maintained in constant numbers, but on antigen stimulation undergo a developmental program characterized by distinct phases encompassing the expansion and then contraction of antigen-specific effector (T(E)) populations, followed by the persistence of long-lived memory (T(M)) cells. Although this predictable pattern of CD8 T-cell responses is well established, the underlying cellular mechanisms regulating the transition to T(M) cells remain undefined. T-cell-specific TRAF6 deletion; daily metformin (250 mg/kg); daily rapamycin (1.5 mg/kg) CD8 T-cell fatty acid oxidation and memory formation Mouse TRAF6 loss abolished CD8 memory formation; metformin or rapamycin increased memory CD8 T cells, and metformin improved anti-tumour vaccine protection" }, { "sid": "WAN2011", "entities": [ "glutamine" ], "authors": [ "hongbo-chi", "douglas-r-green", "ruoning-wang" ], "author_names": [ "Hongbo Chi", "Douglas R. Green", "Ruoning Wang" ], "text": "To fulfill the bioenergetic and biosynthetic demand of proliferation, T cells reprogram their metabolic pathways from fatty acid beta-oxidation and pyruvate oxidation via the TCA cycle to the glycolytic, pentose-phosphate, and glutaminolytic pathways. Two of the top-ranked candidate transcription factors potentially responsible for the activation-induced T cell metabolic transcriptome, HIF1alpha and Myc, were induced upon T cell activation, but only the acute deletion of Myc markedly inhibited activation-induced glycolysis and glutaminolysis in T cells. Genetic (Myc) Myc (mTOR-linked metabolism) Mouse T cells Myc controls the metabolic reprogramming (glycolysis, glutaminolysis) upon T-lymphocyte activation not stated not stated not stated not stated" }, { "sid": "COL2025", "entities": [ "longevity", "rapamycin", "mtor" ], "authors": [ "matt-kaeberlein", "kate-e-creevy", "amanda-erickson-coleman" ], "author_names": [ "Matt Kaeberlein", "Kate E. Creevy", "Amanda Erickson Coleman" ], "text": "Companion dogs are a powerful model for aging research given their morphologic and genetic variability, risk for age-related disease, and habitation of the human environment. In addition, the shorter life expectancy of dogs compared to human beings provides a unique opportunity for an accelerated timeline to test interventions that might extend healthy lifespan. Rapamycin vs placebo, planned 3-year treatment mTOR Companion dogs - RCT (design paper, ongoing, no results yet) No results yet - first placebo-controlled lifespan trial of rapamycin outside the lab (dogs)" }, { "sid": "COR2018", "entities": [ "age-related-pathology", "cellular-senescence", "nf-b" ], "authors": [ "viktor-i-korolchuk", "satomi-miwa", "joao-f-passos", "clara-correia-melo" ], "author_names": [ "Viktor I. Korolchuk", "Satomi Miwa", "João F. Passos", "Clara Correia-Melo" ], "text": "Increased activation of the major pro-inflammatory NF-κB pathway leads to numerous age-related diseases, including chronic liver disease (CLD). Rapamycin, an inhibitor of mTOR, extends lifespan and healthspan, potentially via suppression of inflammaging, a process which is partially dependent on NF-κB signalling. However, it is unknown if rapamycin has beneficial effects in the context of compromised NF-κB signalling, such as that which occurs in several age-related chronic diseases. Dietary rapamycin mTOR (mTORC1) Mouse (nfkb1-/-, enhanced NF-kB activity) Rapamycin reduced frailty and senescence markers and improved memory and coordination, but did not extend lifespan or reduce inflammaging." }, { "sid": "YAN2017", "entities": [ "pras40" ], "authors": [ "nikola-p-pavletich", "haijuan-yang", "hyo-j-yang" ], "author_names": [ "Nikola P. Pavletich", "Haijuan Yang", "Hyo J Yang" ], "text": "The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 angstrom cryo-electron microscopy structure of mTORC1 and the 3.4 angstrom structure of activated RHEB-mTORC1. Structural (cryo-EM) mTORC1 / RHEB / PRAS40 Cryo-EM structure Structures reveal how RHEB allosterically activates mTORC1 and how PRAS40 inhibits it" }, { "sid": "SAR2005", "entities": [ "akt-pkb", "mtorc2" ], "authors": [ "david-m-sabatini", "dos-d-sarbassov", "siraj-m-ali", "david-a-guertin" ], "author_names": [ "David M. Sabatini", "Dos D. Sarbassov", "Siraj M. Ali", "David A. Guertin" ], "text": "Deregulation of Akt/protein kinase B (PKB) is implicated in the pathogenesis of cancer and diabetes. Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. We show that in Drosophila and human cells the target of rapamycin (TOR) kinase and its associated protein rictor are necessary for Ser473 phosphorylation and that a reduction in rictor or mammalian TOR (mTOR) expression inhibited an Akt/PKB effector. Genetic/biochemical (rictor-mTOR) mTORC2 (rictor) / Akt Ser473 Human cells; Drosophila The rictor-mTOR complex (mTORC2) phosphorylates Akt/PKB at Ser473" }, { "sid": "PET2013", "entities": [ "flcn-fnip1-2" ], "authors": [ "shawn-m-ferguson", "constance-petit" ], "author_names": [ "Shawn M. Ferguson", "Constance Petit" ], "text": "Birt-Hogg-Dube syndrome, a human disease characterized by fibrofolliculomas (hair follicle tumors) as well as a strong predisposition toward the development of pneumothorax, pulmonary cysts, and renal carcinoma, arises from loss-of-function mutations in the folliculin (FLCN) gene. In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). Our results indicate that FLCN is specifically required for the amino acid-stimulated recruitment of mTORC1 to lysosomes by Rag GTPases. Genetic/biochemical (FLCN) FLCN / Rag GTPases / mTORC1 Mammalian cells FLCN is recruited to lysosomes on amino-acid depletion, binds RagA, and is required for amino-acid-stimulated recruitment of mTORC1 to lysosomes by the Rag GTPases" }, { "sid": "BRU1997", "entities": [ "eif4e", "rapamycin", "mtor", "4e-bp1" ], "authors": [ "robert-t-abraham" ], "author_names": [ "Robert T. Abraham" ], "text": "The immunosuppressant rapamycin interferes with G1-phase progression in lymphoid and other cell types by inhibiting the function of the mammalian target of rapamycin (mTOR). mTOR was determined to be a terminal kinase in a signaling pathway that couples mitogenic stimulation to the phosphorylation of the eukaryotic initiation factor (eIF)-4E-binding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulated human embryonic kidney cells. Biochemical (mTOR/PHAS-I) mTOR / PHAS-I (4E-BP1) / eIF4E HEK293; in vitro mTOR is a terminal kinase phosphorylating the translational repressor PHAS-I (4E-BP1)" }, { "sid": "JEF1997", "entities": [ "rapamycin", "5top-mrna", "mtorc1", "s6k1" ], "authors": [ "george-thomas", "harold-jefferies" ], "author_names": [ "George Thomas", "Harold Jefferies" ], "text": "Treatment of mammalian cells with the immunosuppressant rapamycin, a bacterial macrolide, selectively suppresses mitogen-induced translation of an essential class of mRNAs which contain an oligopyrimidine tract at their transcriptional start (5'TOP), most notably mRNAs encoding ribosomal proteins and elongation factors. In parallel, rapamycin blocks mitogen-induced p70 ribosomal protein S6 kinase (p70s6k) phosphorylation and activation. Rapamycin; dominant-interfering and T389E p70s6k mutants 5'TOP mRNA translation; p70s6k activation Mammalian cell lines Rapamycin inhibits 5'TOP mRNA translation and p70s6k activation; rapamycin-resistant p70s6k prevents the translational block" }, { "sid": "DAL2012", "entities": [ "tsc1-tsc2", "akt-pkb", "pi3k", "mtorc1", "mtorc2", "s6k1" ], "authors": [ "ralf-baumeister", "piero-dalle-pezze", "mirja-tamara-prentzell", "daryl-p-shanley", "annika-g-sonntag", "kathrin-thedieck" ], "author_names": [ "Ralf Baumeister", "Piero Dalle Pezze", "Mirja Tamara Prentzell", "Daryl P. Shanley", "Annika G. Sonntag", "Kathrin Thedieck" ], "text": "The kinase mammalian target of rapamycin (mTOR) exists in two multiprotein complexes (mTORC1 and mTORC2) and is a central regulator of growth and metabolism. Insulin activation of mTORC1, mediated by phosphoinositide 3-kinase (PI3K), Akt, and the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2), initiates a negative feedback loop that ultimately inhibits PI3K. We present a data-driven dynamic insulin-mTOR network model that integrates the entire core network and used this model to investigate the less well understood mechanisms by which insulin regulates mTORC2. In silico and experimental perturbations (insulin, inhibitors, knockdowns) mTORC1; mTORC2; TSC1-TSC2; PI3K; negative feedback loop Human cell lines mTORC2 is not regulated by TSC1-TSC2 or by the mTORC1-driven negative feedback loop" }, { "sid": "COR2004", "entities": [ "tsc1-tsc2", "mtorc1", "lkb1-stk11", "ampk" ], "authors": [ "kun-liang-guan", "ken-inoki", "michael-n-corradetti" ], "author_names": [ "Kun-Liang Guan", "Ken Inoki", "Michael N. Corradetti" ], "text": "Tuberous sclerosis complex (TSC) and Peutz-Jeghers syndrome (PJS) are dominantly inherited benign tumor syndromes that share striking histopathological similarities. Here we show that LKB1, the gene mutated in PJS, acts as a tumor suppressor by activating TSC2, the gene mutated in TSC. Like TSC2, LKB1 inhibits the phosphorylation of the key translational regulators S6K and 4EBP1. Furthermore, we show that LKB1 activates TSC2 through the AMP-dependent protein kinase (AMPK), indicating that LKB1 plays a role in cell growth regulation in response to cellular energy levels. LKB1 re-expression and RNAi knockdown; AMPK and TSC2 dependence LKB1 -> AMPK -> TSC2 -> mTORC1 Human cell lines (HeLa, HEK293), mouse embryonic fibroblasts LKB1 activates AMPK and, through TSC2, lowers mTORC1 signalling to S6K and 4E-BP1" }, { "sid": "SET2011", "entities": [ "tfeb", "lysosomal-biogenesis", "mtorc1", "autophagy" ], "authors": [ "andrea-ballabio", "carmine-settembre", "tuong-huynh" ], "author_names": [ "Andrea Ballabio", "Carmine Settembre", "Tuong Huynh" ], "text": "Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes. We found that starvation activates a transcriptional program that controls major steps of the autophagic pathway, including autophagosome formation, autophagosome-lysosome fusion, and substrate degradation. The transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Genetic (TFEB) TFEB / autophagy-lysosome Human/mouse cells TFEB drives a transcriptional program that links autophagy to lysosomal biogenesis" }, { "sid": "ARA2009", "entities": [ "mtor" ], "authors": [ "rafi-ahmed", "koichi-araki" ], "author_names": [ "Rafi Ahmed", "Koichi Araki" ], "text": "Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. Rapamycin (mTOR modulation) mTOR Mouse mTOR regulates memory CD8 T-cell differentiation; rapamycin enhances memory T-cell quantity and quality Rapamycin administered continuously (day -1~35), during expansion (days -1~8), or contraction (days 8~35) post-infection; specific quantitative dose not stated. not stated Rapamycin enhanced LCMV-specific CD8 T cell responses, decreased T cell contraction, and improved functional qualities of memory CD8 T cells. Memory T cell numbers remained 10-fold higher even 165 days after stopping drug treatment, and rapamycin treatment during contraction resulted in significantly higher numbers of functional memory cells (p <0.0001~0.0022). mTOR knockdown does not completely mimic rapamycin treatment." }, { "sid": "FU2026", "entities": [ "rubcn-rubicon" ], "authors": [ "cong-xu", "yulian-xiao" ], "author_names": [ "Cong Xu", "Yulian Xiao" ], "text": "Drug resistance limits the long-term survival of patients with multiple myeloma. The role of tRNA-derived fragments (tsRNAs) in bortezomib resistance in myeloma remains unknown. tRF-17-8SPOL52 was identified as the most highly expressed tsRNA in relapsed/refractory myeloma. tRF-17-8SPOL52 promoted bortezomib resistance in vitro and in vivo. Ago-RIP-sequencing and dual-luciferase reporter assay showed that tRF-17-8SPOL52 negatively regulated RUBCN. The regulation of RUBCN by tRF-17-8SPOL52 was Ago-dependent. tRF-17-8SPOL52 (tsRNA) RUBCN / autophagy Human (myeloma) Activates autophagy via RUBCN suppression, inducing bortezomib resistance" }, { "sid": "BLA2006", "entities": [ "longevity", "mtor", "mtorc1" ], "authors": [ "mikhail-v-blagosklonny" ], "author_names": [ "Mikhail V. Blagosklonny" ], "text": "While ruling out programmed aging, evolutionary theory predicts a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging. Could it be switched off pharmacologically? This would require identification of a molecular target involved in cell senescence, organism aging and diseases of aging. Notably, cell senescence is associated with activation of the TOR (target of rapamycin) nutrient- and mitogen-sensing pathway, which promotes cell growth, even though cell cycle is blocked. Not applicable (theoretical/review; proposes rapamycin) mTOR Theoretical / review article Proposes aging as a quasi-programmed, hyperfunctional mTOR-driven process that rapamycin could pharmacologically slow" }, { "sid": "TEE2002", "entities": [ "tsc1-tsc2", "eif4e", "mtorc1", "s6k1", "4e-bp1" ], "authors": [ "brendan-d-manning", "john-blenis", "lewis-c-cantley", "andrew-r-tee", "david-j-kwiatkowski", "diane-c-fingar" ], "author_names": [ "Brendan D. Manning", "John Blenis", "Lewis C. Cantley", "Andrew R. Tee", "David J. Kwiatkowski", "Diane C. Fingar" ], "text": "Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that occurs upon mutation of either the TSC1 or TSC2 genes, which encode the protein products hamartin and tuberin, respectively. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). Coexpression of TSC1 + TSC2 (and patient-derived TSC2 mutant) 4E-BP1 phosphorylation, 4E-BP1-eIF4E binding, S6K1 activity Mammalian cell lines TSC1/TSC2 coexpression decreases mTOR signalling to 4E-BP1 and S6K1" }, { "sid": "KEL2026", "entities": [ "rapamycin", "immune-function", "cellular-senescence" ], "authors": [ "loren-kell", "ghada-alsaleh" ], "author_names": [ "Loren Kell", "Ghada Alsaleh" ], "text": "mTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugs are senomorphic, that is, they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we tested whether mTOR inhibition enhances genome stability. Rapamycin and other mTOR inhibitors (ex vivo); low-dose oral rapamycin vs placebo (older adults) mTOR; DNA damage-induced senescence (p21) Human (T cells ex vivo; older adults in vivo) mTOR inhibition reduced DNA lesion burden and senescence in T cells, and low-dose rapamycin lowered immune-cell p21 versus placebo." }, { "sid": "SIN2026", "entities": [ "lc3b-map1lc3b", "autophagy", "macronutrient-ratio" ], "authors": [ "timothy-j-sargeant", "sanjna-singh" ], "author_names": [ "Timothy J. Sargeant", "Sanjna Singh" ], "text": "Autophagy activation is a promising strategy to counteract age-related cellular dysfunction. While preclinical studies suggest dietary protein restriction can induce autophagy via mTORC1 inhibition, direct human evidence using dynamic, flux-based measurements remains limited. The aim of this study was to determine whether a low protein diet could modulate autophagic flux in humans. Dietary protein restriction (10% vs 20% of energy) for 4 weeks each, randomized crossover, no caloric deficit mTORC1-mediated autophagy (autophagic flux) Human (healthy adults, n=63 completers) No significant change in autophagic flux with protein restriction (negative result); suggests protein reduction alone, without caloric deficit, is insufficient to activate autophagy in human blood" }, { "sid": "ZHU2026", "entities": [ "rapamycin", "mtor", "lkb1-stk11", "ampk" ], "authors": [ "lifu-zhu" ], "author_names": [ "Lifu Zhu" ], "text": "In a TCE-sensitized mouse liver injury model, LKB1/AMPK deficiency aggravated mTOR-dependent impairment of mitophagy, causing mitochondrial DNA leakage and exacerbated immune-mediated liver damage. Rapamycin treatment, LKB1 overexpression, and AICAR (AMPK activator) each rescued mitophagy and reduced liver injury. Rapamycin; AICAR; LKB1 overexpression LKB1/AMPK/mTOR axis; mitophagy Mouse Rapamycin and AMPK activation restore mTOR-dependent mitophagy; LKB1/AMPK deficiency worsens mitochondrial DNA leakage and liver injury" }, { "sid": "KIM2012", "entities": [ "lysosome", "rag-gtpases", "mtorc1" ], "authors": [ "do-hyung-kim", "young-mi-kim" ], "author_names": [ "Do-Hyung Kim", "Young-Mi Kim" ], "text": "Amino acids stimulate cell growth and suppress autophagy through activation of mTORC1. The activation of mTORC1 by amino acids is mediated by Rag guanosine triphosphatase (GTPase) heterodimers on the lysosome. The molecular mechanism by which amino acids regulate the Rag GTPase heterodimers remains to be elucidated. Here, we identify SH3 domain-binding protein 4 (SH3BP4) as a binding protein and a negative regulator of Rag GTPase complex. Biochemical/genetic (SH3BP4) SH3BP4 / Rag GTPase / mTORC1 Mammalian cells SH3BP4 is a negative regulator of amino-acid-Rag-GTPase-mTORC1 signaling" }, { "sid": "RAO2010", "entities": [ "t-cell-differentiation", "rapamycin", "mtor", "pi3k", "s6k1" ], "authors": [ "rajesh-r-rao", "protul-a-shrikant" ], "author_names": [ "Rajesh R. Rao", "Protul A. Shrikant" ], "text": "The mechanisms underpinning integration of instructions that program naive CD8+ T cells for effector and/or memory differentiation are not well understood. Herein, we demonstrate that interleukin-12 (IL-12) enhanced and sustained antigen and costimulatory molecule (B7.1)-induced mTOR kinase activity in naive CD8+ (OT-I) T cells via phosphoinositide 3-kinase and STAT4 transcription factor pathways. Blocking mTOR activity by rapamycin reversed IL-12-induced effector functions because of loss of persistent expression of the transcription factor T-bet. Rapamycin during in vitro antigen plus IL-12 conditioning; PI3K inhibitor LY294002; insulin; 2-deoxyglucose; STAT4 deficiency; inducible T-bet mTORC1 (S6K1/S6 phosphorylation), T-bet and Eomesodermin expression in CD8 T cells Mouse mTOR inhibition lowered sustained T-bet and effector function and raised Eomesodermin and memory-precursor features" }, { "sid": "GU2017", "entities": [ "samtor", "mtorc1", "s-adenosylmethionine-sam", "methionine", "gator1" ], "authors": [ "david-m-sabatini", "robert-a-saxton", "j-wade-harper", "steven-p-gygi", "grace-y-liu", "kendall-j-condon", "sonia-m-scaria", "jose-m-orozco", "xin-gu" ], "author_names": [ "David M. Sabatini", "Robert A. Saxton", "J. Wade Harper", "Steven P. Gygi", "Grace Y. Liu", "Kendall J. Condon", "Sonia M. Scaria", "Jose M. Orozco", "Xin Gu" ], "text": "mTOR complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple environmental cues. Nutrients signal via the Rag guanosine triphosphatases (GTPases) to promote the localization of mTORC1 to the lysosomal surface, its site of activation. We identified SAMTOR, a previously uncharacterized protein, which inhibits mTORC1 signaling by interacting with GATOR1, the GTPase activating protein (GAP) for RagA/B. We found that the methyl donor-adenosylmethionine (SAM) disrupts the SAMTOR-GATOR1 complex by binding directly to SAMTOR with a dissociation constant of approximately 7 μM. Biochemical/genetic (SAMTOR) SAMTOR / GATOR1 / mTORC1 (SAM/methionine) Human cells (biochemistry) SAMTOR is an S-adenosylmethionine sensor that inhibits mTORC1 by interacting with GATOR1" }, { "sid": "HOS2009", "entities": [ "ulk1", "mtorc1", "autophagy" ], "authors": [ "noriko-oshiro-rapley", "noboru-mizushima", "nao-hosokawa" ], "author_names": [ "Noriko Oshiro-Rapley", "Noboru Mizushima", "Nao Hosokawa" ], "text": "Autophagy is an intracellular degradation system, by which cytoplasmic contents are degraded in lysosomes. Autophagy is dynamically induced by nutrient depletion to provide necessary amino acids within cells, thus helping them adapt to starvation. Although it has been suggested that mTOR is a major negative regulator of autophagy, how it controls autophagy has not yet been determined. Here, we report a novel mammalian autophagy factor, Atg13, which forms a stable approximately 3-MDa protein complex with ULK1 and FIP200. Genetic/biochemical (mTORC1/ULK1-Atg13-FIP200) mTORC1 / ULK1-Atg13-FIP200 Mammalian cells Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex controls autophagy induction" }, { "sid": "LAN2026", "entities": [ "rapamycin" ], "authors": [ "dudley-w-lamming", "mandeep-singh", "james-l-kirkland", "conor-m-lane" ], "author_names": [ "Dudley W. Lamming", "Mandeep Singh", "James L. Kirkland", "Conor M. Lane" ], "text": "[Abstract not yet available in PubMed - ahead-of-print, indexed 2026-09-18] Low-dose rapamycin (details not available) mTOR Human (frail older adults with HFpEF)" }, { "sid": "YUX2011", "entities": [ "grb10" ], "authors": [ "john-blenis", "lewis-c-cantley", "steven-p-gygi", "yonghao-yu" ], "author_names": [ "John Blenis", "Lewis C. Cantley", "Steven P. Gygi", "Yonghao Yu" ], "text": "The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Phosphoproteomics (mTORC1/Grb10) mTORC1 / Grb10 / insulin signaling Mammalian cells Grb10 is an mTORC1 substrate that negatively feeds back on insulin/IGF signaling" }, { "sid": "PAN2013", "entities": [ "rag-gtpases", "mtorc1", "gator1" ], "authors": [ "claudio-de-virgilio", "nicolas-panchaud" ], "author_names": [ "Claudio De Virgilio", "Nicolas Panchaud" ], "text": "The Rag family of guanosine triphosphatases (GTPases) regulates eukaryotic cell growth in response to amino acids by activating the target of rapamycin complex 1 (TORC1). In humans, this pathway is often deregulated in cancer. In yeast, amino acids promote binding of GTP (guanosine 5'-triphosphate) to the Rag family GTPase Gtr1, which, in combination with a GDP (guanosine diphosphate)-bound Gtr2, forms the active, TORC1-stimulating GTPase heterodimer. We identified Iml1, which functioned in a complex with Npr2 and Npr3, as a GAP (GTPase-activating protein) for Gtr1. Biochemical/genetic (SEACIT/GAP for Gtr1) TORC1 / Gtr1 (Rag) / SEACIT Yeast Amino-acid deprivation inhibits TORC1 through a GAP complex (SEACIT) for the Rag-family GTPase Gtr1" }, { "sid": "PLEDGER2026", "entities": [ "5top-mrna" ], "authors": [ "jamie-h-d-cate", "erica-pledger" ], "author_names": [ "Jamie H. D. Cate", "Erica Pledger" ], "text": "T cell exhaustion is a dysfunctional state that arises during chronic infections and cancer, characterized by impaired effector functions and sustained expression of inhibitory receptors. We performed ribosome profiling and RNA sequencing on chronically activated human CD8+ T cells to globally assess translational control during a model of T cell exhaustion. Our analyses reveal a marked repression of 5' terminal oligopyrimidine (TOP) mRNAs during chronic activation. Unexpectedly, we demonstrate that this translational repression occurs despite evidence of elevated mTOR activity. Chronic T cell activation mTOR / 5'TOP mRNA translation Human 5'TOP mRNAs repressed despite elevated mTOR activity in exhausted CD8+ T cells" }, { "sid": "LIANG2026", "entities": [ "mtor", "cellular-senescence" ], "authors": [ "xiaoting-liang", "chunting-zhang" ], "author_names": [ "Xiaoting Liang", "Chunting Zhang" ], "text": "LINP1 is a markedly upregulated lncRNA following ionizing radiation (IR). LINP1 promotes cell survival and limits radiation-induced DNA damage accumulation. Mechanistically, LINP1 attenuates radiation-induced cellular senescence through modulation of the mTOR-p53 signaling axis: LINP1 associates with the FAT domain of mTOR, attenuates the interaction between mTOR and p53, thereby reducing p53 Ser15 phosphorylation and downstream senescence-associated signaling. LINP1 overexpression/knockdown; ionizing radiation mTOR FAT domain; mTOR-p53 interaction; p53 Ser15 phosphorylation; cellular senescence Human LINP1 directly binds mTOR FAT domain to reduce mTOR-p53 interaction, decrease p53 activation, and suppress radiation-induced senescence" }, { "sid": "DEN2026B", "entities": [ "rapamycin" ], "authors": [ "luca-marchetti", "alex-de-nardi" ], "author_names": [ "Luca Marchetti", "Alex De Nardi" ], "text": "Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by considerable variability in survival times. This retrospective study aims to evaluate the prognostic value of a broad range of variables by conducting a comprehensive survival analysis on longitudinal data from RAP-ALS, a clinical trial investigating the effects of rapamycin in ALS patients (n = 63). Covariates were classified as risk or protective factors according to their hazard ratios. Regularized Cox regression was utilized to select the best-performing multivariate models in cross-validation. Rapamycin (RAP-ALS trial), post hoc survival analysis mTOR Human (ALS patients, n=63; treated C9orf72 carriers n=6) Exploratory association between rapamycin treatment and longer survival in C9orf72 carriers; confounding not excluded." }, { "sid": "MIL2014", "entities": [ "mtor" ], "authors": [ "randy-strong", "richard-a-miller", "david-e-harrison", "adam-b-salmon", "clinton-astle", "kevin-flurkey", "nancy-l-nadon", "zelton-dave-sharp" ], "author_names": [ "Randy Strong", "Richard A. Miller", "David E. Harrison", "Adam B. Salmon", "Clinton Astle", "Kevin Flurkey", "Nancy L. Nadon", "Zelton Dave Sharp" ], "text": "Rapamycin, an inhibitor of mTOR kinase, increased median lifespan of genetically heterogeneous mice by 23% (males) to 26% (females) when tested at a dose threefold higher than that used in our previous studies; maximal longevity was also increased in both sexes. Rapamycin increased lifespan more in females than in males at each dose evaluated, perhaps reflecting sexual dimorphism in blood levels of this drug. Rapamycin (dose-response) mTOR Mouse (genetically heterogeneous) Rapamycin extends lifespan 23-26% in a dose- and sex-dependent way, metabolically distinct from dietary restriction Rapamycin in food at 4.7, 14, or 42 ppm, administered from 9 months of age until death. Pooled data from 3 sites: 300 control males, 156 males per rapamycin dose group; 280 control females, 136 females per rapamycin dose group. Highest dose (42 ppm) increased median lifespan by 23% in males (P<0.0001) and 26% in females (P<0.0001); all three doses extended lifespan in females, and the two highest doses extended lifespan in males. Lower statistical power for site-independent analyses; Gompertz parameter estimates should be interpreted with caution due to small data sets, low statistical power, and no adjustment for site-to-site variation; increased fighting (11-22% cages removed) in highest dose male group with unknown cause." }, { "sid": "GUL2008", "entities": [ "mtorc1", "vps34-pik3c3" ], "authors": [ "george-thomas", "takahiro-nobukuni", "sara-c-kozma", "pawan-gulati" ], "author_names": [ "George Thomas", "Takahiro Nobukuni", "Sara C. Kozma", "Pawan Gulati" ], "text": "Excess levels of circulating amino acids (AAs) play a causal role in specific human pathologies, including obesity and type 2 diabetes. Moreover, obesity and diabetes are contributing factors in the development of cancer, with recent studies suggesting that this link is mediated in part by AA activation of mammalian target of rapamycin (mTOR) Complex 1. AAs appear to mediate this response through class III phosphatidylinositol 3-kinase (PI3K), or human vacuolar protein sorting 34 (hVps34), rather than through the canonical class I PI3K pathway used by growth factors and hormones. Amino acid stimulation; Ca2+ chelation; hVps34 CaM-binding motif mutants hVps34 lipid kinase activity; mTORC1 signalling Human cell lines Amino acids -> rise in intracellular Ca2+ -> Ca2+/CaM binds hVps34 -> increased mTORC1 signalling" }, { "sid": "POR2008", "entities": [ "lipid-synthesis", "srebp1-srebp2" ], "authors": [ "almut-schulze", "thomas-porstmann" ], "author_names": [ "Almut Schulze", "Thomas Porstmann" ], "text": "Cell growth (accumulation of mass) needs to be coordinated with metabolic processes that are required for the synthesis of macromolecules. The PI3-kinase/Akt signaling pathway induces cell growth via activation of complex 1 of the target of rapamycin (TORC1). Here we show that Akt-dependent lipogenesis requires mTORC1 activity. Furthermore, nuclear accumulation of the mature form of the sterol responsive element binding protein (SREBP1) and expression of SREBP target genes was blocked by the mTORC1 inhibitor rapamycin. Genetic/pharmacologic (mTORC1/SREBP) mTORC1 / SREBP / Akt Mammalian cells SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth (lipogenesis)" }, { "sid": "SCH2006", "entities": [ "rapamycin", "raptor", "oxidative-phosphorylation", "mtorc1" ], "authors": [ "toren-finkel", "stefan-m-schieke" ], "author_names": [ "Toren Finkel", "Stefan M. Schieke" ], "text": "Metabolic rate and the subsequent production of reactive oxygen species are thought to contribute to the rate of aging in a wide range of species. The target of rapamycin (TOR) is a well conserved serine/threonine kinase that regulates cell growth in response to nutrient status. Here we demonstrate that in mammalian cells the mammalian TOR (mTOR) pathway plays a significant role in determining both resting oxygen consumption and oxidative capacity. Rapamycin; RNAi against TSC2, S6K1, raptor, rictor Mitochondrial oxygen consumption, membrane potential, ATP synthesis; mitochondrial phosphoproteome Human cell line mTOR inhibition with rapamycin lowers mitochondrial respiration and oxidative capacity" }, { "sid": "HU2026B", "entities": [ "mtorc1" ], "authors": [ "ke-hu", "stefan-feske" ], "author_names": [ "Ke Hu", "Stefan Feske" ], "text": "Antibody-producing plasmablasts (PB) and plasma cells (PC) are critical for humoral immunity, autoimmunity and vaccine responses. Despite the importance of environmental stressors in regulating humoral immune responses, the influence of pH on PB and PC differentiation remains elusive. Here, we identify SLC4A7/NBCn1, a Na/HCO3- cotransporter, as a selective regulator of PB differentiation in vitro. SLC4A7 deletion also impairs the formation of antibody secreting cells (ASCs) and antibody responses in mice in vivo following immunization and influenza A virus infection." }, { "sid": "GAN2009", "entities": [], "authors": [ "ian-g-ganley", "xuejun-jiang" ], "author_names": [ "Ian G. Ganley", "Xuejun Jiang" ], "text": "Autophagy is a degradative process that recycles long-lived and faulty cellular components. It is linked to many diseases and is required for normal development. ULK1, a mammalian serine/threonine protein kinase, plays a key role in the initial stages of autophagy, though the exact molecular mechanism is unknown. Here we report identification of a novel protein complex containing ULK1 and two additional protein factors, FIP200 and ATG13, all of which are essential for starvation-induced autophagy. Genetic/biochemical (ULK1-ATG13-FIP200) mTOR / ULK1-ATG13-FIP200 Mammalian cells The ULK1-ATG13-FIP200 complex mediates mTOR signaling and is essential for autophagy" }, { "sid": "SUN2026", "entities": [ "autoimmune-cytopenia", "rapamycin" ], "authors": [ "zexing-sun" ], "author_names": [ "Zexing Sun" ], "text": "Cyclosporine A (CsA) is standard first-line treatment for acquired pure red cell aplasia (PRCA), but outcomes vary and salvage strategies for CsA-refractory patients are poorly defined. Retrospective single-centre comparative study of patients treated 2021-2025: 36 received first-line CsA and 22 switched to sirolimus for lack of response or intolerance. The ORR for first-line CsA was 25.0% (9/36), significantly higher in primary cases (42.1%) than secondary (5.9%). In the salvage sirolimus group ORR was 54.5%, with efficacy in both primary (37.5%) and secondary (64.3%) cases. Sirolimus (second-line salvage) mTOR Human 54.5% ORR in CsA-refractory PRCA; sustained remission in responders; effective regardless of STAT3/5b mutation status" }, { "sid": "BRU2004", "entities": [ "hypoxia", "redd1-ddit4" ], "authors": [ "brendan-d-manning", "william-g-kaelin-jr", "ernst-hafen", "james-brugarolas" ], "author_names": [ "Brendan D. Manning", "William G. Kaelin Jr.", "Ernst Hafen", "James Brugarolas" ], "text": "Mammalian target of rapamycin (mTOR) is a central regulator of protein synthesis whose activity is modulated by a variety of signals. Energy depletion and hypoxia result in mTOR inhibition. While energy depletion inhibits mTOR through a process involving the activation of AMP-activated protein kinase (AMPK) by LKB1 and subsequent phosphorylation of TSC2, the mechanism of mTOR inhibition by hypoxia is not known. Here we show that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801. Genetic (REDD1 / TSC1-TSC2) mTOR / REDD1 / TSC1-TSC2 Mammalian cells Hypoxia inhibits mTOR via REDD1 acting through the TSC1/TSC2 tumor-suppressor complex" }, { "sid": "XU2026B", "entities": [ "t-cell-differentiation", "rictor", "macrophage-polarization", "immune-function", "mtorc2" ], "authors": [ "jingting-xu", "fengjing-guo" ], "author_names": [ "Jingting Xu", "Fengjing Guo" ], "text": "mTORC2, defined by its core component RICTOR, is a key regulator of immune cell function and inflammation, yet its roles have long been underappreciated due to lack of specific inhibitors and in vivo tools. This review summarizes the current understanding of mTORC2-specific signaling (via AKT, SGK1, and PKC) in regulating the development, differentiation, and effector functions of diverse immune cells, and discusses its emerging roles in immune cell inflammation and tissue-specific inflammation. none (review) mTORC2/RICTOR in immune cells Review (mouse conditional knockouts, immune cells, clinical samples) Summarises context-dependent roles of mTORC2 in immune cell differentiation and tissue inflammation." }, { "sid": "DEM2009", "entities": [ "rapamycin", "mtor", "cellular-senescence", "mtorc1" ], "authors": [ "mikhail-v-blagosklonny", "zoya-n-demidenko" ], "author_names": [ "Mikhail V. Blagosklonny", "Zoya N Demidenko" ], "text": "When the cell cycle is arrested but cellular growth is not, then cells senesce, permanently losing proliferative potential. Here we demonstrated that the duration of cell cycle arrest determines a progressive loss of proliferative capacity. In human and rodent cell lines, rapamycin (an inhibitor of mTOR) dramatically decelerated loss of proliferative potential caused by ectopic p21, p16 and sodium butyrate-induced p21. Rapamycin (mTOR inhibition) mTOR Human + rodent cell lines Rapamycin decelerates cellular senescence (geroconversion) during cell-cycle arrest" }, { "sid": "DUV2010", "entities": [ "hif-1alpha", "lipid-synthesis", "mtorc1", "srebp1-srebp2", "s6k1" ], "authors": [ "brendan-d-manning", "sue-menon", "katrin-duvel", "peter-m-finan", "leon-o-murphy" ], "author_names": [ "Brendan D. Manning", "Sue Menon", "Katrin Düvel", "Peter M Finan", "Leon O Murphy" ], "text": "Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) is a common molecular event in a variety of pathological settings, including genetic tumor syndromes, cancer, and obesity. However, the cell-intrinsic consequences of mTORC1 activation remain poorly defined. Through a combination of unbiased genomic, metabolomic, and bioinformatic approaches, we demonstrate that mTORC1 activation is sufficient to stimulate specific metabolic pathways, including glycolysis, the oxidative arm of the pentose phosphate pathway, and de novo lipid biosynthesis. Tsc2 loss (constitutive mTORC1); rapamycin; SREBP and S6K1 knockdown mTORC1 -> HIF1alpha, SREBP1/2 (via S6K1) Mouse embryonic fibroblasts and other cell lines mTORC1 activates glycolysis, oxidative PPP and lipid synthesis via HIF1alpha and SREBP" }, { "sid": "MA2026", "entities": [ "p62-sqstm1", "pip4k2a" ], "authors": [ "hongxuan-feng", "bodun-ma", "shuai-yu", "mei-li", "xiaotian-yu" ], "author_names": [ "Hongxuan Feng", "Bodun Ma", "Shuai Yu", "Mei Li", "Xiaotian Yu" ], "text": "Ischemic stroke is the most prevalent form of stroke worldwide and remains a major cause of long-term disability. Impaired autophagic flux is a critical pathological mechanism that worsens neuronal injury after ischemia. This study aimed to elucidate the role of phosphatidylinositol-5-phosphate 4-kinase type II alpha (PIP4K2A) and its regulation of autophagy in cerebral ischemia/reperfusion (I/R) injury. Exploratory TMT-based serum proteomics identified PIP4K2A as an elevated candidate protein in patients with acute ischemic stroke (AIS). PIP4K2A overexpression AKT/mTOR / autophagy / TRIB3-p62 Mouse PIP4K2A restored autophagic flux and reduced neuronal injury via AKT/mTOR modulation in I/R stroke" }, { "sid": "DUR2012", "entities": [ "glutamine" ], "authors": [ "michael-n-hall", "raul-v-duran", "wolfgang-oppliger" ], "author_names": [ "Michael N. Hall", "Raúl V. Durán", "Wolfgang Oppliger" ], "text": "Amino acids control cell growth via activation of the highly conserved kinase TORC1. Glutamine is a particularly important amino acid in cell growth control and metabolism. However, the role of glutamine in TORC1 activation remains poorly defined. Glutamine is metabolized through glutaminolysis to produce alpha-ketoglutarate. We demonstrate that glutamine in combination with leucine activates mammalian TORC1 (mTORC1) by enhancing glutaminolysis and alpha-ketoglutarate production. Biochemical/genetic (glutaminolysis) mTORC1 / Rag GTPases (α-ketoglutarate) Mammalian cells Glutaminolysis (with leucine) activates Rag-mTORC1 signaling via α-ketoglutarate production" }, { "sid": "ZHANG2026B", "entities": [ "mtor", "cellular-senescence", "autophagy", "beclin-1-becn1" ], "authors": [ "shiting-yu", "yiwen-zhang", "siming-wang" ], "author_names": [ "Shiting Yu", "Yiwen Zhang", "Siming Wang" ], "text": "This study investigated the efficacy of Chinese yam protein extract (CYCSE) from Dioscorea polystachya in attenuating aging-related reproductive decline. In aged rats and D-galactose-induced senescent mouse Leydig and Sertoli cells, CYCSE ameliorated testicular histopathology, restored sperm parameters, increased testosterone levels, reduced senescence markers (SA-beta-gal, p16, p21, p53), and mitigated oxidative stress. TEM confirmed restored autophagic flux in senescent cells. Mechanistically, CYCSE restored autophagic activity via the mTOR-Beclin-1 signaling axis. Chinese yam protein extract (CYCSE); mTOR activator (control) mTOR-Beclin-1 axis; autophagy; Star; Cyp11a1 Rat; Mouse CYCSE suppresses mTOR to activate autophagy via Beclin-1, reducing senescence markers and restoring reproductive function in aged testicular cells" }, { "sid": "LAP2026", "entities": [ "tsc1-tsc2", "muscle-growth", "akt-pkb", "mtorc1", "protein-synthesis" ], "authors": [ "brendan-d-manning", "krystle-c-kalafut", "madi-y-cisse", "yann-cormerais", "karen-e-inouye", "samuel-c-lapp" ], "author_names": [ "Brendan D. Manning", "Krystle C. Kalafut", "Madi Y. Cissé", "Yann Cormerais", "Karen E. Inouye", "Samuel C. Lapp" ], "text": "Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these two major modes of muscle mTORC1 regulation. Genetic knock-in of AKT-phosphorylation-resistant TSC2 (5A mutant), muscle-specific – separates feeding- from contraction-induced mTORC1 activation AKT-TSC2-mTORC1 axis in skeletal muscle Mouse (skeletal muscle-specific knock-in, both sexes) Blocked feeding-induced (not contraction-induced) mTORC1 activation and postprandial protein synthesis; muscle mass/myofiber size unchanged; improved maximal endurance and modestly increased mitochondrial content" }, { "sid": "MAN2002", "entities": [ "tsc1-tsc2", "pten", "akt-pkb", "pi3k", "s6k1" ], "authors": [ "brendan-d-manning", "john-blenis", "lewis-c-cantley", "andrew-r-tee" ], "author_names": [ "Brendan D. Manning", "John Blenis", "Lewis C. Cantley", "Andrew R. Tee" ], "text": "The S/T-protein kinases activated by phosphoinositide 3-kinase (PI3K) regulate a myriad of cellular processes. Here, we show that an approach using a combination of biochemistry and bioinformatics can identify substrates of these kinases. This approach identifies the tuberous sclerosis complex-2 gene product, tuberin, as a potential target of Akt/PKB. We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. PI3K activation; Akt/PKB kinase; phospho-site mutant tuberin (S939/T1462) TSC2 (tuberin) phosphorylation; S6K1 activation Mouse and human cell lines; in vitro Akt phosphorylates tuberin (inhibitory); non-phosphorylatable tuberin blocks S6K1 activation" }, { "sid": "TEE2003", "entities": [ "tsc1-tsc2", "mtorc1", "rheb" ], "authors": [ "brendan-d-manning", "john-blenis", "lewis-c-cantley", "andrew-r-tee" ], "author_names": [ "Brendan D. Manning", "John Blenis", "Lewis C. Cantley", "Andrew R. Tee" ], "text": "Tuberous Sclerosis Complex (TSC) is a genetic disorder that occurs through the loss of heterozygosity of either TSC1 or TSC2, which encode Hamartin or Tuberin, respectively. Tuberin and Hamartin form a tumor suppressor heterodimer that inhibits the mammalian target of rapamycin (mTOR) nutrient signaling input, but how this occurs is unclear. We show that the small G protein Rheb (Ras homolog enriched in brain) is a molecular target of TSC1/TSC2 that regulates mTOR signaling. Biochemical/genetic (TSC1/TSC2) TSC1-TSC2 (Hamartin/Tuberin) / Rheb / mTOR Human cell lines Tuberin-Hamartin (TSC1-TSC2) control mTOR by acting as a GAP complex toward Rheb" }, { "sid": "ARI2015", "entities": [ "lysosome", "chaperone-mediated-autophagy", "akt-pkb", "mtorc2" ], "authors": [ "esperanza-arias-perez", "ana-maria-cuervo" ], "author_names": [ "Esperanza Arias-Perez", "Ana Maria Cuervo" ], "text": "Chaperone-mediated autophagy (CMA), a selective form of degradation of cytosolic proteins in lysosomes, contributes to maintenance of proteostasis and to the cellular adaptation to stress. CMA substrates are delivered by a cytosolic chaperone to the lysosomal surface, where, upon unfolding, they are internalized through a membrane translocation complex. The molecular components that participate in CMA substrate targeting and translocation are well characterized, but those involved in CMA regulation remain mostly unknown. Genetic and pharmacological manipulation of mTORC2, PHLPP1 and Akt Lysosomal mTORC2/PHLPP1/Akt axis; chaperone-mediated autophagy Mouse and rat liver; NIH3T3 cells mTORC2 inhibits chaperone-mediated autophagy via lysosomal Akt, while PHLPP1 counteracts it." }, { "sid": "ALI2022", "entities": [ "mtorc1", "nucleotide-synthesis", "s6k1" ], "authors": [ "issam-ben-sahra", "eunus-s-ali", "brendan-p-ohara", "john-m-asara", "peng-gao" ], "author_names": [ "Issam Ben-Sahra", "Eunus S. Ali", "Brendan P. O'Hara", "John M. Asara", "Peng Gao" ], "text": "Bicarbonate (HCO3-) ions maintain pH homeostasis in eukaryotic cells and serve as a carbonyl donor to support cellular metabolism. However, whether the abundance of HCO3- is regulated or harnessed to promote cell growth is unknown. The mechanistic target of rapamycin complex 1 (mTORC1) adjusts cellular metabolism to support biomass production and cell growth. We find that mTORC1 stimulates the intracellular transport of HCO3- to promote nucleotide synthesis through the selective translational regulation of the sodium bicarbonate cotransporter SLC4A7. Genetic (SLC4A7 loss); mTORC1 modulation mTORC1 / S6K / eIF4B / SLC4A7 (NBCn1) Human cells; mouse xenograft tumors mTORC1 raises SLC4A7 translation to import bicarbonate and sustain de novo purine and pyrimidine synthesis, cell growth and tumor growth" }, { "sid": "STO2003", "entities": [ "rheb" ], "authors": [ "george-thomas", "ernst-hafen", "hugo-stocker" ], "author_names": [ "George Thomas", "Ernst Hafen", "Hugo Stocker" ], "text": "Understanding the mechanisms through which multicellular organisms regulate cell, organ and body growth is of relevance to developmental biology and to research on growth-related diseases such as cancer. Here we describe a new effector in growth control, the small GTPase Rheb (Ras homologue enriched in brain). Mutations in the Drosophila melanogaster Rheb gene were isolated as growth-inhibitors, whereas overexpression of Rheb promoted cell growth. Genetic (Rheb mutants/overexpression) Rheb / S6K / TOR Drosophila Rheb is an essential regulator of S6K controlling cell growth in Drosophila" }, { "sid": "LEE2026", "entities": [ "cognition", "mtor", "alzheimers-disease" ], "authors": [ "won-suk-chung", "se-young-lee", "seongbin-kim", "eunjoon-kim" ], "author_names": [ "Won-Suk Chung", "Se Young Lee", "Seongbin Kim", "Eunjoon Kim" ], "text": "Neuroinflammation and synapse loss are associated with cognitive decline in Alzheimer's disease (AD). Although microglial hyperphagocytic activity has been implicated in synapse loss, the mechanisms underlying these pathologies remain obscure. Here we demonstrate that, during AD progression in mice, astrocytes and microglia increase phagocytic elimination of excitatory synapses while reducing elimination of inhibitory synapses, suggesting that neuroinflammation alone may be dispensable for early AD synapse loss. Excitatory-neuron-specific Erbb4 deletion and Erbb4 overexpression; mTOR pathway inhibition ERBB4 -> mTOR signalling in excitatory neurons Mouse; human transcriptomic data Erbb4 deletion rescued synapse loss, gliosis, amyloid plaque deposition and cognitive deficits; Erbb4 overexpression recapitulated these phenotypes without amyloid plaques - both requiring mTOR signalling downstream" }, { "sid": "HAR2009", "entities": [ "longevity", "rapamycin", "mtor", "mtorc1" ], "authors": [ "randy-strong", "richard-a-miller", "david-e-harrison", "clinton-astle", "kevin-flurkey", "nancy-l-nadon", "zelton-dave-sharp" ], "author_names": [ "Randy Strong", "Richard A. Miller", "David E. Harrison", "Clinton Astle", "Kevin Flurkey", "Nancy L. Nadon", "Zelton Dave Sharp" ], "text": "Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. Rapamycin (late-life feeding) mTOR Mouse (genetically heterogeneous, 3 sites) Rapamycin fed from 600 days extended median and maximal lifespan in both sexes – first pharmacological lifespan extension in a mammal Dietary encapsulated rapamycin, initiated at 600 days of age (or 270 days in a separate study), resulting in blood levels of 60-70 ng/ml. 1901 mice (38 still alive at analysis date). Pooled mean lifespan increased by 9% for males and 13% for females; life expectancy at 600 days increased by 28% for males and 38% for females (p < 0.0001). Improved survival among males at UT and UM might reflect pre-treatment nutritional/health differences, not solely rapamycin effects; additional data needed for accurate effect size and maximal longevity for 270-day start." }, { "sid": "SAR2009", "entities": [ "lysosome", "tfeb", "lysosomal-biogenesis" ], "authors": [ "andrea-ballabio", "marco-sardiello" ], "author_names": [ "Andrea Ballabio", "Marco Sardiello" ], "text": "Lysosomes are organelles central to degradation and recycling processes in animal cells. Whether lysosomal activity is coordinated to respond to cellular needs remains unclear. We found that most lysosomal genes exhibit coordinated transcriptional behavior and are regulated by the transcription factor EB (TFEB). Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes. TFEB overexpression; induction of lysosomal storage TFEB / CLEAR lysosomal gene network Human and mouse cultured cells TFEB overexpression increased lysosomal gene expression, lysosome number and clearance of glycosaminoglycans and mutant huntingtin" }, { "sid": "SHI2026", "entities": [ "atg5", "caloric-restriction", "reactive-oxygen-species", "autophagy" ], "authors": [ "edward-t-chouchani", "william-b-mair" ], "author_names": [ "Edward T. Chouchani", "William B. Mair" ], "text": "Dietary restriction (DR) protects against metabolic disease, extends lifespan, and is associated with remodeling of tissue reactive oxygen species (ROS). ROS control biological adaptation through reversible oxidation of protein cysteines, yet the targets of DR-initiated redox signaling are unknown. Here we generate OxiDR, a tissue-resolved atlas of the cysteine redox proteome that quantifies oxidation state under DR. Dietary restriction; ATG5 Cys19 redox-dead mutation ATG5 Cys19 oxidation; autophagy Human cell lines and mice Oxidation of ATG5 Cys19 was required for nutrient-restriction-induced autophagy; mice lacking it developed tissue pathology and early death." }, { "sid": "REN2026", "entities": [ "kynurenic-acid", "itga2-integrin-alpha-2" ], "authors": [ "yingxin-ren", "jiaqiang-jiang", "xiang-yu" ], "author_names": [ "Yingxin Ren", "Jiaqiang Jiang", "Xiang Yu" ], "text": "The tumor microbiota critically shapes responses to immunotherapy; however, the mechanisms by which specific microbial species drive immune checkpoint blockade (ICB) resistance in gastric cancer (GC) remain poorly defined. Bacterial enrichment was assessed in ICB-unresponsive GC tissues from patients and multiple preclinical models. Orthotopic, subcutaneous, and germ-free mono-colonized mouse models were employed to evaluate the impact on antitumor immunity and PD-1 blockade efficacy. ITGA2 targeting / anti-PD-1 mTOR (ITGA2-mTOR-CTSV axis) Mouse + Human Kynurenic acid induces ITGA2 and inhibits an mTOR-dependent cascade, sustaining cathepsin V and suppressing CD8+ T cells, driving immunotherapy resistance" }, { "sid": "SHAW2004", "entities": [ "tsc1-tsc2", "mtorc1", "energy-cellular-stress", "lkb1-stk11", "ampk" ], "authors": [ "brendan-d-manning", "reuben-j-shaw", "lewis-c-cantley" ], "author_names": [ "Brendan D. Manning", "Reuben J. Shaw", "Lewis C. Cantley" ], "text": "Germline mutations in LKB1, TSC2, or PTEN tumor suppressor genes result in hamartomatous syndromes with shared tumor biological features. The recent observations of LKB1-mediated activation of AMP-activated protein kinase (AMPK) and AMPK inhibition of mTOR through TSC2 prompted us to examine the biochemical and biological relationship between LKB1 and mTOR regulation. Lkb1 deletion; energy stress (low ATP) LKB1 -> AMPK -> TSC2 -> mTOR Mouse embryonic fibroblasts; Lkb1 mutant mice Loss of LKB1 prevents repression of mTOR under low ATP and raises mTOR signalling in polyps" }, { "sid": "SET2013", "entities": [ "tfeb", "pgc-1alpha-yy1", "autophagy" ], "authors": [ "andrea-ballabio", "carmine-settembre", "tuong-huynh" ], "author_names": [ "Andrea Ballabio", "Carmine Settembre", "Tuong Huynh" ], "text": "The lysosomal-autophagic pathway is activated by starvation and plays an important role in both cellular clearance and lipid catabolism. However, the transcriptional regulation of this pathway in response to metabolic cues is uncharacterized. Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via Ppargc1α and Ppar1α. Fasting; liver-specific Tfeb deletion; liver-directed TFEB overexpression (HDAd-TFEB); high-fat diet; ob/ob mice; hlh-30 mutant worms TFEB -> PGC-1alpha / PPARalpha lipid catabolism programme Mouse; C. elegans TFEB raised lipid catabolism gene expression and fat breakdown; liver TFEB overexpression prevented diet-induced obesity, TFEB loss worsened it" }, { "sid": "ZID2009", "entities": [ "longevity", "caloric-restriction", "mtorc1", "4e-bp1" ], "authors": [ "pankaj-kapahi", "seymour-benzer", "brian-m-zid" ], "author_names": [ "Pankaj Kapahi", "Seymour Benzer", "Brian M. Zid" ], "text": "Dietary restriction (DR) extends lifespan in multiple species. To examine the mechanisms of lifespan extension upon DR, we assayed genome-wide translational changes in Drosophila. A number of nuclear encoded mitochondrial genes, including those in Complex I and IV of the electron transport chain, showed increased ribosomal loading and enhanced overall activity upon DR. We found that various mitochondrial genes possessed shorter and less structured 5'UTRs, which were important for their enhanced mRNA translation. Genetic (4E-BP) 4E-BP / mitochondria Drosophila 4E-BP extends lifespan under dietary restriction by enhancing mitochondrial activity Reducing the concentration of yeast or yeast extract in the fly diet while sucrose was constant (Dietary Restriction) not stated Upon DR, approximately 30% decrease of labeled methionine incorporation into newly synthesized proteins; mitochondrial protein density increased 25% in control flies; 20% upregulation in Complex I activity in DR flies; Cytochrome C oxidase (COX) activity increased 60% in control flies upon DR; 55 genes were differentially translationally downregulated and 201 upregulated upon DR (FDR < 5%) not stated" }, { "sid": "JIB2026", "entities": [ "rapamycin", "mtor" ], "authors": [ "wafiya-jibrin", "federica-lopes" ], "author_names": [ "Wafiya Jibrin", "Federica Lopes" ], "text": "This study assessed whether rapamycin could protect male spermatogonial stem cells (GC6-spg line) from cisplatin-induced cytotoxicity, analogous to its protective role reported in female fertility preservation. Rapamycin co-exposure did not prevent cisplatin-induced cell loss or damage in this spermatogonial cell line, suggesting limited utility for male fertility preservation during cancer treatment. Rapamycin mTOR inhibition; spermatogonial stem cell survival Mouse (GC6-spg spermatogonial cell line) No protective effect – rapamycin does not rescue cisplatin-induced spermatogonial stem cell loss (negative result)" }, { "sid": "KIM2011", "entities": [ "ulk1", "mtorc1", "autophagy", "ampk" ], "authors": [ "kun-liang-guan", "benoit-viollet", "joungmok-kim", "mondira-kundu" ], "author_names": [ "Kun-Liang Guan", "Benoit Viollet", "Joungmok Kim", "Mondira Kundu" ], "text": "Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Genetic/biochemical (AMPK, mTOR, ULK1) AMPK / mTOR / ULK1 Human/mouse cells AMPK and mTOR reciprocally phosphorylate ULK1 to regulate autophagy" }, { "sid": "LIP2017", "entities": [ "tsc1-tsc2", "mtor", "mtorc1", "tuberous-sclerosis-complex" ], "authors": [ "lara-m-boyle", "fred-c-davis", "jonathan-o-lipton", "ashwin-nathan", "mustafa-sahin", "elizabeth-d-yuan", "peter-t-tsai" ], "author_names": [ "Lara M. Boyle", "Fred C. Davis", "Jonathan O. Lipton", "Ashwin Nathan", "Mustafa Sahin", "Elizabeth D. Yuan", "Peter T. Tsai" ], "text": "Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder characterized by mutations in either the TSC1 or TSC2 genes, whose products form a critical inhibitor of the mechanistic target of rapamycin (mTOR). Loss of TSC1/2 gene function renders an mTOR-overactivated state. Clinically, TSC manifests with epilepsy, intellectual disability, autism, and sleep dysfunction. Here, we report that mouse models of TSC have abnormal circadian rhythms. We show that mTOR regulates the proteostasis of the core clock protein BMAL1, affecting its translation, degradation, and subcellular localization. Genetic loss of Tsc1/Tsc2; reduced Bmal1 dose mTOR; BMAL1 proteostasis Mouse mTOR overactivation elevates BMAL1 and disrupts circadian timekeeping; lowering BMAL1 rescues behaviour" }, { "sid": "POU2013", "entities": [ "resveratrol" ], "authors": [ "morten-poulsen", "jens-otto-l-jrgensen" ], "author_names": [ "Morten Poulsen", "Jens Otto L Jørgensen" ], "text": "Obesity, diabetes, hypertension, and hyperlipidemia constitute risk factors for morbidity and premature mortality. Based on animal and in vitro studies, resveratrol reverts these risk factors via stimulation of silent mating type information regulation 2 homolog 1 (SIRT1), but data in human subjects are scarce. The objective of this study was to examine the metabolic effects of high-dose resveratrol in obese human subjects. Resveratrol (high-dose) SIRT1 (mTOR-adjacent) Human – RCT (obese men, n=24) High-dose resveratrol did NOT improve insulin sensitivity, substrate metabolism or body composition in obese men (negative trial) High-dose resveratrol daily for 4 weeks vs placebo; investigator-initiated randomized double-blind parallel-group trial. 26 obese men enrolled; 1 dropout (claustrophobia), 1 excluded (rash) -> ~24 analyzed. NEGATIVE trial: no significant change in insulin sensitivity, resting energy expenditure, respiratory quotient, glucose/lipid oxidation, inflammatory biomarkers, leptin, or liver function. Small sample; null result contradicts the SIRT1/CR-mimetic hype for resveratrol." }, { "sid": "THE2026", "entities": [ "mtorc1" ], "authors": [ "laure-bally-cuif" ], "author_names": [ "Laure Bally-Cuif" ], "text": "Neural stem cells (NSCs) sustain lifelong neurogenesis through the tight regulation of quiescence, self-renewal and differentiation. Quiescent NSCs (qNSCs) exist in distinct substates, ranging from deep to shallow quiescence, yet the mechanisms governing these transitions remain unclear. In long-term self-renewing NSCs of the adult zebrafish pallium, we show that mTORC1 activity is specifically enriched during a prolonged quiescence phase in which NSCs acquire activation competence. Functional mTORC1 perturbation in vivo mTORC1 in quiescent neural stem cells Zebrafish mTORC1 sets the tempo of quiescent neural stem cells' progression toward activation" }, { "sid": "STU2018", "entities": [ "sin1-mapkap1" ], "authors": [ "michael-n-hall", "timm-maier", "nenad-ban", "christopher-aylett", "daniel-boehringer", "stefan-imseng", "evelyn-sauer", "alain-scaiola", "edward-stuttfeld" ], "author_names": [ "Michael N. Hall", "Timm Maier", "Nenad Ban", "Christopher Aylett", "Daniel Boehringer", "Stefan Imseng", "Evelyn Sauer", "Alain Scaiola", "Edward Stuttfeld" ], "text": "The mammalian target of rapamycin (mTOR) is a key protein kinase controlling cellular metabolism and growth. It is part of the two structurally and functionally distinct multiprotein complexes mTORC1 and mTORC2. Dysregulation of mTOR occurs in diabetes, cancer and neurological disease. We report the architecture of human mTORC2 at intermediate resolution, revealing a conserved binding site for accessory proteins on mTOR and explaining the structural basis for the rapamycin insensitivity of the complex. Structural (cryo-EM) mTORC2 core Cryo-EM structure Architecture of the human mTORC2 core complex, revealing a conserved accessory-protein binding site" }, { "sid": "PIC2014", "entities": [ "everolimus", "breast-cancer" ], "authors": [ "gabriel-n-hortobagyi", "martine-j-piccart", "jose-baselga", "howard-a-burris", "mario-campone", "ines-deleu", "michael-gnant", "yoshinori-ito", "fabienne-lebrun", "shinzaburo-noguchi", "alejandra-perez", "kathleen-pritchard", "hope-rugo" ], "author_names": [ "Gabriel N. Hortobagyi", "Martine J. Piccart", "José Baselga", "Howard A Burris", "Mario Campone", "Ines Deleu", "Michael Gnant", "Yoshinori Ito", "Fabienne Lebrun", "Shinzaburo Noguchi", "Alejandra Perez", "Kathleen Pritchard", "Hope Rugo" ], "text": "The BOLERO-2 study previously demonstrated that adding everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) by more than twofold in patients with hormone-receptor-positive (HR(+)), HER2-negative advanced breast cancer that recurred or progressed during/after treatment with nonsteroidal aromatase inhibitors (NSAIs). The overall survival (OS) analysis is presented here. Everolimus 10 mg/day + exemestane 25 mg/day vs placebo + exemestane mTORC1 (via FKBP12) Human PFS improved (7.8 vs 3.2 mo); overall survival not significantly improved (HR 0.89, P = 0.14)" }, { "sid": "KUS2026", "entities": [ "immune-function", "castor1", "mtorc1" ], "authors": [ "keishi-fujio", "takeshi-kusuda" ], "author_names": [ "Keishi Fujio", "Takeshi Kusuda" ], "text": "CASTOR1 senses arginine and regulates mammalian target of rapamycin complex 1 (mTORC1), a central metabolic signaling molecule. This study aimed to elucidate the roles of CASTOR1 in humoral immune responses. We analyzed human B cell transcriptomes from healthy controls and patients with systemic lupus erythematosus (SLE) via correlation analysis and gene set variation analysis using our database, Immune Cell Gene Expression Atlas from the University of Tokyo (ImmuNexUT). Whole-body and B cell-specific Castor1 knockout; human B cell transcriptomics CASTOR1-mTORC1 in B cells Mouse; human (SLE patient transcriptomes) Castor1 loss expanded plasma cells and caused lupus-like autoimmunity in mice; lower CASTOR1 in plasmablasts correlated with higher SLE activity." }, { "sid": "LEL2016", "entities": [ "rapamycin", "mtor", "autophagy" ], "authors": [ "adam-b-salmon", "matthew-lelegren", "corinna-ross", "suzette-tardif" ], "author_names": [ "Adam B. Salmon", "Matthew Lelegren", "Corinna Ross", "Suzette Tardif" ], "text": "Inhibition of mechanistic target of rapamycin (mTOR) has emerged as a viable means to lengthen lifespan and healthspan in mice, although it is still unclear whether these benefits will extend to other mammalian species. We previously reported results from a pilot experiment wherein common marmosets (Callithrix jacchus) were treated orally with rapamycin to reduce mTOR signaling in vivo in line with previous reports in mice and humans. Further, long-term treatment did not significantly alter body weight, daily activity, blood lipid concentrations, or glucose metabolism in this cohort. Oral rapamycin (pilot cohort) Proteostasis network: proteasome (PSMB5), mitochondrial chaperones, autophagy Common marmoset (Callithrix jacchus) Tissue-specific: higher PSMB5 and mitochondrial chaperones in muscle, higher autophagy in muscle and adipose, no change in proteasome activity or in liver autophagy" }, { "sid": "MA2005", "entities": [ "tsc1-tsc2", "mtorc1", "tuberous-sclerosis-complex", "erk-rsk-mapk" ], "authors": [ "hediye-erdjument-bromage", "paul-tempst", "pier-paolo-pandolfi" ], "author_names": [ "Hediye Erdjument-Bromage", "Paul Tempst", "Pier Paolo Pandolfi" ], "text": "Tuberous sclerosis (TSC) is a tumor syndrome caused by mutation in TSC1 or TSC2 genes. TSC tumorigenesis is not always accompanied by loss of heterozygosity (LOH). Recently, extracellular signal-regulated kinase (Erk) has been found activated in TSC lesions lacking TSC1 or TSC2 LOH. Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. ERK activation; ERK-nonphosphorylatable TSC2 mutant ERK -> TSC2 -> mTORC1 Mammalian cells; TSC2+/- tumour cells ERK phosphorylates TSC2, splits TSC1-TSC2 and weakens its brake on mTORC1, promoting proliferation and transformation" }, { "sid": "NCT05835999", "entities": [ "longevity", "everolimus", "insulin-resistance" ], "authors": [], "author_names": [], "text": "The objective of this project is to determine if mTORC1 inhibition by 24 weeks of daily (0.5 mg/day) or weekly (5 mg/week) everolimus can safely improve physiological and molecular hallmarks of aging in humans. Participants who are 55-80 years old and insulin resistant or prediabetic will be randomized to treatment and can expect to be on study for up to approximately 38 weeks; participants aged 18-35 will not receive the intervention and can expect to be on study up to approximately 8 weeks. Everolimus – daily 0.5 mg vs weekly 5 mg, 24 weeks mTORC1 Human – RCT (registered, completed, no results posted; age 55–80, insulin-resistant/prediabetic) No results posted yet (registry status COMPLETED; primary completion 2026-06-30) – tests whether dosing improves aging hallmarks without metabolic penalty" }, { "sid": "NOJ2003", "entities": [ "raptor", "mtor", "s6k1", "4e-bp1" ], "authors": [ "joseph-avruch", "kazuyoshi-yonezawa", "kenta-hara", "noriko-oshiro-rapley", "hiroki-nojima", "sujuti-hidayat", "chiharu-tokunaga" ], "author_names": [ "Joseph Avruch", "Kazuyoshi Yonezawa", "Kenta Hara", "Noriko Oshiro-Rapley", "Hiroki Nojima", "Sujuti Hidayat", "Chiharu Tokunaga" ], "text": "The mammalian target of rapamycin (mTOR) controls multiple cellular functions in response to amino acids and growth factors, in part by regulating the phosphorylation of p70 S6 kinase (p70S6k) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Raptor (regulatory associated protein of mTOR) is a recently identified mTOR binding partner that also binds p70S6k and 4E-BP1 and is essential for TOR signaling in vivo. Biochemical (TOS motif) mTOR / raptor / p70 S6K / 4E-BP1 In vitro Raptor binds the mTOR substrates p70 S6K and 4E-BP1 through their TOR-signaling (TOS) motif" }, { "sid": "HAL2026", "entities": [ "ulk1", "rapamycin", "protein-synthesis", "autophagy", "ampk" ], "authors": [ "jessica-l-halle", "james-a-carson" ], "author_names": [ "Jessica L. Halle", "James A. Carson" ], "text": "5-Fluorouracil-based chemotherapies, such as FOLFOX (5-fluorouracil, leucovorin, oxaliplatin), are used to treat colon cancer but also induce skeletal muscle toxicities. While FOLFOX can disrupt muscle autophagy signaling in vivo, the upstream mechanisms underlying this effect, as well as the roles of mTORC1 and AMPK signaling, require further investigation. 5-FU, 5-FU+leucovorin, oxaliplatin, combined FOLFOX regimen; rescue with rapamycin or metformin mTORC1/AMPK/ULK1 signaling and autophagy flux Mouse (C2C12 myotubes, in vitro) FOLFOX/oxaliplatin suppressed autophagy flux, AMPK and ULK1(S555) phosphorylation, and protein synthesis; effect persisted after drug withdrawal; rapamycin (not metformin) restored autophagy flux and AMPK phosphorylation without restoring protein synthesis" }, { "sid": "DEN2026", "entities": [ "foxo", "integrated-stress-response", "mtorc1", "spalt-related-salr" ], "authors": [ "onur-deniz", "ville-hietakangas" ], "author_names": [ "Onur Deniz", "Ville Hietakangas" ], "text": "Anabolic and catabolic processes are coordinated by a conserved regulatory network including mTORC1 and FoxO. Spalt-related (Salr), previously implicated in organogenesis, is identified as a negative regulator of growth and lipid storage in Drosophila. Salr activates catabolic gene expression and restricts mTORC1-mediated cell growth in the fat body. Salr is activated in a slow and sustained manner through the integrated stress response, distinct from transient FoxO activation. Once activated, Salr counters nuclear localization of FoxO. Integrated stress response activation (genetic) mTORC1 / Spalt-related (Salr) / FoxO Drosophila melanogaster Inhibition of mTORC1-mediated cell growth; activation of catabolic gene expression; restriction of lipid storage" }, { "sid": "HE2025", "entities": [ "mtorc1" ], "authors": [ "john-blenis", "long-he" ], "author_names": [ "John Blenis", "Long He" ], "text": "The mechanistic target of rapamycin (mTOR) pathway senses and integrates various environmental and intracellular cues to regulate cell growth and proliferation. As a key conductor of the balance between anabolic and catabolic processes, mTOR complex 1 (mTORC1) orchestrates the symphonic regulation of glycolysis, nucleic acid and lipid metabolism, protein translation and degradation, and gene expression. Dysregulation of the mTOR pathway is linked to numerous human diseases, including cancer, neurodegenerative disorders, obesity, diabetes, and aging. N/A (review) mTORC1 pathway (nutrient/growth factor integration) N/A Comprehensive review of mTORC1 regulation, metabolic control, and clinical outlook" }, { "sid": "FRA2013", "entities": [ "mtor", "everolimus", "mtorc1", "tuberous-sclerosis-complex" ], "authors": [ "michael-d-frost", "david-n-franz", "sergiusz-jozwiak", "david-lebwohl", "tarek-sahmoud", "elena-belousova", "vicky-h-whittemore" ], "author_names": [ "Michael D. Frost", "David N. Franz", "Sergiusz Jóźwiak", "David Lebwohl", "Tarek Sahmoud", "Elena Belousova", "Vicky H Whittemore" ], "text": "Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. Everolimus mTOR Human – phase 3 RCT (EXIST-1, n=117, TSC) Everolimus reduced subependymal giant cell astrocytoma (SEGA) volume vs placebo in tuberous sclerosis" }, { "sid": "GAN2011", "entities": [ "akt-pkb", "pi3k", "mtorc2" ], "authors": [ "bing-su", "dianqing-dan-wu", "xiaoqing-gan" ], "author_names": [ "Bing Su", "Dianqing (Dan) Wu", "Xiaoqing Gan" ], "text": "mTORC2 (mammalian target of rapamycin complex 2) plays important roles in signal transduction by regulating an array of downstream effectors, including protein kinase AKT. However, its regulation by upstream regulators remains poorly characterized. Although phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) is known to regulate the phosphorylation of AKT Ser(473), the hydrophobic motif (HM) site, by mTORC2, it is not clear whether PtdIns(3,4,5)P(3) can directly regulate mTORC2 kinase activity. Biochemical (PtdIns(3,4,5)P3) mTORC2 / PIP3 / Akt Ser473 In vitro; cells PtdIns(3,4,5)P3 (PIP3) directly activates mTORC2 kinase activity toward Akt Ser473" }, { "sid": "GOB2016", "entities": [ "lysosome", "mtorc1" ], "authors": [ "adrian-l-harris", "deborah-c-i-goberdhan" ], "author_names": [ "Adrian L. Harris", "Deborah C. I. Goberdhan" ], "text": "Cell metabolism and growth are matched to nutrient availability via the amino-acid-regulated mechanistic target of rapamycin complex 1 (mTORC1). Transporters have emerged as important amino acid sensors controlling mTOR recruitment and activation at the surface of multiple intracellular compartments. Classically, this has involved late endosomes and lysosomes, but now, in a recent twist, also the Golgi apparatus. Here we propose a model in which specific amino acids in assorted compartments activate different mTORC1 complexes, which may have distinct drug sensitivities and functions. Not applicable (review) mTORC1 / amino-acid transporters Review Reviews how intracellular amino-acid transporters mark the sites (lysosome, Golgi) of mTORC1 activation" }, { "sid": "ABR2026", "entities": [ "p62-sqstm1", "mtorc1", "autophagy" ], "authors": [ "dale-d-o-martin", "fatima-abrar" ], "author_names": [ "Dale D. O. Martin", "Fatima Abrar" ], "text": "SQSTM1/p62 (sequestosome 1) is an important receptor protein involved in many cellular signaling processes, including macroautophagy/autophagy. It is a molecular hub for cellular homeostasis and cellular responses. Within autophagy, SQSTM1 targets ubiquitinated cargo for degradation, maintaining cellular proteostasis. Structurally, SQSTM1 consists of several domains that facilitate its binding to ubiquitinated cargo, the formation of SQSTM1 aggregate inclusions, interactions with MAP1LC3/LC3, and the mediation of clearance via the autophagy pathway. none (review) SQSTM1/p62 / MTORC1 / autophagy Review Summarises how PTMs of SQSTM1 tune its autophagy-receptor function and its regulation of and by MTORC1." }, { "sid": "HAN2012", "entities": [ "lars-leucyl-trna-synthetase", "leucine" ], "authors": [ "jung-min-han", "sunghoon-kim" ], "author_names": [ "Jung Min Han", "Sunghoon Kim" ], "text": "Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase, which regulates protein translation, cell size, and autophagy. However, the amino acid sensor that directly couples intracellular amino acid-mediated signaling to mTORC1 is unknown. Here we show that leucyl-tRNA synthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation by sensing intracellular leucine concentration and initiating molecular events leading to mTORC1 activation. Biochemical/genetic (leucyl-tRNA synthetase) Leucyl-tRNA synthetase (LRS) / RagD / mTORC1 Mammalian cells Leucyl-tRNA synthetase acts as an intracellular leucine sensor for the mTORC1 pathway" }, { "sid": "LU2026", "entities": [ "integrated-stress-response", "mtorc1" ], "authors": [ "lingjun-lu", "ioannis-p-androulakis" ], "author_names": [ "Lingjun Lu", "Ioannis P. Androulakis" ], "text": "Independent of the suprachiasmatic nucleus, peripheral clocks can be strongly entrained by dietary signals. Although feeding time has been widely studied, the effects of food quality-particularly nutrient availability and stress-on peripheral circadian entrainment and metabolic regulation remain less understood. We developed a semi-mechanistic mathematical model of peripheral clock synchronization and clock-controlled ribosome biogenesis (RiBi) in response to feeding/fasting cycles and rhythms in dietary essential amino acid (EAA) availability. In silico feeding/fasting schedules and dietary essential amino acid rhythms; simulated GCN2-ISR modulation mTORC1 and GCN2-ISR; clock-controlled ribosome biogenesis Computational model (mammalian liver) Timing and quality of amino acid intake, not average level, set circadian entrainment and ribosome biogenesis dynamics" }, { "sid": "LAR2012", "entities": [ "pp242", "rapamycin", "metformin", "mtorc1", "4e-bp1" ], "authors": [ "nahum-sonenberg", "ola-larsson" ], "author_names": [ "Nahum Sonenberg", "Ola Larsson" ], "text": "Metformin has been reported to lower cancer incidence among type II diabetics. Metformin exhibits antiproliferative and antineoplastic effects associated with inhibition of mammalian target of rapamycin complex 1 (mTORC1), but the mechanisms are poorly understood. We provide a unique genome-wide analysis of translational targets of canonical mTOR inhibitors (rapamycin and PP242) compared with metformin, revealing that metformin controls gene expression at the level of mRNA translation to an extent comparable to that of canonical mTOR inhibitors. Metformin; rapamycin; PP242 Genome-wide mRNA translation (translatome); cell-cycle regulator mRNAs; proliferation Human cancer cells Metformin selectively suppresses translation of cell-cycle regulator mRNAs via mTORC1/4E-BP, reducing proliferation" }, { "sid": "CHE2009", "entities": [ "tsc1-tsc2", "longevity", "rapamycin", "immune-function", "cellular-senescence" ], "authors": [ "chong-chen", "pan-zheng" ], "author_names": [ "Chong Chen", "Pan Zheng" ], "text": "Age-related declines in hematopoietic stem cell (HSC) function may contribute to anemia, poor response to vaccination, and tumorigenesis. Here, we show that mammalian target of rapamycin (mTOR) activity is increased in HSCs from old mice compared to those from young mice. mTOR activation through conditional deletion of Tsc1 in the HSCs of young mice mimicked the phenotype of HSCs from aged mice in various ways. Genetic (Tsc1 deletion) + rapamycin mTOR / TSC1 Mouse (hematopoietic stem cells) mTOR is elevated in aged HSCs; rapamycin rejuvenates HSC function and immune response 4 mg/kg rapamycin by i.p. injection every other day for 6 weeks 9/12 vehicle-treated old mice succumbed to infection Pretreatment with rapamycin increased antigen-specific IgG by approximately 10 times; all rapamycin-treated mice were protected from lethal influenza infection, compared to 75% mortality in vehicle-treated old mice. not stated" }, { "sid": "PET2009", "entities": [ "akt-pkb", "mtorc1", "deptor", "mtorc2" ], "authors": [ "david-m-sabatini", "yasemin-sancak", "carson-c-thoreen", "nathanael-s-gray", "seong-a-kang", "timothy-r-peterson", "mathieu-laplante", "w-michael-kuehl" ], "author_names": [ "David M. Sabatini", "Yasemin Sancak", "Carson C. Thoreen", "Nathanael S. Gray", "Seong A. Kang", "Timothy R. Peterson", "Mathieu Laplante", "W. Michael Kuehl" ], "text": "The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Genetic/biochemical (DEPTOR) DEPTOR / mTORC1 & mTORC2 Human cancer cell lines DEPTOR is an mTOR inhibitor overexpressed in multiple myeloma and required for myeloma-cell survival" } ] }