{ "meta": { "api_version": "1.0.0", "dataset_version": "2.0.0", "corpus_snapshot": "2026-10-01T14:49:35+0200", "source_commit": "03bba2194c4832a1bcdfb704d54dd458ab0df021", "license": "CC-BY-4.0", "cite": "Barton O. Oliver's mTOR Atlas. doi:10.5281/zenodo.22059963", "docs": "https://mtor-atlas.org/api/" }, "data": { "id": "mtorc1", "name": "mTORC1", "type": "Pathway/Complex", "synonyms": [ "TORC1", "mTOR complex 1", "mTOR complex-1" ], "description": "mTOR Complex 1; regulates protein synthesis, autophagy, and growth in response to nutrients and growth factors.", "study_count": 92, "relation_count": 38, "url": "https://mtor-atlas.org/complex/mtorc1/", "api_url": "https://mtor-atlas.org/api/v1/entities/mtorc1.json", "description_beginner": "The first of the two mTOR complexes, and the one most people mean when they just say 'mTOR.' It controls protein-building, cellular cleanup, and growth in response to nutrients and growth-factor signals.", "studies": [ { "sid": "SAX2017", "title": "mTOR Signaling in Growth, Metabolism, and Disease", "authors": "Saxton RA; Sabatini DM", "year": 2017, "journal": "Cell", "doi": "10.1016/j.cell.2017.02.004", "pmid": "28283069", "pmcid": "PMC5394987", "evidence": { "code": "R", "label": "Review — secondary literature, not a new result", "note": "this describes the kind of study, not its quality" }, "category": "Review", "model_system": "Review article", "peer_reviewed": true, "finding": "Comprehensive synthesis of mTORC1/mTORC2 signaling, growth regulation, metabolism, and disease relevance.", "url": "https://mtor-atlas.org/study/SAX2017/", "api_url": "https://mtor-atlas.org/api/v1/studies/SAX2017.json" }, { "sid": "HAR2009", "title": "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice", "authors": "Harrison DE et al.", "year": 2009, "journal": "Nature", "doi": "10.1038/nature08221", "pmid": "19587680", "pmcid": "PMC2786175", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Mouse (genetically heterogeneous, 3 sites)", "peer_reviewed": true, "finding": "Rapamycin fed from 600 days of age extended median and maximal lifespan in both sexes; age at 90% mortality rose 14% in females and 9% in males.", "url": "https://mtor-atlas.org/study/HAR2009/", "api_url": "https://mtor-atlas.org/api/v1/studies/HAR2009.json" }, { "sid": "SOL2014", "title": "The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice", "authors": "Solon-Biet SM et al.", "year": 2014, "journal": "Cell Metabolism", "doi": "10.1016/j.cmet.2014.02.009", "pmid": "24606899", "pmcid": "PMC5087279", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Mouse, 25 ad libitum diets", "peer_reviewed": true, "finding": "Lifespan and cardiometabolic health were determined not by caloric intake but by the protein:carbohydrate ratio; a low protein ratio was associated with lower hepatic mTOR activation.", "url": "https://mtor-atlas.org/study/SOL2014/", "api_url": "https://mtor-atlas.org/api/v1/studies/SOL2014.json" }, { "sid": "INO2002", "title": "TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling", "authors": "Inoki K; Guan KL et al.", "year": 2002, "journal": "Nature Cell Biology", "doi": "10.1038/ncb839", "pmid": "12172553", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cell lines", "peer_reviewed": true, "finding": "Akt directly phosphorylates and inactivates TSC2, disrupting the TSC1-TSC2 complex and releasing its inhibition of mTOR - the link between growth-factor/insulin signaling and mTORC1 activation.", "url": "https://mtor-atlas.org/study/INO2002/", "api_url": "https://mtor-atlas.org/api/v1/studies/INO2002.json" }, { "sid": "TEE2003", "title": "Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb", "authors": "Tee AR; Cantley LC et al.", "year": 2003, "journal": "Current Biology", "doi": "10.1016/s0960-9822(03)00506-2", "pmid": "12906785", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cell lines", "peer_reviewed": true, "finding": "TSC1-TSC2 acts as a GTPase-activating protein (GAP) for Rheb; when TSC is inactive, Rheb accumulates in its active GTP-bound form and activates mTOR signalling.", "url": "https://mtor-atlas.org/study/TEE2003/", "api_url": "https://mtor-atlas.org/api/v1/studies/TEE2003.json" }, { "sid": "SAN2008", "title": "The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1", "authors": "Sancak Y; Sabatini DM et al.", "year": 2008, "journal": "Science", "doi": "10.1126/science.1157535", "pmid": "18497260", "pmcid": "PMC2475333", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cell lines", "peer_reviewed": true, "finding": "Identifies the Rag GTPase family as the missing link that lets mTORC1 sense amino acids by controlling whether mTOR is positioned near its activator Rheb.", "url": "https://mtor-atlas.org/study/SAN2008/", "api_url": "https://mtor-atlas.org/api/v1/studies/SAN2008.json" }, { "sid": "SAX2015", "title": "Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway", "authors": "Saxton RA; Wolfson RL; Sabatini DM et al.", "year": 2015, "journal": "Science", "doi": "10.1126/science.aad2087", "pmid": "26586190", "pmcid": "PMC4698039", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cell lines (crystal structure)", "peer_reviewed": true, "finding": "Solves the crystal structure of Sestrin2 bound to leucine, revealing the molecular pocket that lets it act as mTORC1's dedicated leucine sensor.", "url": "https://mtor-atlas.org/study/SAX2015/", "api_url": "https://mtor-atlas.org/api/v1/studies/SAX2015.json" }, { "sid": "SEL2009", "title": "Ribosomal protein S6 kinase 1 signaling regulates mammalian life span", "authors": "Selman C; Withers DJ et al.", "year": 2009, "journal": "Science", "doi": "10.1126/science.1177221", "pmid": "19797661", "pmcid": "PMC4954603", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Mouse (S6K1 knockout)", "peer_reviewed": true, "finding": "Deleting S6K1 (a direct mTORC1 effector) extended lifespan in FEMALE mice (+19% median); the effect was not significant in males. It also protected against age-related bone, immune and motor decline. One of the clearest cases of the sex dimorphism catalogued in gap H6 - and a reminder that a single downstream branch, not mTORC1 as a whole, can carry much of the ageing signal.", "url": "https://mtor-atlas.org/study/SEL2009/", "api_url": "https://mtor-atlas.org/api/v1/studies/SEL2009.json" }, { "sid": "ROM2001", "title": "Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways", "authors": "Rommel C; Bodine SC et al.", "year": 2001, "journal": "Nature Cell Biology", "doi": "10.1038/ncb1101-1009", "pmid": "11715022", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Cultured muscle cells (mouse)", "peer_reviewed": true, "finding": "Shows IGF-1 drives muscle fiber hypertrophy through Akt, via both the mTOR and GSK3 branches, in cultured myotubes, establishing mTOR as a central node for muscle growth signaling.", "url": "https://mtor-atlas.org/study/ROM2001/", "api_url": "https://mtor-atlas.org/api/v1/studies/ROM2001.json" }, { "sid": "KAP2004", "title": "Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway", "authors": "Kapahi P et al.", "year": 2004, "journal": "Current Biology", "doi": "10.1016/j.cub.2004.03.059", "pmid": "15186745", "pmcid": "PMC2754830", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Drosophila melanogaster", "peer_reviewed": true, "finding": "Genetically reducing TOR pathway activity extends fruit fly lifespan, overlapping with dietary restriction effects.", "url": "https://mtor-atlas.org/study/KAP2004/", "api_url": "https://mtor-atlas.org/api/v1/studies/KAP2004.json" }, { "sid": "BJE2010", "title": "Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster", "authors": "Bjedov I; Partridge L et al.", "year": 2010, "journal": "Cell Metabolism", "doi": "10.1016/j.cmet.2009.11.010", "pmid": "20074526", "pmcid": "PMC2824086", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Drosophila melanogaster", "peer_reviewed": true, "finding": "Feeding rapamycin extended fly lifespan through autophagy and reduced translation, and worked even in flies already on a lifespan-maximizing diet.", "url": "https://mtor-atlas.org/study/BJE2010/", "api_url": "https://mtor-atlas.org/api/v1/studies/BJE2010.json" }, { "sid": "GUE2007", "title": "Defining the role of mTOR in cancer", "authors": "Guertin DA; Sabatini DM", "year": 2007, "journal": "Cancer Cell", "doi": "10.1016/j.ccr.2007.05.008", "pmid": "17613433", "pmcid": null, "evidence": { "code": "R", "label": "Review — secondary literature, not a new result", "note": "this describes the kind of study, not its quality" }, "category": "Review", "model_system": "Review article", "peer_reviewed": true, "finding": "Comprehensive review arguing mTOR signaling is commonly deregulated in human cancers, laying out the rationale for rapalog trials in oncology.", "url": "https://mtor-atlas.org/study/GUE2007/", "api_url": "https://mtor-atlas.org/api/v1/studies/GUE2007.json" }, { "sid": "BLA2006", "title": "Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition", "authors": "Blagosklonny MV", "year": 2006, "journal": "Cell Cycle", "doi": "10.4161/cc.5.18.3288", "pmid": "17012837", "pmcid": null, "evidence": { "code": "R", "label": "Review — secondary literature, not a new result", "note": "this describes the kind of study, not its quality" }, "category": "Review", "model_system": "Theoretical / review article", "peer_reviewed": true, "finding": "Proposes the 'hyperfunction theory' of aging: TOR signaling, useful in youth, stays switched on into old age and becomes actively damaging.", "url": "https://mtor-atlas.org/study/BLA2006/", "api_url": "https://mtor-atlas.org/api/v1/studies/BLA2006.json" }, { "sid": "DRU2009", "title": "Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis", "authors": "Drummond MJ; Rasmussen BB et al.", "year": 2009, "journal": "Journal of Physiology", "doi": "10.1113/jphysiol.2008.163816", "pmid": "19188252", "pmcid": "PMC2678224", "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Human", "model_system": "Humans, controlled trial", "peer_reviewed": true, "finding": "Rapamycin given before resistance exercise completely blocked the normal post-exercise increase in human muscle protein synthesis.", "url": "https://mtor-atlas.org/study/DRU2009/", "api_url": "https://mtor-atlas.org/api/v1/studies/DRU2009.json" }, { "sid": "DEL2009", "title": "The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment", "authors": "Delgoffe GM; Powell JD et al.", "year": 2009, "journal": "Immunity", "doi": "10.1016/j.immuni.2009.04.014", "pmid": "19538929", "pmcid": "PMC2768135", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Mouse (T cells)", "peer_reviewed": true, "finding": "T cells lacking mTOR fail to become normal effector cells and default toward regulatory T cells, showing mTOR is a master switch for immune cell fate.", "url": "https://mtor-atlas.org/study/DEL2009/", "api_url": "https://mtor-atlas.org/api/v1/studies/DEL2009.json" }, { "sid": "RAV2004", "title": "Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease", "authors": "Ravikumar B; Rubinsztein DC et al.", "year": 2004, "journal": "Nature Genetics", "doi": "10.1038/ng1362", "pmid": "15146184", "pmcid": null, "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Drosophila and mouse models of Huntington's disease", "peer_reviewed": true, "finding": "Induced autophagy cleared toxic clumped proteins and improved symptoms in fly (rapamycin) and mouse (the rapalog CCI-779) models of Huntington's disease.", "url": "https://mtor-atlas.org/study/RAV2004/", "api_url": "https://mtor-atlas.org/api/v1/studies/RAV2004.json" }, { "sid": "TAN2024", "title": "Targeting mTOR restores tau-induced metabolic, mitochondrial, and cognitive deficits in a tauopathy mouse model", "authors": "Tang Z; Guo M; Ding Y; Wen Y; Li B; Xiao Y; Ni R; Guan Z; Qi XL", "year": 2024, "journal": "bioRxiv (preprint)", "doi": "10.1101/2024.11.24.625068", "pmid": null, "pmcid": null, "evidence": { "code": "PP", "label": "Preprint, not peer-reviewed", "note": "this describes the kind of study, not its quality" }, "category": "Preprint", "model_system": "Mouse (Tau3E-overexpressing, hippocampal CA3)", "peer_reviewed": false, "finding": "In mice engineered to overexpress a phosphomimetic tau variant, one week of rapamycin partially mitigated tau-driven mitochondrial dysfunction and cognitive impairment in the Morris water maze - extends the mTOR-autophagy-neurodegeneration link (already seen with Huntington's) to a direct tau-phosphorylation mechanism relevant to Alzheimer's.", "url": "https://mtor-atlas.org/study/TAN2024/", "api_url": "https://mtor-atlas.org/api/v1/studies/TAN2024.json" }, { "sid": "MUT2026", "title": "ER-Lysosome Cholesterol Exchange Regulates Lysosomal Motility Through mTOR-Dependent LAMTOR1 Phosphorylation", "authors": "Muthukottiappan P; Winter D et al.", "year": 2026, "journal": "bioRxiv (preprint)", "doi": "10.64898/2026.03.31.715514", "pmid": null, "pmcid": null, "evidence": { "code": "PP", "label": "Preprint, not peer-reviewed", "note": "this describes the kind of study, not its quality" }, "category": "Preprint", "model_system": "Human cell lines", "peer_reviewed": false, "finding": "Identifies a new layer of control over mTORC1's lysosomal machinery: cholesterol exchange between the ER and lysosome regulates lysosome movement via mTOR-dependent phosphorylation of LAMTOR1, a core component of the Ragulator complex that anchors the Rag GTPases already in this Atlas.", "url": "https://mtor-atlas.org/study/MUT2026/", "api_url": "https://mtor-atlas.org/api/v1/studies/MUT2026.json" }, { "sid": "KIM2002", "title": "mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery", "authors": "Kim DH; Sarbassov DD; Ali SM; King JE; Latek RR; Erdjument-Bromage H; Tempst P; Sabatini DM", "year": 2002, "journal": "Cell", "doi": "10.1016/s0092-8674(02)00808-5", "pmid": "12150925", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human/rodent cell lines (biochemistry)", "peer_reviewed": true, "finding": "Discovery of Raptor as the defining partner of mTOR in mTORC1. This is the paper that gives mTORC1 its identity: Raptor is the scaffold that lets mTOR find and phosphorylate its targets (S6K1), and the complex is stabilized under starvation. Companion paper to Hara 2002.", "url": "https://mtor-atlas.org/study/KIM2002/", "api_url": "https://mtor-atlas.org/api/v1/studies/KIM2002.json" }, { "sid": "HARA2002", "title": "Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action", "authors": "Hara K; Maruki Y; Long X; Yoshino K; Oshiro N; Hidayat S; Tokunaga C; Avruch J; Yonezawa K", "year": 2002, "journal": "Cell", "doi": "10.1016/s0092-8674(02)00833-4", "pmid": "12150926", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cells + C. elegans RNAi", "peer_reviewed": true, "finding": "Independent co-discovery of Raptor (same issue of Cell as Kim 2002). Showed Raptor is essential for mTOR to phosphorylate 4E-BP1 and S6K1, and that knocking it down in worms mimics loss of TOR - confirming Raptor as a core, conserved mediator of TOR action.", "url": "https://mtor-atlas.org/study/HARA2002/", "api_url": "https://mtor-atlas.org/api/v1/studies/HARA2002.json" }, { "sid": "SAN2010", "title": "Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids", "authors": "Sancak Y; Bar-Peled L; Zoncu R; Markhard AL; Nada S; Sabatini DM", "year": 2010, "journal": "Cell", "doi": "10.1016/j.cell.2010.02.024", "pmid": "20381137", "pmcid": "PMC3024592", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cells + Drosophila", "peer_reviewed": true, "finding": "Established WHERE mTORC1 gets switched on: the lysosome surface. Identified Ragulator as the lysosomal dock that recruits the Rag GTPases and drags mTORC1 to the membrane where its activator Rheb lives. Amino acids work by controlling this translocation.", "url": "https://mtor-atlas.org/study/SAN2010/", "api_url": "https://mtor-atlas.org/api/v1/studies/SAN2010.json" }, { "sid": "PET2009", "title": "DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival", "authors": "Peterson TR; Laplante M; Thoreen CC; Sancak Y; Kang SA; Kuehl WM; Gray NS; Sabatini DM", "year": 2009, "journal": "Cell", "doi": "10.1016/j.cell.2009.03.046", "pmid": "19446321", "pmcid": "PMC2758791", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cancer cell lines", "peer_reviewed": true, "finding": "Identified DEPTOR as a built-in brake on BOTH mTOR complexes. The twist: in some multiple myelomas DEPTOR is overexpressed, which by relieving a feedback loop actually keeps pro-survival Akt signaling ON - a neat example of how an 'inhibitor' can be co-opted by cancer.", "url": "https://mtor-atlas.org/study/PET2009/", "api_url": "https://mtor-atlas.org/api/v1/studies/PET2009.json" }, { "sid": "ZON2011", "title": "mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase", "authors": "Zoncu R; Bar-Peled L; Efeyan A; Wang S; Sancak Y; Sabatini DM", "year": 2011, "journal": "Science", "doi": "10.1126/science.1207056", "pmid": "22053050", "pmcid": "PMC3211112", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cells + cell-free reconstitution", "peer_reviewed": true, "finding": "Showed amino acid sensing starts INSIDE the lysosome: amino acids accumulate in the lumen and the v-ATPase relays that signal outward ('inside-out') to Ragulator-Rag. A surprising twist on where the cell measures its nutrient status.", "url": "https://mtor-atlas.org/study/ZON2011/", "api_url": "https://mtor-atlas.org/api/v1/studies/ZON2011.json" }, { "sid": "BAR2013", "title": "A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1", "authors": "Bar-Peled L; Chantranupong L; Cherniack AD; Chen WW; Ottina KA; Grabiner BC; Spear ED; Carter SL; Meyerson M; Sabatini DM", "year": 2013, "journal": "Science", "doi": "10.1126/science.1232044", "pmid": "23723238", "pmcid": "PMC3728654", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cells + cancer genomics", "peer_reviewed": true, "finding": "Found the OFF switch for amino acid signaling: the GATOR1 complex is a GAP that shuts the Rag GTPases (and thus mTORC1) down when amino acids run low, while GATOR2 opposes it. GATOR1 genes are mutated in cancers, making those tumors 'blind' to starvation and hypersensitive to rapamycin.", "url": "https://mtor-atlas.org/study/BAR2013/", "api_url": "https://mtor-atlas.org/api/v1/studies/BAR2013.json" }, { "sid": "CHA2016", "title": "The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway", "authors": "Chantranupong L; Scaria SM; Saxton RA; Gygi MP; Shen K; Wyant GA; Wang T; Harper JW; Gygi SP; Sabatini DM", "year": 2016, "journal": "Cell", "doi": "10.1016/j.cell.2016.02.035", "pmid": "26972053", "pmcid": "PMC4808398", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cells (biochemistry)", "peer_reviewed": true, "finding": "Identified CASTOR1 as the direct arginine sensor: when arginine binds CASTOR1, it lets go of GATOR2, switching mTORC1 on. Together with Sestrin2 (leucine) this built the picture of mTORC1 as a cell that literally tastes individual amino acids.", "url": "https://mtor-atlas.org/study/CHA2016/", "api_url": "https://mtor-atlas.org/api/v1/studies/CHA2016.json" }, { "sid": "GU2017", "title": "SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway", "authors": "Gu X; Orozco JM; Saxton RA; Condon KJ; Liu GY; Krawczyk PA; Scaria SM; Harper JW; Gygi SP; Sabatini DM", "year": 2017, "journal": "Science", "doi": "10.1126/science.aao3265", "pmid": "29123071", "pmcid": "PMC5747364", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cells (biochemistry)", "peer_reviewed": true, "finding": "Extended nutrient sensing beyond amino acids to METABOLITES: SAMTOR reads S-adenosylmethionine (SAM), the cell's methyl-donor currency, linking methionine and one-carbon metabolism to mTORC1. Relevant to why methionine restriction affects aging.", "url": "https://mtor-atlas.org/study/GU2017/", "api_url": "https://mtor-atlas.org/api/v1/studies/GU2017.json" }, { "sid": "THO2012", "title": "A unifying model for mTORC1-mediated regulation of mRNA translation", "authors": "Thoreen CC; Chantranupong L; Keys HR; Wang T; Gray NS; Sabatini DM", "year": 2012, "journal": "Nature", "doi": "10.1038/nature11083", "pmid": "22552098", "pmcid": "PMC3347774", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Mouse cells (ribosome profiling)", "peer_reviewed": true, "finding": "Used ribosome profiling with the complete inhibitor Torin1 to address a long-standing debate: in these cells, mTORC1's translational control runs largely through the 4E-BP family acting on a specific class of mRNAs (TOP motifs). Losing just the 4E-BPs makes translation of TOP mRNAs resistant to mTOR inhibition - naming them the master effectors.", "url": "https://mtor-atlas.org/study/THO2012/", "api_url": "https://mtor-atlas.org/api/v1/studies/THO2012.json" }, { "sid": "HSI2012", "title": "The translational landscape of mTOR signalling steers cancer initiation and metastasis", "authors": "Hsieh AC; Liu Yi; Edlind MP; Ingolia NT; Janes MR; Sher A; et al.; Ruggero D", "year": 2012, "journal": "Nature", "doi": "10.1038/nature10912", "pmid": "22367541", "pmcid": "PMC3663483", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Mouse models + human prostate cancer", "peer_reviewed": true, "finding": "Showed WHY mTOR-driven translation matters for cancer: in prostate cancer, oncogenic mTOR selectively translates a specific set of pro-invasion mRNAs that drive metastasis. An ATP-competitive mTOR inhibitor (INK128) reversed that signature - an early preclinical rationale from mouse models and cell lines, not a clinical result.", "url": "https://mtor-atlas.org/study/HSI2012/", "api_url": "https://mtor-atlas.org/api/v1/studies/HSI2012.json" }, { "sid": "SET2011", "title": "TFEB links autophagy to lysosomal biogenesis", "authors": "Settembre C; Di Malta C; Polito VA; Garcia Arencibia M; Vetrini F; Erdin S; et al.; Ballabio A", "year": 2011, "journal": "Science", "doi": "10.1126/science.1204592", "pmid": "21617040", "pmcid": "PMC3638014", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human/mouse cells", "peer_reviewed": true, "finding": "Showed that TFEB drives a coordinated autophagy and lysosomal gene programme during starvation. In this paper TFEB was regulated by ERK2 phosphorylation; its control by mTORC1 at the lysosome was established in later work (SET2012).", "url": "https://mtor-atlas.org/study/SET2011/", "api_url": "https://mtor-atlas.org/api/v1/studies/SET2011.json" }, { "sid": "MAR2012", "title": "MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB", "authors": "Martina JA; Chen Yong; Gucek M; Puertollano R", "year": 2012, "journal": "Autophagy", "doi": "10.4161/auto.19653", "pmid": "22576015", "pmcid": "PMC3427256", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cells", "peer_reviewed": true, "finding": "Showed mTORC1-dependent TFEB Ser211 phosphorylation: mTORC1 (docked at the lysosome via Ragulator) phosphorylates TFEB on Ser211, which traps it in the cytosol via 14-3-3 proteins. Inhibit mTORC1 and TFEB rushes to the nucleus to switch on autophagy - explaining how mTORC1 controls recycling at the level of gene transcription.", "url": "https://mtor-atlas.org/study/MAR2012/", "api_url": "https://mtor-atlas.org/api/v1/studies/MAR2012.json" }, { "sid": "HOS2009", "title": "Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy", "authors": "Hosokawa N; Hara T; Kaizuka T; Kishi C; Takamura A; Miura Y; et al.; Mizushima N", "year": 2009, "journal": "Molecular Biology of the Cell", "doi": "10.1091/mbc.e08-12-1248", "pmid": "19211835", "pmcid": "PMC2663915", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Mammalian cells", "peer_reviewed": true, "finding": "Showed the DIRECT brake mTORC1 uses on autophagy: when nutrients are plentiful, mTORC1 physically joins the ULK1-Atg13-FIP200 complex (the autophagy-starter kinase) and phosphorylates ULK1 to keep it off. Starvation or rapamycin releases this brake and autophagy begins.", "url": "https://mtor-atlas.org/study/HOS2009/", "api_url": "https://mtor-atlas.org/api/v1/studies/HOS2009.json" }, { "sid": "KIM2011", "title": "AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1", "authors": "Kim J; Kundu M; Viollet B; Guan KL", "year": 2011, "journal": "Nature Cell Biology", "doi": "10.1038/ncb2152", "pmid": "21258367", "pmcid": "PMC3987946", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human/mouse cells", "peer_reviewed": true, "finding": "Revealed the tug-of-war over ULK1: the energy sensor AMPK phosphorylates ULK1 at activating sites to turn autophagy ON when energy is low, while mTORC1 phosphorylates a different site (Ser757) to keep it OFF and even blocks AMPK from reaching ULK1. Two opposing kinases wired to the same switch.", "url": "https://mtor-atlas.org/study/KIM2011/", "api_url": "https://mtor-atlas.org/api/v1/studies/KIM2011.json" }, { "sid": "THO2009", "title": "An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1", "authors": "Thoreen CC; Kang SA; Chang JW; Liu Q; Zhang Jianming; Gao Y; Reichling LJ; Sim T; Sabatini DM; Gray NS", "year": 2009, "journal": "Journal of Biological Chemistry", "doi": "10.1074/jbc.M900301200", "pmid": "19150980", "pmcid": "PMC2658096", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Mouse/human cells", "peer_reviewed": true, "finding": "Dropped a bombshell: rapamycin does NOT fully block mTORC1. Using Torin1 (which jams the active site directly), the authors showed rapamycin leaves important mTORC1 jobs running - notably 4E-BP1 phosphorylation and autophagy suppression. This reframed a decade of rapamycin experiments and launched the search for complete inhibitors.", "url": "https://mtor-atlas.org/study/THO2009/", "api_url": "https://mtor-atlas.org/api/v1/studies/THO2009.json" }, { "sid": "FEL2009", "title": "Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2", "authors": "Feldman ME; Apsel B; Uotila A; Loewith R; Knight ZA; Ruggero D; Shokat KM", "year": 2009, "journal": "PLoS Biology", "doi": "10.1371/journal.pbio.1000038", "pmid": "19209957", "pmcid": "PMC2637922", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Mouse fibroblasts + primary cells", "peer_reviewed": true, "finding": "The parallel discovery to Thoreen 2009 (same year), from the Shokat lab. Their TORKinibs (PP242, PP30) block mTOR's active site, hitting both complexes and shutting down cap-dependent translation that rapamycin misses. Together these two papers established a whole new drug class beyond rapamycin.", "url": "https://mtor-atlas.org/study/FEL2009/", "api_url": "https://mtor-atlas.org/api/v1/studies/FEL2009.json" }, { "sid": "DEM2009", "title": "Rapamycin decelerates cellular senescence", "authors": "Demidenko ZN; Zubova SG; Bukreeva EI; Pospelov VA; Pospelova TV; Blagosklonny MV", "year": 2009, "journal": "Cell Cycle", "doi": "10.4161/cc.8.12.8606", "pmid": "19471117", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human + rodent cell lines", "peer_reviewed": true, "finding": "Blagosklonny's key experiment behind his 'hyperfunction' theory of aging. When a cell's division is blocked but mTOR keeps driving growth, the cell tips into permanent senescence. Rapamycin uncouples the two - keeping arrested cells reversible instead of senescent. Direct evidence that mTOR actively drives the senescent state, not just passively accompanies it.", "url": "https://mtor-atlas.org/study/DEM2009/", "api_url": "https://mtor-atlas.org/api/v1/studies/DEM2009.json" }, { "sid": "LAB2015", "title": "mTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation", "authors": "Laberge RM; Sun Y; Orjalo AV; Patil CK; Freund A; et al.; Campisi J", "year": 2015, "journal": "Nature Cell Biology", "doi": "10.1038/ncb3195", "pmid": "26147250", "pmcid": "PMC4691706", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cells + mouse xenografts", "peer_reviewed": true, "finding": "Explained HOW rapamycin calms 'inflammaging'. Senescent cells spew inflammatory signals (the SASP) that damage surrounding tissue and even feed tumors. mTOR powers this by translating IL1A, the cytokine at the top of the cascade. Rapamycin selectively shuts it down - and blocked senescent cells from fueling prostate tumor growth in mice.", "url": "https://mtor-atlas.org/study/LAB2015/", "api_url": "https://mtor-atlas.org/api/v1/studies/LAB2015.json" }, { "sid": "ZID2009", "title": "4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila", "authors": "Zid BM; Rogers AN; Katewa SD; Vargas MA; Kolipinski MC; Lu TA; Benzer S; Kapahi P", "year": 2009, "journal": "Cell", "doi": "10.1016/j.cell.2009.07.034", "pmid": "19804760", "pmcid": "PMC2759400", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Drosophila (fruit fly)", "peer_reviewed": true, "finding": "Connected the dots between diet, mTOR, and lifespan. 4E-BP, an mTOR target, is upregulated on dietary restriction and here was shown to be REQUIRED for the lifespan boost, working by selectively boosting translation of mitochondrial genes. A rare case pinning a specific mTOR effector to the longevity benefit of eating less.", "url": "https://mtor-atlas.org/study/ZID2009/", "api_url": "https://mtor-atlas.org/api/v1/studies/ZID2009.json" }, { "sid": "CHE2008", "title": "TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species", "authors": "Chen C; Liu Yu; Liu R; Ikenoue T; Guan KL; Liu Yang; Zheng P", "year": 2008, "journal": "Journal of Experimental Medicine", "doi": "10.1084/jem.20081297", "pmid": "18809716", "pmcid": "PMC2556783", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Mouse (conditional Tsc1 knockout)", "peer_reviewed": true, "finding": "Showed why blood stem cells must keep mTOR LOW. Deleting TSC1 (which unleashes mTOR) drove resting stem cells into rapid division, flooded them with reactive oxygen species, and burned out their ability to self-renew. An antioxidant rescued them. A key link between mTOR, stem-cell exhaustion, and tissue aging.", "url": "https://mtor-atlas.org/study/CHE2008/", "api_url": "https://mtor-atlas.org/api/v1/studies/CHE2008.json" }, { "sid": "WIL2012", "title": "Rapamycin slows aging in mice", "authors": "Wilkinson JE; Burmeister L; Brooks SV; Chan CC; Friedline S; Harrison DE; Hejtmancik JF; Nadon N; Strong R; Wood LK; Woodward MA; Miller RA", "year": 2012, "journal": "Aging Cell", "doi": "10.1111/j.1474-9726.2012.00832.x", "pmid": "22587563", "pmcid": "PMC3434687", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Genetically heterogeneous mice", "peer_reviewed": true, "finding": "Answered a crucial objection: does rapamycin really slow AGING, or just prevent the cancers that kill mice? By showing slower age-related change across many tissues (heart, liver, tendon, activity), it argued for genuine slowing of aging. Honestly reported harms too - more cataracts and testicular degeneration - making it a balanced landmark, not hype.", "url": "https://mtor-atlas.org/study/WIL2012/", "api_url": "https://mtor-atlas.org/api/v1/studies/WIL2012.json" }, { "sid": "KEN2016", "title": "The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging", "authors": "Kennedy BK; Lamming DW", "year": 2016, "journal": "Cell Metabolism", "doi": "10.1016/j.cmet.2016.05.009", "pmid": "27304501", "pmcid": "PMC4910876", "evidence": { "code": "R", "label": "Review — secondary literature, not a new result", "note": "this describes the kind of study, not its quality" }, "category": "Review", "model_system": "Review (metabolism/aging)", "peer_reviewed": true, "finding": "A Cell Metabolism review framing mTOR as the 'grand conductor' that coordinates whole-body metabolism, tissue by tissue. Especially valuable for its clear-eyed section on WHY rapamycin causes metabolic side effects (the mTORC2 problem) - which is the main barrier to using it against aging. Pairs perfectly with Lamming's own 2012 mechanism paper.", "url": "https://mtor-atlas.org/study/KEN2016/", "api_url": "https://mtor-atlas.org/api/v1/studies/KEN2016.json" }, { "sid": "FON2010", "title": "Extending healthy life span--from yeast to humans", "authors": "Fontana L; Partridge L; Longo VD", "year": 2010, "journal": "Science", "doi": "10.1126/science.1172539", "pmid": "20395504", "pmcid": "PMC3607354", "evidence": { "code": "R", "label": "Review — secondary literature, not a new result", "note": "this describes the kind of study, not its quality" }, "category": "Review", "model_system": "Review (yeast to humans)", "peer_reviewed": true, "finding": "Influential review proposing that dietary restriction and reduced nutrient-sensing signalling (mTOR, GH/IGF-1) may slow ageing through similar, evolutionarily conserved mechanisms. Lifespan extension is shown in yeast, invertebrates, rodents and rhesus monkeys; in humans the evidence is limited to protective biomarker changes and genetic associations.", "url": "https://mtor-atlas.org/study/FON2010/", "api_url": "https://mtor-atlas.org/api/v1/studies/FON2010.json" }, { "sid": "MAN2018", "title": "TORC1 inhibition enhances immune function and reduces infections in the elderly", "authors": "Mannick JB; Morris M; Hockey HP; Roma G; Beibel M; et al.; Klickstein LB", "year": 2018, "journal": "Science Translational Medicine", "doi": "10.1126/scitranslmed.aaq1564", "pmid": "29997249", "pmcid": null, "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Human", "model_system": "Humans, phase 2a RCT (n=264, elderly)", "peer_reviewed": true, "finding": "A phase 2a RCT in 264 older adults: 6 weeks of a low-dose combination of BEZ235 (a catalytic PI3K/mTOR inhibitor) and everolimus (RAD001) was associated with fewer reported infections over the following year, plus higher antiviral gene expression and a better flu-vaccine response. The later phase 3 trial of RTB101 (BEZ235) alone (MAN2021) did not confirm a clinical benefit.", "url": "https://mtor-atlas.org/study/MAN2018/", "api_url": "https://mtor-atlas.org/api/v1/studies/MAN2018.json" }, { "sid": "MAN2021", "title": "Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials", "authors": "Mannick JB; Teo G; Bernardo P; Quinn D; Russell K; Klickstein L; Marshall W; Shergill S", "year": 2021, "journal": "Lancet Healthy Longevity", "doi": "10.1016/S2666-7568(21)00062-3", "pmid": "33977284", "pmcid": "PMC8102040", "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Negative_result", "model_system": "Humans, phase 2b + phase 3 RCT (n=1024 phase 3)", "peer_reviewed": true, "finding": "The crucial reality check. After the promising phase 2a, the large phase 3 trial (n=1024) FAILED its primary endpoint - RTB101 did not reduce clinically symptomatic respiratory illness (26% vs 25%, p=0.65). It still reliably switched on antiviral genes, so the biomarker moved but the clinical outcome did not. A textbook lesson that a promising biomarker is not a proven benefit.", "url": "https://mtor-atlas.org/study/MAN2021/", "api_url": "https://mtor-atlas.org/api/v1/studies/MAN2021.json" }, { "sid": "BAS2012", "title": "Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer (BOLERO-2)", "authors": "Baselga J; Campone M; Piccart M; Burris HA; Rugo HS; et al.; Hortobagyi GN", "year": 2012, "journal": "New England Journal of Medicine", "doi": "10.1056/NEJMoa1109653", "pmid": "22149876", "pmcid": "PMC5705195", "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Human", "model_system": "Humans, phase 3 RCT (n=724)", "peer_reviewed": true, "finding": "A phase 3 RCT (n=724) proving mTOR matters in a common cancer. Resistance to hormone therapy in breast cancer is associated with mTOR activation. Adding everolimus more than doubled progression-free survival (10.6 vs 4.1 months by central review) - leading to FDA approval. Main toxicity was stomatitis.", "url": "https://mtor-atlas.org/study/BAS2012/", "api_url": "https://mtor-atlas.org/api/v1/studies/BAS2012.json" }, { "sid": "YAO2011", "title": "Everolimus for advanced pancreatic neuroendocrine tumors (RADIANT-3)", "authors": "Yao JC; Shah MH; Ito T; Bohas CL; Wolin EM; et al.; Oberg K", "year": 2011, "journal": "New England Journal of Medicine", "doi": "10.1056/NEJMoa1009290", "pmid": "21306238", "pmcid": "PMC4208619", "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Human", "model_system": "Humans, phase 3 RCT (n=410)", "peer_reviewed": true, "finding": "A phase 3 RCT (n=410) that made everolimus a standard treatment for pancreatic neuroendocrine tumors. It more than doubled progression-free survival (11.0 vs 4.6 months, a 65% reduction in risk of progression/death) with mostly mild side effects. Another FDA-approved indication built on blocking mTOR.", "url": "https://mtor-atlas.org/study/YAO2011/", "api_url": "https://mtor-atlas.org/api/v1/studies/YAO2011.json" }, { "sid": "MCC2011", "title": "Efficacy and safety of sirolimus in lymphangioleiomyomatosis (MILES)", "authors": "McCormack FX; Inoue Y; Moss J; Singer LG; Strange C; et al.; Trapnell BC", "year": 2011, "journal": "New England Journal of Medicine", "doi": "10.1056/NEJMoa1100391", "pmid": "21410393", "pmcid": "PMC3118601", "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Human", "model_system": "Humans, RCT (n=89, women with LAM)", "peer_reviewed": true, "finding": "A landmark placebo-controlled RCT (n=89) - the first to show that rapamycin (sirolimus) benefits a human lung disease. In LAM, lung function normally declines relentlessly; sirolimus STOPPED that decline while patients took it (and it resumed after stopping). Randomised human evidence that mTOR inhibition can suspend progression of this disease; the benefit did not persist after withdrawal.", "url": "https://mtor-atlas.org/study/MCC2011/", "api_url": "https://mtor-atlas.org/api/v1/studies/MCC2011.json" }, { "sid": "CHU2019", "title": "Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial", "authors": "Chung CL; Lawrence I; Hoffman M; Elgindi D; Nadhan K; et al.; Sell C", "year": 2019, "journal": "GeroScience", "doi": "10.1007/s11357-019-00113-y", "pmid": "31761958", "pmcid": "PMC6925069", "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Human", "model_system": "Humans, RCT (skin, age >40; n=17 completed)", "peer_reviewed": true, "finding": "A small human trial testing whether rapamycin can slow aging in a tissue you can actually see and biopsy - skin. Topical rapamycin significantly lowered the senescence marker p16 and raised collagen VII, with visible improvement in skin appearance. Early, small-scale evidence (17 of 36 completed) that topical rapamycin can reduce a senescence marker in human skin.", "url": "https://mtor-atlas.org/study/CHU2019/", "api_url": "https://mtor-atlas.org/api/v1/studies/CHU2019.json" }, { "sid": "KRA2018", "title": "A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort", "authors": "Kraig E; Linehan LA; Liang H; Romo TQ; Liu Q; et al.; Kellogg DL", "year": 2018, "journal": "Experimental Gerontology", "doi": "10.1016/j.exger.2017.12.026", "pmid": "29408453", "pmcid": "PMC5869166", "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Human", "model_system": "Humans, pilot RCT (n=25, ages 70-95)", "peer_reviewed": true, "finding": "A safety-first pilot RCT (n=25, ages 70-95) asking the basic question before any longevity trial: is daily rapamycin safe in healthy older people? Over 8+ weeks it was well tolerated with only minor red-blood-cell changes and - importantly - NO rise in blood glucose or insulin resistance in this short window. Groundwork for larger aging trials like PEARL.", "url": "https://mtor-atlas.org/study/KRA2018/", "api_url": "https://mtor-atlas.org/api/v1/studies/KRA2018.json" }, { "sid": "BIS2013", "title": "Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial", "authors": "Bissler JJ; Kingswood JC; Radzikowska E; Zonnenberg BA; Frost M; et al.; Budde K", "year": 2013, "journal": "Lancet", "doi": "10.1016/S0140-6736(12)61767-X", "pmid": "23312829", "pmcid": null, "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Human", "model_system": "Humans, phase 3 RCT (n=118, TSC/LAM)", "peer_reviewed": true, "finding": "The companion phase 3 RCT (n=118) to EXIST-1, targeting kidney tumors (angiomyolipomas) in tuberous sclerosis and LAM. Everolimus shrank them by >=50% in 42% of patients versus 0% on placebo. Together EXIST-1 and -2 sealed everolimus as a disease-modifying therapy across multiple TSC tumor types.", "url": "https://mtor-atlas.org/study/BIS2013/", "api_url": "https://mtor-atlas.org/api/v1/studies/BIS2013.json" }, { "sid": "SPI2010", "title": "Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease", "authors": "Spilman P; Podlutskaya N; Hart MJ; Debnath J; Gorostiza O; Bredesen D; Richardson A; Strong R; Galvan V", "year": 2010, "journal": "PLoS ONE", "doi": "10.1371/journal.pone.0009979", "pmid": "20376313", "pmcid": "PMC2848616", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "PDAPP transgenic mice (Alzheimer's model)", "peer_reviewed": true, "finding": "Connected the longevity drug to a specific age-related disease. Long-term rapamycin prevented memory deficits and lowered toxic amyloid-beta in an Alzheimer's mouse model - and the benefit tracked with INCREASED autophagy in neurons. Suggested that the same autophagy boost that may slow aging could also help clear disease-causing proteins.", "url": "https://mtor-atlas.org/study/SPI2010/", "api_url": "https://mtor-atlas.org/api/v1/studies/SPI2010.json" }, { "sid": "CAC2010", "title": "Molecular interplay between mTOR, amyloid-beta, and Tau: effects on cognitive impairments", "authors": "Caccamo A; Majumder S; Richardson A; Strong R; Oddo S", "year": 2010, "journal": "Journal of Biological Chemistry", "doi": "10.1074/jbc.M110.100420", "pmid": "20178983", "pmcid": "PMC2857107", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "3xTg-AD transgenic mice", "peer_reviewed": true, "finding": "Revealed a vicious cycle: amyloid-beta RAISES mTOR activity, and high mTOR in turn blocks the autophagy needed to clear amyloid and tau - so the disease feeds itself. Rapamycin broke the loop in 3xTg-AD mice, rescuing memory and lowering BOTH amyloid and tau, with autophagy induction shown to be necessary for the reduction in amyloid levels.", "url": "https://mtor-atlas.org/study/CAC2010/", "api_url": "https://mtor-atlas.org/api/v1/studies/CAC2010.json" }, { "sid": "FLY2013", "title": "Late-life rapamycin treatment reverses age-related heart dysfunction", "authors": "Flynn JM; O'Leary MN; Zambataro CA; Academia EC; Presley MP; et al.; Melov S", "year": 2013, "journal": "Aging Cell", "doi": "10.1111/acel.12109", "pmid": "23734717", "pmcid": "PMC4098908", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Aged (24-month) female mice", "peer_reviewed": true, "finding": "Striking evidence that in mice mTOR inhibition doesn't just SLOW aging - it can partly reverse an established age-related phenotype. Giving rapamycin to already-old (24-month) female mice for 3 months improved aged heart function, reversing or attenuating age-related cardiac changes, with RNA-seq changes suggesting anti-hypertrophic and anti-inflammatory effects. Started late, still worked.", "url": "https://mtor-atlas.org/study/FLY2013/", "api_url": "https://mtor-atlas.org/api/v1/studies/FLY2013.json" }, { "sid": "HAL2012", "title": "Chronic inhibition of mTOR by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice", "authors": "Halloran J; Hussong SA; Burbank R; Podlutskaya N; Fischer KE; et al.; Galvan V", "year": 2012, "journal": "Neuroscience", "doi": "10.1016/j.neuroscience.2012.06.054", "pmid": "22750207", "pmcid": "PMC3454865", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "C57BL/6 mice (lifespan behavior study)", "peer_reviewed": true, "finding": "Asked whether the lifespan-extending dose of rapamycin harms or helps the aging BRAIN. Reassuringly, it enhanced learning and memory in young mice, prevented age-related cognitive decline in old ones, and even reduced anxiety and depression-like behavior - linked to boosted brain monoamines. Cognitive benefit, not cost.", "url": "https://mtor-atlas.org/study/HAL2012/", "api_url": "https://mtor-atlas.org/api/v1/studies/HAL2012.json" }, { "sid": "LIU2020", "title": "mTOR at the nexus of nutrition, growth, ageing and disease", "authors": "Liu GY; Sabatini DM", "year": 2020, "journal": "Nature Reviews Molecular Cell Biology", "doi": "10.1038/s41580-019-0199-y", "pmid": "31937935", "pmcid": "PMC7102936", "evidence": { "code": "R", "label": "Review — secondary literature, not a new result", "note": "this describes the kind of study, not its quality" }, "category": "Review", "model_system": "Review (comprehensive)", "peer_reviewed": true, "finding": "The flagship modern review of the whole field, from Sabatini's own lab (Nature Reviews Molecular Cell Biology). Maps 25+ years of mTOR biology - how it senses nutrients, controls growth and autophagy, and goes wrong in cancer, neurodegeneration, metabolic disease and aging. The single best orientation document for the entire Atlas.", "url": "https://mtor-atlas.org/study/LIU2020/", "api_url": "https://mtor-atlas.org/api/v1/studies/LIU2020.json" }, { "sid": "LAP2012", "title": "mTOR signaling in growth control and disease", "authors": "Laplante M; Sabatini DM", "year": 2012, "journal": "Cell", "doi": "10.1016/j.cell.2012.03.017", "pmid": "22500797", "pmcid": "PMC3331679", "evidence": { "code": "R", "label": "Review — secondary literature, not a new result", "note": "this describes the kind of study, not its quality" }, "category": "Review", "model_system": "Review (comprehensive)", "peer_reviewed": true, "finding": "The classic 2012 Cell review that became the standard reference for mTOR signaling. Comprehensive yet readable synthesis of how mTOR integrates environmental cues to control growth, and how its deregulation drives cancer, obesity, diabetes and neurodegeneration. A perfect companion to the newer 2020 review.", "url": "https://mtor-atlas.org/study/LAP2012/", "api_url": "https://mtor-atlas.org/api/v1/studies/LAP2012.json" }, { "sid": "GWI2008", "title": "AMPK phosphorylation of raptor mediates a metabolic checkpoint", "authors": "Gwinn DM; Shackelford DB; Egan DF; Mihaylova MM; Mery A; Vasquez DS; Turk BE; Shaw RJ", "year": 2008, "journal": "Molecular Cell", "doi": "10.1016/j.molcel.2008.03.003", "pmid": "18439900", "pmcid": "PMC2674027", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human/mouse cells (biochemistry)", "peer_reviewed": true, "finding": "Found a SECOND way the energy sensor AMPK shuts mTORC1 down. Besides acting through TSC2, AMPK directly phosphorylates Raptor - the core mTORC1 subunit - to halt growth when energy runs low. This 'metabolic checkpoint' is exactly the switch that drugs like metformin and exercise tap into.", "url": "https://mtor-atlas.org/study/GWI2008/", "api_url": "https://mtor-atlas.org/api/v1/studies/GWI2008.json" }, { "sid": "HOW2017", "title": "Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex", "authors": "Howell JJ; Hellberg K; Turner M; Talbott G; Kolar MJ; Ross DS; Hoxhaj G; Saghatelian A; Shaw RJ; Manning BD", "year": 2017, "journal": "Cell Metabolism", "doi": "10.1016/j.cmet.2016.12.009", "pmid": "28089566", "pmcid": "PMC5299044", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Mouse liver + primary hepatocytes", "peer_reviewed": true, "finding": "Pinned down HOW the diabetes drug metformin - a major longevity candidate - actually reaches mTOR. In the liver, metformin lowers cellular energy, and at low doses this shuts down mTORC1 specifically through AMPK and the TSC complex. Direct mechanistic bridge between a widely-used drug, energy sensing, and the mTOR pathway.", "url": "https://mtor-atlas.org/study/HOW2017/", "api_url": "https://mtor-atlas.org/api/v1/studies/HOW2017.json" }, { "sid": "SAN2007", "title": "PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase", "authors": "Sancak Y; Thoreen CC; Peterson TR; Lindquist RA; Kang SA; Spooner E; Carr SA; Sabatini DM", "year": 2007, "journal": "Molecular Cell", "doi": "10.1016/j.molcel.2007.03.003", "pmid": "17386266", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cells (biochemistry)", "peer_reviewed": true, "finding": "Identified PRAS40 as the missing insulin-controlled brake INSIDE mTORC1. When insulin is absent PRAS40 clamps the complex shut; insulin makes Akt phosphorylate PRAS40, releasing the brake so Rheb can fully switch mTORC1 on. Explained how hormone signals set the exact strength of mTORC1 activity.", "url": "https://mtor-atlas.org/study/SAN2007/", "api_url": "https://mtor-atlas.org/api/v1/studies/SAN2007.json" }, { "sid": "KIM2003", "title": "GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR", "authors": "Kim DH; Sarbassov DD; Ali SM; Latek RR; Guntur KVP; Erdjument-Bromage H; Tempst P; Sabatini DM", "year": 2003, "journal": "Molecular Cell", "doi": "10.1016/s1097-2765(03)00114-x", "pmid": "12718876", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cells (biochemistry)", "peer_reviewed": true, "finding": "Discovered mLST8 (GbetaL), the third core subunit that clamps onto mTOR's kinase domain and stabilizes the complex. It fine-tunes how tightly Raptor holds mTOR in response to nutrients - a small but essential cog that later turned out to be especially critical for the mTORC2 complex.", "url": "https://mtor-atlas.org/study/KIM2003/", "api_url": "https://mtor-atlas.org/api/v1/studies/KIM2003.json" }, { "sid": "CUN2007", "title": "mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex", "authors": "Cunningham JT; Rodgers JT; Arlow DH; Vazquez F; Mootha VK; Puigserver P", "year": 2007, "journal": "Nature", "doi": "10.1038/nature06322", "pmid": "18046414", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Skeletal muscle cells + tissue", "peer_reviewed": true, "finding": "Showed mTOR isn't just about building proteins - it also runs the cell's POWER plants. mTORC1 drives mitochondrial gene expression and oxygen consumption through a YY1-PGC-1alpha transcriptional program; block mTOR with rapamycin and mitochondrial output falls. Explains part of why mTOR inhibition reshapes metabolism.", "url": "https://mtor-atlas.org/study/CUN2007/", "api_url": "https://mtor-atlas.org/api/v1/studies/CUN2007.json" }, { "sid": "GUE2006", "title": "Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1", "authors": "Guertin DA; Stevens DM; Thoreen CC; Burds AA; Kalaany NY; Moffat J; Brown M; Fitzgerald KJ; Sabatini DM", "year": 2006, "journal": "Developmental Cell", "doi": "10.1016/j.devcel.2006.10.007", "pmid": "17141160", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Knockout mice (raptor/rictor/mLST8)", "peer_reviewed": true, "finding": "The foundational genetic 'dissection' of the two complexes in living mice. Deleting Raptor was lethal early (mTORC1 essential); deleting Rictor or mLST8 selectively knocked out mTORC2 signaling to Akt and PKCalpha but spared S6K1. This cleanly assigned jobs to each complex and showed mLST8 is an mTORC2-specific requirement in mice.", "url": "https://mtor-atlas.org/study/GUE2006/", "api_url": "https://mtor-atlas.org/api/v1/studies/GUE2006.json" }, { "sid": "INO2003", "title": "TSC2 mediates cellular energy response to control cell growth and survival", "authors": "Inoki K; Zhu T; Guan KL", "year": 2003, "journal": "Cell", "doi": "10.1016/s0092-8674(03)00929-2", "pmid": "14651849", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Mammalian cells (biochemistry)", "peer_reviewed": true, "finding": "Established the energy-sensing arm of the pathway. When energy runs low, AMPK phosphorylates TSC2, boosting its ability to shut mTOR down - protecting the cell from burning through resources and from starvation-induced death. The founding paper for how mTOR reads the cell's fuel gauge (complements the Akt-TSC2 growth-factor arm).", "url": "https://mtor-atlas.org/study/INO2003/", "api_url": "https://mtor-atlas.org/api/v1/studies/INO2003.json" }, { "sid": "JOS2024", "title": "mTORC1 activity oscillates throughout the cell cycle, promoting mitotic entry and differentially influencing autophagy induction", "authors": "Joshi JN; Valvezan AJ et al.", "year": 2024, "journal": "Cell Reports", "doi": "10.1016/j.celrep.2024.114543", "pmid": "39067023", "pmcid": "PMC12730006", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human and mouse cell lines (synchronised populations; fixed-cell single-cell imaging)", "peer_reviewed": true, "finding": "mTORC1 activity oscillates across the cell cycle (lowest in mitosis/G1, highest in S/G2) via the TSC complex, independent of Akt/Mek-Erk; low mTORC1 in G1 sensitizes cells to autophagy induction from the same partial inhibition or nutrient drop -- direct evidence that the TIMING/pattern of mTORC1 activity, not just its average level, shapes autophagy outcome.", "url": "https://mtor-atlas.org/study/JOS2024/", "api_url": "https://mtor-atlas.org/api/v1/studies/JOS2024.json" }, { "sid": "SCH2025", "title": "The Bi-steric, mTORC1-Selective Inhibitor, RMC-5552, in Advanced Solid Tumors: A Phase 1 Trial", "authors": "Schram AM; Meyerowitz JG et al.", "year": 2025, "journal": "Clinical Cancer Research", "doi": "10.1158/1078-0432.CCR-25-2112", "pmid": "41056387", "pmcid": "PMC12666311", "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Human", "model_system": "Human (Phase 1 dose escalation, n=57, advanced solid tumors, NCT04774952)", "peer_reviewed": true, "finding": "First-in-human, open-label dose-escalation trial (n=57, advanced solid tumors, no comparator arm) of a bi-steric mTORC1-selective inhibitor. Treatment-related hyperglycemia was low (4%) and not dose-limiting, alongside a 64% disease control rate. Because the trial was uncontrolled and made no head-to-head comparison against rapamycin or an ATP-site inhibitor, this is encouraging early clinical evidence consistent with the hypothesis that sparing mTORC2 reduces metabolic toxicity -- it does not establish mTORC2 sparing as the cause.", "url": "https://mtor-atlas.org/study/SCH2025/", "api_url": "https://mtor-atlas.org/api/v1/studies/SCH2025.json" }, { "sid": "MEN2023", "title": "A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer", "authors": "Meng D; Bandyopadhyay S et al.", "year": 2023, "journal": "Oncogene", "doi": "10.1038/s41388-023-02737-z", "pmid": "37264081", "pmcid": "PMC10328828", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Human ER+/HER2- breast cancer cell lines; mouse patient-derived xenografts (PDX)", "peer_reviewed": true, "finding": "RMC-6272, a bi-steric molecule with >25-fold selectivity for mTORC1 over mTORC2, completely suppresses mTORC1 (hitting the rapamycin-resistant substrate 4E-BP1) and overcomes hormone- and CDK4/6-inhibitor resistance in breast cancer cell lines and PDX -- the preclinical basis for the RMC-5552 selective-inhibitor clinical program.", "url": "https://mtor-atlas.org/study/MEN2023/", "api_url": "https://mtor-atlas.org/api/v1/studies/MEN2023.json" }, { "sid": "HE2025", "title": "mTORC1, the maestro of cell metabolism and growth", "authors": "He L; Cho S; Blenis J", "year": 2025, "journal": "Genes & Development", "doi": "10.1101/gad.352084.124", "pmid": "39572234", "pmcid": "PMC11789495", "evidence": { "code": "R", "label": "Review — secondary literature, not a new result", "note": "this describes the kind of study, not its quality" }, "category": "Review", "model_system": "N/A (narrative review)", "peer_reviewed": true, "finding": "Comprehensive current review of how nutrients and growth signals are integrated by mTORC1 and the metabolic programs it commands, plus the clinical outlook for mTORC1-targeted therapy across cancer, neurodegeneration, obesity, diabetes and aging -- anchor reference for the pathway map.", "url": "https://mtor-atlas.org/study/HE2025/", "api_url": "https://mtor-atlas.org/api/v1/studies/HE2025.json" }, { "sid": "DEN2026", "title": "Spalt-related is an inhibitor of mTORC1-mediated growth activated by the integrated stress response", "authors": "Onur Deniz, Ying Liu, Tuuli Kirkinen, Krista Kokki, Kateryna Gaertner, Pau Clavell-Revelles, Jaakko Mattila, Ville Hietakangas", "year": 2026, "journal": "The EMBO Journal", "doi": "10.1038/s44318-026-00858-1", "pmid": "42436355", "pmcid": null, "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Drosophila melanogaster", "peer_reviewed": true, "finding": "Transcription factor Spalt-related (Salr) is a novel mTORC1 inhibitor in Drosophila activated by the integrated stress response, restricting anabolic growth and lipid storage during nutrient stress. Salr responds to a distinct, ISR-driven cue, acting convergently with FoxO rather than downstream of it.", "url": "https://mtor-atlas.org/study/DEN2026/", "api_url": "https://mtor-atlas.org/api/v1/studies/DEN2026.json" }, { "sid": "GIL2026", "title": "Association of rapamycin treatment with the modulation of purine metabolism, reduced microglial inflammatory responses, improved mitochondrial energy metabolism, and alleviation of fatigue symptoms in ME/CFS subjects: pilot findings from phase-II observational study", "authors": "Brooke Gile, Sarojini Bulbule, Mubaraq A Toriola, Brian T Ruan, Shabnam Marium, Anna Benko, Stephanie Grach, Michael Mueller, Lucinda Bateman, Jennifer Bell, Brayden Yellman, Jon Berner, Bela Chheda, David Kaufman, Gunnar Gottschalk, Avik Roy", "year": 2026, "journal": "Journal of Translational Medicine", "doi": "10.1186/s12967-026-08575-3", "pmid": "42432754", "pmcid": "PMC13374298", "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Human", "model_system": "Human (ME/CFS patients)", "peer_reviewed": true, "finding": "In an uncontrolled phase-II pilot (no placebo), low-dose rapamycin was associated with reduced fatigue in ME/CFS. In plasma from responders, purine intermediates shifted, consistent with lower IMP dehydrogenase activity in PBMCs. Lab assays suggest that altered purines can impair mitochondrial metabolism and promote microglial inflammation; these links were not measured in patients.", "url": "https://mtor-atlas.org/study/GIL2026/", "api_url": "https://mtor-atlas.org/api/v1/studies/GIL2026.json" }, { "sid": "MAR2026", "title": "EVERolimus effectiveness after proGREssion on ENdocrine therapy plus CDK4/6 inhibitor for ER-positive/HER2-negative advanced breast cancer: EVERGREEN study", "authors": "Diogo Martins-Branco, Soraia Lobo-Martins, Philippe Aftimos, Bernardo Pereira, Leonor Vasconcelos de Matos, Leonor Fernandes, Guilherme Nader-Marta, Michel Moreau, Donatienne Taylor, Francois P Duhoux, Evandro de Azambuja", "year": 2026, "journal": "Breast Cancer Research and Treatment", "doi": "10.1007/s10549-026-08012-5", "pmid": "42429895", "pmcid": null, "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Human", "model_system": "Human (multicenter retrospective cohort)", "peer_reviewed": true, "finding": "Everolimus added to endocrine therapy provided modest but statistically significant PFS benefit (5.0 vs 4.3 months; HR 0.68) in ER+/HER2- advanced breast cancer post-CDK4/6 inhibitor progression, without demonstrable OS benefit, supporting selective use. Retrospective and non-randomised, so treatment-selection bias cannot be excluded.", "url": "https://mtor-atlas.org/study/MAR2026/", "api_url": "https://mtor-atlas.org/api/v1/studies/MAR2026.json" }, { "sid": "PIR2026", "title": "Biological limits of lifespan extension: evidence for a shift from pathway leverage to system-level buffering across species", "authors": "Denisa Fv Pirscoveanu, Mihai-Cristian Papa, Britta Kaltwasser, Dirk M Hermann, Ulf Brockmeier, Andrea Cercel, Anthony Oliver, Johannes Gruillari, Marius Viorel Ionica, Aurel Popa-Wagner", "year": 2026, "journal": "Mechanisms of Ageing and Development", "doi": "10.1016/j.mad.2026.112231", "pmid": "42437600", "pmcid": null, "evidence": { "code": "R", "label": "Review — secondary literature, not a new result", "note": "this describes the kind of study, not its quality" }, "category": "Review", "model_system": "Multi-species (C. elegans, Drosophila, rodents)", "peer_reviewed": true, "finding": "mTOR/TOR pathway interventions achieve large lifespan extensions in simple organisms but face declining efficacy in mammals due to distributed multi-tissue buffering, redundancy, and pharmacokinetic complexity - proposing a unifying framework for the translational challenge of aging pathway targeting.", "url": "https://mtor-atlas.org/study/PIR2026/", "api_url": "https://mtor-atlas.org/api/v1/studies/PIR2026.json" }, { "sid": "YAN2026", "title": "SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation.", "authors": "Yang H; Zingaro VA; Boardman K; Noronha A; Guney E; et al.; Ruggero D", "year": 2026, "journal": "Journal of Clinical Investigation", "doi": "10.1172/JCI199709", "pmid": "42454485", "pmcid": "PMC13367966", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Lymphoma cell lines / mouse", "peer_reviewed": true, "finding": "SLC15A3-mediated dipeptide import sustains mTORC1 activation in B cell lymphomas, enabling resistance to antimetabolite chemotherapy. Silencing SLC15A3 lowered mTORC1 activity and restored sensitivity to 6-mercaptopurine, and the resistant lymphomas, but not the parental tumours, were selectively sensitive to rapamycin in culture and in vivo.", "url": "https://mtor-atlas.org/study/YAN2026/", "api_url": "https://mtor-atlas.org/api/v1/studies/YAN2026.json" }, { "sid": "FRA2013", "title": "Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial", "authors": "Franz DN; Belousova E; Sparagana S; Bebin EM; Frost M; et al.; Jozwiak S", "year": 2013, "journal": "Lancet", "doi": "10.1016/S0140-6736(12)61134-9", "pmid": "23158522", "pmcid": null, "evidence": { "code": "H", "label": "Human study", "note": "this describes the kind of study, not its quality" }, "category": "Human", "model_system": "Humans, phase 3 RCT (n=117, TSC)", "peer_reviewed": true, "finding": "Phase 3 RCT (n=117) in tuberous sclerosis, the disease where mTOR is stuck ON by a genetic fault. Everolimus shrank brain tumors (SEGA) by >=50% in 35% of patients versus 0% on placebo. Because the underlying cause here is direct mTOR overactivation, this is arguably the cleanest randomised human evidence that blocking mTOR works in a genetically defined mTORopathy -- which does not extend to mTOR inhibition in people without such a mutation.", "url": "https://mtor-atlas.org/study/FRA2013/", "api_url": "https://mtor-atlas.org/api/v1/studies/FRA2013.json" }, { "sid": "JOH2013", "title": "mTOR is a key modulator of ageing and age-related disease", "authors": "Johnson SC; Rabinovitch PS; Kaeberlein M", "year": 2013, "journal": "Nature", "doi": "10.1038/nature11861", "pmid": "23325216", "pmcid": "PMC3687363", "evidence": { "code": "R", "label": "Review — secondary literature, not a new result", "note": "this describes the kind of study, not its quality" }, "category": "Review", "model_system": "Review (multi-species synthesis)", "peer_reviewed": true, "finding": "The landmark Nature review that put mTOR at the center of aging biology. Lays out the case that inhibiting mTOR extends lifespan across species and guards against a growing list of age-related diseases - while being candid that side effects currently block its use in healthy people. Excellent orientation map for the whole field.", "url": "https://mtor-atlas.org/study/JOH2013/", "api_url": "https://mtor-atlas.org/api/v1/studies/JOH2013.json" }, { "sid": "BCH2026", "title": "Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERRα-dependent manner", "authors": "B'chir W; Giguère V et al.", "year": 2026, "journal": "Journal of Endocrinology", "doi": "10.1530/JOE-26-0176", "pmid": "42544714", "pmcid": null, "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Side effect", "model_system": "Mouse (rapamycin-induced MASLD model; ERRα-null mice)", "peer_reviewed": true, "finding": "Chloroquine co-treatment attenuates rapamycin-induced hepatic steatosis (a known mTORC1-inhibitor side effect) in mice, and this rescue depends on the nuclear receptor ERRα; RNA-seq shows chloroquine reverses rapamycin-driven upregulation of lipid-metabolism genes, with ERRα identified as a top transcriptional regulator of the effect.", "url": "https://mtor-atlas.org/study/BCH2026/", "api_url": "https://mtor-atlas.org/api/v1/studies/BCH2026.json" }, { "sid": "ULL2026", "title": "FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer", "authors": "Ullern H; Johannessen JA; Kasikci F; Formica M; Karimi Melve N; Andresen S; Brech A; Axcrona K; Jørgensen K; Farkas L; Enserink JM; Knævelsrud H", "year": 2026, "journal": "Autophagy Reports", "doi": "10.1080/27694127.2026.2705631", "pmid": "42569319", "pmcid": "PMC13449739", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "BHD patient-derived kidney cancer cell line; Norwegian BHD patient tumor cohort", "peer_reviewed": true, "finding": "In BHD patient-derived kidney cancer cells, FLCN loss causes constitutive nuclear TFEB localization and mTORC1 hyperactivation, but leaves bulk autophagy flux and LC3 lipidation unaffected; however, the autophagy receptor SQSTM1/p62 accumulates in enlarged puncta, a finding replicated in a Norwegian cohort of BHD patient kidney tumors, showing p62 accumulation is dissociable from bulk autophagic flux.", "url": "https://mtor-atlas.org/study/ULL2026/", "api_url": "https://mtor-atlas.org/api/v1/studies/ULL2026.json" }, { "sid": "FAN2026", "title": "mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency", "authors": "Fan W; Liu H; Yang L; Sinha N; Catipovic M; Dong D; Easawaran H; Green R; Laiho M", "year": 2026, "journal": "Genes & Development", "doi": "10.1101/gad.353708.126", "pmid": "42575690", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cancer cell lines (functional genomics/CRISPR screens)", "peer_reviewed": true, "finding": "mTORC1 inhibition does not restore ribosome biogenesis but redistributes limited ribosomes away from highly-translated 5'TOP mRNAs toward survival-essential transcripts, defining a 'translational fitness' mechanism that lets cancer cells survive ribosome biogenesis deficiency.", "url": "https://mtor-atlas.org/study/FAN2026/", "api_url": "https://mtor-atlas.org/api/v1/studies/FAN2026.json" }, { "sid": "TIW2026", "title": "Firefox, a protein encoded by circular RNA circPVT1, is essential for MYC-driven oncogenesis", "authors": "Tiwari A, Paithane U, Tashiro K, Hall B, Friedlein J, Saraswat M, Saulnier O, Barbosa K, Trinh Q, Bagchi A, et al.", "year": 2026, "journal": "Genes & Development", "doi": "10.1101/gad.353355.125", "pmid": "42618323", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human MYC-amplified cancer cell lines; xenograft mouse models", "peer_reviewed": true, "finding": "A micropeptide (Firefox/FFX) encoded by the circular RNA circPVT1 stimulates AKT-mTORC1 signaling and cap-dependent translation to sustain MYC protein abundance and transcriptional output. FFX depletion reduces MYC levels and impairs tumor growth in MYC-amplified xenograft models, identifying an mTORC1-linked vulnerability in MYC-driven cancers.", "url": "https://mtor-atlas.org/study/TIW2026/", "api_url": "https://mtor-atlas.org/api/v1/studies/TIW2026.json" }, { "sid": "DAB2026", "title": "mTORC1 inhibition upregulates CD20 and enhances anti-CD20 antibody efficacy in B-cell precursor acute lymphoblastic leukemia", "authors": "Dąbkowska A, Janowska M, Pastorczak A, Domka K, Nowicka Z, Urbanska Z, Zając W, Bugajewski M, Grzybowska J, Pruchniak P, Fidyt K, Fendler W, Taslim J, Crump NT, Ushmorov A, Patkowska E, Firczuk M", "year": 2026, "journal": "Leukemia", "doi": "10.1038/s41375-026-03093-z", "pmid": "42618701", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "BCP-ALL cell lines; patient-derived and in vivo models", "peer_reviewed": true, "finding": "mTORC1 inhibitors upregulate CD20 via the AKT-FOXO1 axis and promote B-lineage maturation in B-cell precursor ALL, enhancing the antitumor efficacy of anti-CD20 monoclonal antibodies -- including in high-risk IKZF1-deleted disease -- providing a rationale for combining mTORC1 inhibition with CD20-directed immunotherapy.", "url": "https://mtor-atlas.org/study/DAB2026/", "api_url": "https://mtor-atlas.org/api/v1/studies/DAB2026.json" }, { "sid": "WANG2026C", "title": "Fluorescent protein ticker tape (FPTT): Multiplexed recording of transcriptional dynamics in living cells and in vivo", "authors": "Wang R; Jiang J et al.", "year": 2026, "journal": "Science Advances", "doi": "10.1126/sciadv.aef9406", "pmid": "42685187", "pmcid": "PMC13537258", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "HEK293T cells, synchronised (live recording of mTOR-driven transcription, SREBP1 response element)", "peer_reviewed": true, "finding": "Engineered a multiplexed fluorescent-protein 'ticker tape' biosensor platform (self-assembling protein fibers + multispectral fluorescent proteins) for longitudinal, single-cell recording of signaling-pathway transcriptional histories (mTOR, NF-κB, STAT3, NFAT, cAMP). Applying the mTOR-FPTT reporter, the authors independently observed cell-cycle-dependent OSCILLATING mTOR activity dynamics -- a new, orthogonal tool corroborating that mTOR signaling is patterned over time rather than static, consistent with JOS2024's cell-cycle oscillation finding.", "url": "https://mtor-atlas.org/study/WANG2026C/", "api_url": "https://mtor-atlas.org/api/v1/studies/WANG2026C.json" }, { "sid": "KUS2026", "title": "CASTOR1 regulates humoral immune responses and contributes to the pathogenesis of systemic lupus erythematosus", "authors": "Kusuda T; Komai T; Itamiya T; Abe T; Okamura T; Fujio K", "year": 2026, "journal": "Arthritis & Rheumatology", "doi": "10.1002/art.70314", "pmid": "42695806", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human B cells (ImmuNexUT transcriptomes, n=136 SLE patients) + whole-body and B cell-specific Castor1-knockout mice", "peer_reviewed": true, "finding": "Gives the arginine sensor CASTOR1 a defined physiological job upstream of mTORC1: losing it de-represses mTORC1 in B cells and drives plasma-cell expansion, IgG and anti-dsDNA autoantibodies, and lupus-like glomerulonephritis. In human SLE, CASTOR1 expression in plasmablasts was inversely correlated with disease activity (r = -0.32, p = 0.00031). One of the few studies to tie a specific upstream amino-acid sensor to a human autoimmune phenotype rather than to cancer or growth.", "url": "https://mtor-atlas.org/study/KUS2026/", "api_url": "https://mtor-atlas.org/api/v1/studies/KUS2026.json" }, { "sid": "CUI2023", "title": "Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex", "authors": "Cui Z; Napolitano G; de Araujo MEG; Esposito A; Monfregola J; Huber LA; Ballabio A; Hurley JH", "year": 2023, "journal": "Nature", "doi": "10.1038/s41586-022-05652-7", "pmid": "36697823", "pmcid": "PMC9931586", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Cryo-EM structure (human proteins, cell-free reconstitution)", "peer_reviewed": true, "finding": "First structural view of how mTORC1 actually reaches TFEB to phosphorylate it: two full Rag-Ragulator complexes present a single TFEB molecule to the mTOR active site, one in the normal Raptor-docking arrangement and a second, non-canonical one that grips TFEB's own first helix. Mutating that grip point drives TFEB straight into the nucleus (turning on autophagy/lysosome genes) without disturbing where mTORC1 itself sits. Explains, at the level of atoms, why TFEB phosphorylation needs the tumour suppressor FLCN and the GDP-loaded state of RagC in a way no other mTORC1 substrate does. Boundary: cryo-EM of a complex reconstituted from purified human proteins — a static structural snapshot, not a live cell or a real-time measurement.", "url": "https://mtor-atlas.org/study/CUI2023/", "api_url": "https://mtor-atlas.org/api/v1/studies/CUI2023.json" }, { "sid": "CUI2025", "title": "Structural basis for mTORC1 activation on the lysosomal membrane", "authors": "Cui Z; Esposito A; Napolitano G; Ballabio A; Hurley JH", "year": 2025, "journal": "Nature", "doi": "10.1038/s41586-025-09545-3", "pmid": "40963021", "pmcid": "PMC12448111", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Cryo-EM structure (human proteins, reconstituted on membranes)", "peer_reviewed": true, "finding": "Resolves how mTORC1 flips from 'parked on the lysosome' to 'catalytically switched on'. Reconstituting the whole assembly on membranes from purified Rheb, Rag GTPases, Ragulator and mTORC1, cryo-EM shows the kinase reaches full activity only after two separate anchoring steps: Rag-Ragulator first pulls it to within about 100 angstroms of the membrane, then Rheb pulls it to within about 40 angstroms, and only when Raptor and mTOR itself also touch the membrane directly do the catalytic residues line up for full activity. Growth-factor input (via Rheb) and nutrient input (via the Rags) are shown converging on the same physical docking event rather than acting through separate switches. Boundary: reconstituted on synthetic membranes from purified components — a structural/biochemical model, not a measurement inside a living cell.", "url": "https://mtor-atlas.org/study/CUI2025/", "api_url": "https://mtor-atlas.org/api/v1/studies/CUI2025.json" }, { "sid": "ROG2019", "title": "Structural basis for the docking of mTORC1 on the lysosomal surface", "authors": "Rogala KB; Sabatini DM et al.", "year": 2019, "journal": "Science", "doi": "10.1126/science.aay0166", "pmid": "31601708", "pmcid": "PMC7176403", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Cryo-EM structure (human proteins, cell-free reconstitution) + cell-based mutagenesis", "peer_reviewed": true, "finding": "3.2-angstrom cryo-EM structure of Raptor bound to Rag-Ragulator, showing how Raptor reads out the nutrient-dependent nucleotide state of the Rag GTPases: one part of Raptor senses RagA's nucleotide state, a separate 'claw' senses RagC's, and both have to be in the correct nutrient-signalling combination before Raptor is allowed to dock. Mutating the contact points blocks mTORC1 from reaching the lysosome and inhibits its signalling, which is the functional evidence behind the structural claim. Combined with a separate structure of mTORC1 bound to its activator Rheb, the paper builds a model of the complete, active mTORC1 sitting on the lysosome. Boundary: cryo-EM of a complex reconstituted from purified human proteins, not a live-cell measurement.", "url": "https://mtor-atlas.org/study/ROG2019/", "api_url": "https://mtor-atlas.org/api/v1/studies/ROG2019.json" }, { "sid": "ZHO2015", "title": "Dynamic Visualization of mTORC1 Activity in Living Cells", "authors": "Zhou X; Clister TL; Lowry PR; Seldin MM; Wong GW; Zhang J", "year": 2015, "journal": "Cell Reports", "doi": "10.1016/j.celrep.2015.02.031", "pmid": "25772363", "pmcid": "PMC4567530", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Mammalian cell lines (live-cell FRET imaging, subcellularly targeted reporter)", "peer_reviewed": true, "finding": "TORCAR, the first genetically encoded FRET reporter of mTORC1 activity, lets mTORC1 be watched in living cells as it changes. It showed mTORC1 activity not only at the lysosome but also in the cytosol, nucleus and at the plasma membrane; growth factor spread activity widely, while a leucine surrogate kept it at the lysosome and nucleus. A growth-factor-induced calcium transient contributed to mTORC1 activity. The earliest live reader of mTORC1 held in the atlas.", "url": "https://mtor-atlas.org/study/ZHO2015/", "api_url": "https://mtor-atlas.org/api/v1/studies/ZHO2015.json" }, { "sid": "KUB2012", "title": "Temporal coding of insulin action through multiplexing of the AKT pathway", "authors": "Kubota H; Noguchi R; Toyoshima Y; Ozaki YI; Uda S; Watanabe K; Ogawa W; Kuroda S", "year": 2012, "journal": "Molecular Cell", "doi": "10.1016/j.molcel.2012.04.018", "pmid": "22633957", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Rat hepatoma cells (Fao); pulse vs sustained insulin, time-course phosphorylation plus kinetic modelling", "peer_reviewed": true, "finding": "The same pathway can carry different messages in the shape of its signal over time. A short insulin pulse produced transient AKT phosphorylation and a sustained dose produced sustained AKT phosphorylation. S6K read only the transient part, G6Pase only the sustained part and GSK3-beta both. Which output responds depends on the pattern, not just the amount - the clearest cell-level case in the atlas that timing carries information in this pathway.", "url": "https://mtor-atlas.org/study/KUB2012/", "api_url": "https://mtor-atlas.org/api/v1/studies/KUB2012.json" }, { "sid": "KUB2018", "title": "In Vivo Decoding Mechanisms of the Temporal Patterns of Blood Insulin by the Insulin-AKT Pathway in the Liver", "authors": "Kubota H; Uda S; Matsuzaki F; Yamauchi Y; Kuroda S", "year": 2018, "journal": "Cell Systems", "doi": "10.1016/j.cels.2018.05.013", "pmid": "29960883", "pmcid": null, "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Rat liver in vivo (hyperinsulinemic-euglycemic clamp with different insulin time patterns) plus mathematical model", "peer_reviewed": true, "finding": "The in-vivo follow-up to KUB2012. In rat liver, all temporal patterns of blood insulin were encoded at the insulin receptor, and downstream molecules decoded them selectively through AKT: S6K read the additional (pulse-like) secretion, G6Pase the basal secretion via FoxO1, GSK3-beta all of it. Modelling tied the selectivity to network structure, sensitivity and time constants. Shows that pattern decoding is not only a cell-culture effect.", "url": "https://mtor-atlas.org/study/KUB2018/", "api_url": "https://mtor-atlas.org/api/v1/studies/KUB2018.json" }, { "sid": "DAL2012", "title": "A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation", "authors": "Dalle Pezze P; Sonntag AG; Thien A; Prentzell MT; Gödel M; Fischer S; Neumann-Haefelin E; Huber TB; Baumeister R; Shanley DP; Thedieck K", "year": 2012, "journal": "Science Signaling", "doi": "10.1126/scisignal.2002469", "pmid": "22457331", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Data-driven dynamic model of the insulin-mTOR network, tested in HeLa and other cell lines", "peer_reviewed": true, "finding": "A time-resolved, data-fitted model of the whole core insulin-mTOR network, including the mTORC1 negative feedback loop onto PI3K. Perturbing it in silico and in cells showed that TSC1-TSC2 is not a regulator of mTORC2, directly or through the feedback loop, and that mTORC2 activation runs through a PI3K variant insensitive to that loop. One of the few places where the feedback loops in the atlas are treated as a dynamical system rather than a diagram.", "url": "https://mtor-atlas.org/study/DAL2012/", "api_url": "https://mtor-atlas.org/api/v1/studies/DAL2012.json" }, { "sid": "DAL2016", "title": "A systems study reveals concurrent activation of AMPK and mTOR by amino acids", "authors": "Dalle Pezze P; Ruf S; Sonntag AG; Langelaar-Makkinje M; Hall P; Heberle AM; Razquin Navas P; van Eunen K; Tölle RC; Schwarz JJ; Wiese H; Warscheid B; Deitersen J; Stork B; Fäßler E; Schäuble S; Hahn U; Horvatovich P; Shanley DP; Thedieck K", "year": 2016, "journal": "Nature Communications", "doi": "10.1038/ncomms13254", "pmid": "27869123", "pmcid": "PMC5121333", "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Human cell lines; amino acid re-addition time courses, quantitative proteomics and dynamic modelling", "peer_reviewed": true, "finding": "Adding amino acids back to starved cells switched on AMPK, PI3K and mTORC2 acutely and independently of mTORC1, at the same time as mTOR. AMPK activation ran through CaMKK-beta and, under amino acid sufficiency, AMPK kept autophagy going via ULK1. So the textbook picture of AMPK and mTORC1 as simple opposites does not hold in the first minutes after feeding - which matters for how the AMPK-ULK1 feedback arm behaves over time.", "url": "https://mtor-atlas.org/study/DAL2016/", "api_url": "https://mtor-atlas.org/api/v1/studies/DAL2016.json" }, { "sid": "LIP2015", "title": "The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation", "authors": "Lipton JO; Yuan ED; Boyle LM; Ebrahimi-Fakhari D; Kwiatkowski E; Nathan A; Güttler T; Davis F; Asara JM; Sahin M", "year": 2015, "journal": "Cell", "doi": "10.1016/j.cell.2015.04.002", "pmid": "25981667", "pmcid": "PMC4447213", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Mouse tissues and cultured cells", "peer_reviewed": true, "finding": "S6K1, a main output of mTORC1, phosphorylates the clock protein BMAL1 rhythmically, and that phosphorylation lets BMAL1 join the translation machinery and drive protein synthesis. Protein synthesis rates oscillated over the day in a BMAL1-dependent way. A direct molecular bridge between mTORC1 output and the 24-hour clock.", "url": "https://mtor-atlas.org/study/LIP2015/", "api_url": "https://mtor-atlas.org/api/v1/studies/LIP2015.json" }, { "sid": "LIP2017", "title": "Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy", "authors": "Lipton JO; Boyle LM; Yuan ED; Hochstrasser KJ; Chifamba FF; Nathan A; Tsai PT; Davis F; Sahin M", "year": 2017, "journal": "Cell Reports", "doi": "10.1016/j.celrep.2017.07.008", "pmid": "28746872", "pmcid": "PMC5603761", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Mouse models of tuberous sclerosis complex (Tsc1/Tsc2 loss)", "peer_reviewed": true, "finding": "In mouse models of tuberous sclerosis, where mTOR is stuck on, the circadian clock ran abnormally: poor timekeeping in constant conditions and exaggerated responses to phase resetting. mTOR raised BMAL1 levels by changing its translation, degradation and location; genetically lowering BMAL1 rescued the behavioural rhythm defects. Constant, unpatterned mTOR activity disturbs a rhythm downstream.", "url": "https://mtor-atlas.org/study/LIP2017/", "api_url": "https://mtor-atlas.org/api/v1/studies/LIP2017.json" }, { "sid": "KHA2014", "title": "BMAL1-dependent regulation of the mTOR signaling pathway delays aging", "authors": "Khapre RV; Kondratova AA; Patel S; Dubrovsky Y; Wrobel M; Antoch MP; Kondratov RV", "year": 2014, "journal": "Aging (Albany NY)", "doi": "10.18632/aging.100633", "pmid": "24481314", "pmcid": "PMC3927809", "evidence": { "code": "A", "label": "Animal model", "note": "this describes the kind of study, not its quality" }, "category": "Animal", "model_system": "Bmal1-/- mice and fibroblasts", "peer_reviewed": true, "finding": "Loss of the clock protein BMAL1 raised mTORC1 activity in mice and in cultured cells, and rapamycin extended the lifespan of Bmal1-/- mice by 50%. Places the circadian clock upstream of mTORC1 as a brake, and links that brake to ageing.", "url": "https://mtor-atlas.org/study/KHA2014/", "api_url": "https://mtor-atlas.org/api/v1/studies/KHA2014.json" }, { "sid": "GUE2020", "title": "Crosstalk dynamics between the circadian clock and the mTORC1 pathway", "authors": "Guerrero-Morín JG; Santillán M", "year": 2020, "journal": "Journal of Theoretical Biology", "doi": "10.1016/j.jtbi.2020.110360", "pmid": "32522472", "pmcid": null, "evidence": { "code": "M", "label": "Molecular — cells, biochemistry, structure", "note": "this describes the kind of study, not its quality" }, "category": "Mechanism", "model_system": "Deterministic differential-algebraic equation model (in silico only)", "peer_reviewed": true, "finding": "A mathematical model of how mTORC1 could tune the circadian clock. It suggests mTORC1 raises clock amplitude by controlling BMAL1 translation and shortens the period by controlling where BMAL1 sits in the cell, and that both levels are needed for robust oscillation. A model, not a measurement - it proposes mechanisms for RAM2018's observations rather than testing them.", "url": "https://mtor-atlas.org/study/GUE2020/", "api_url": "https://mtor-atlas.org/api/v1/studies/GUE2020.json" } ], "relations": [ { "id": "AMPK-MTORC1", "claim": "AMPK inhibits mTORC1", "source": { "name": "AMPK", "entity": "ampk" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "inhibits", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": [ "mammalian cells" ], "mechanism": "AMPK also hits mTORC1 directly by phosphorylating Raptor, imposing a metabolic checkpoint independent of TSC.", "mechanism_beginner": "AMPK also hits mTORC1 directly, adding a second, energy-based checkpoint on top of TSC.", "context": "The Raptor arm is the TSC2-independent route, which is why it is measurable in TSC-null cells. Its relative contribution versus the TSC2 arm varies by cell type and by how deep the energy stress is.", "boundary": null, "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Direct biochemical", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "GWI2008" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/AMPK-MTORC1.json" }, { "id": "EVE-MTORC1", "claim": "Everolimus inhibits mTORC1", "source": { "name": "Everolimus", "entity": "everolimus" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "inhibits", "type": "allosteric-inhibition", "directness": "indirect", "timescale": "hours", "compartment": "lyso", "species": [ "human" ], "mechanism": "Everolimus is rapamycin with a solubilising side chain - same FKBP12 mechanism, better oral pharmacokinetics. It is the molecule that carried this pathway into routine clinical use.", "mechanism_beginner": "Everolimus is rapamycin with a small chemical tweak that makes it easier to take as a pill – same mechanism, better drug.", "context": null, "boundary": null, "note": "Six trials behind one arrow. They establish the clinical effect of the drug; the allosteric mechanism itself rests on the rapamycin biochemistry.", "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "established", "consensus": "established" }, "evidence": { "kind": "Pharmacological", "strongest": { "code": "H", "label": "Human study" }, "supporting": [ "MOT2008", "YAO2011", "BAS2012", "KRU2010", "BIS2013", "IYE2012" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/EVE-MTORC1.json" }, { "id": "FKBP12-MTORC1", "claim": "FKBP12 binds mTORC1", "source": { "name": "FKBP12", "entity": "fkbp12" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "binds", "type": "binding", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": [ "human cells" ], "mechanism": "Only when it is carrying rapamycin, FKBP12 docks on the FRB domain next to mTOR's active site. The FKBP12-rapamycin complex, not FKBP12 alone, is what blocks access for some substrates but not all; FKBP12 without the drug does not inhibit mTORC1. The inhibitory arrow is drawn from rapamycin (RAPA-MTORC1).", "mechanism_beginner": "Only when it carries rapamycin does FKBP12 dock on mTORC1; the pair then blocks some, but not all, of what mTORC1 does. FKBP12 on its own does nothing to mTORC1.", "context": null, "boundary": null, "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "established", "consensus": "established" }, "evidence": { "kind": "Structural", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "SAB1994", "SAB1995", "CHU1992", "BRO1994" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/FKBP12-MTORC1.json" }, { "id": "LYSO-MTORC1", "claim": "Lysosome required-for mTORC1", "source": { "name": "Lysosome", "entity": "lysosome" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "required-for", "type": "localisation", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": [ "human cells" ], "mechanism": "In the canonical nutrient-dependent route, mTORC1 has to reach the lysosomal surface to be switched on, because that is where Rheb is waiting. Force it elsewhere and amino acids stop mattering. The requirement is stated for this route, not for every pool of mTOR in the cell.", "mechanism_beginner": "In the amino-acid route, mTORC1 only works while it's sitting on the lysosome, because that is where its activator waits – move it somewhere else and amino acids stop being able to reach it.", "context": null, "boundary": "Scoped to amino-acid-driven activation. Live BRET imaging in this corpus (BOU2020) resolves mTOR activity in the cytosol, at the lysosome, in the nucleus and near mitochondria, so mTOR signalling is measurably not one pool. This map draws the lysosomal route and keeps the other localisations declared as open rather than asserting there are none. FER2024 refines this further: lysosomal mTORC1 (fed by local lysosomal proteolysis) and cytoplasmic mTORC1 (fed by exogenous amino acids) phosphorylate distinct downstream substrates — the lysosome is required for one regulatory sub-pool of mTORC1, not for all of it.", "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "established", "consensus": "established" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "SAN2010", "ZON2011", "FER2024" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/LYSO-MTORC1.json" }, { "id": "METFORMIN-MTORC1", "claim": "Metformin inhibits mTORC1", "source": { "name": "Metformin", "entity": "metformin" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "inhibits", "type": "signal-relay", "directness": "indirect", "timescale": "hours", "compartment": "cytosol", "species": [ "mammalian cells", "mouse liver" ], "mechanism": "Metformin also inhibits mTORC1 WITHOUT going through AMPK: the effect survives in AMPK-null and TSC1/2-null cells and instead requires the Rag GTPases. This is the arm usually left out of the 'metformin works via AMPK' summary.", "mechanism_beginner": "Metformin can also block mTORC1 through a completely separate route that doesn't need AMPK at all – a route often left out of the simple \"metformin works via AMPK\" story.", "context": "Dose is the whole argument. Concentrations used in cell culture are typically far above plasma levels achieved at clinical doses, so in vitro mechanism may not describe what metformin does in a patient.", "boundary": "Runs in parallel with METFORMIN-AMPK, not instead of it. The relative weight of the two routes in humans is unresolved.", "note": "FOR2010 was removed from this edge on 2026-09-21: it measured hepatic gluconeogenesis and never read out mTORC1. It remains correctly cited in the boundary of METFORMIN-AMPK.", "contested": true, "confidence": { "mechanistic": "low", "human_relevance": "plausible", "consensus": "contested" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "KAL2010" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/METFORMIN-MTORC1.json" }, { "id": "MTORC1-4EBP1", "claim": "mTORC1 inhibits 4E-BP1", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "4E-BP1", "entity": "4e-bp1" }, "effect": "inhibits", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": [ "mammalian cells" ], "mechanism": "mTORC1 phosphorylates 4E-BP1, which lets go of eIF4E and frees cap-dependent translation. Rapamycin blocks this arm only partially - the origin of the whole 'rapamycin-resistant output' problem.", "mechanism_beginner": "mTORC1 tags 4E-BP1 so it lets go of another protein, freeing up protein-building – but the standard drug (rapamycin) only partly blocks this step.", "context": null, "boundary": null, "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Direct biochemical", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "BUR1998", "HARA2002", "FEL2009" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-4EBP1.json" }, { "id": "MTORC1-GRB10", "claim": "mTORC1 activates Grb10", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "Grb10", "entity": "grb10" }, "effect": "activates", "type": "stabilization", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": [ "mammalian cells" ], "mechanism": "mTORC1 phosphorylates and stabilises Grb10 - the start of a feedback loop that talks back to the insulin receptor.", "mechanism_beginner": "mTORC1 stabilises Grb10, kicking off a feedback loop that talks back to the insulin receptor.", "context": null, "boundary": null, "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Direct biochemical", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "HSU2011", "YUX2011" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-GRB10.json" }, { "id": "MTORC1-LONGEVITY", "claim": "mTORC1 inhibits Longevity", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "Longevity", "entity": "longevity" }, "effect": "inhibits", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": [ "multiple species" ], "mechanism": "Lowering mTORC1 activity extends lifespan across yeast, worms, flies and mice - one of the most conserved interventions in ageing biology, alongside dietary restriction.", "mechanism_beginner": "Turning mTORC1 down extends lifespan in yeast, worms, flies and mice – one of the most universal anti-ageing effects known.", "context": "Strongly modified by sex, strain, diet and the age at which inhibition starts. Effect direction is reproducible; effect size is not transferable between models.", "boundary": "No human hard-endpoint evidence. This is the Atlas's flagged 'human endpoint desert'.", "note": "Links to ATLAS_FINDINGS human-endpoint desert.", "contested": false, "confidence": { "mechanistic": "medium", "human_relevance": "untested", "consensus": "established" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "A", "label": "Animal model" }, "supporting": [ "HAR2009", "LAM2012", "ROB2012", "VEL2003" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-LONGEVITY.json" }, { "id": "MTORC1-MAPK", "claim": "mTORC1 inhibits ERK / RSK (MAPK)", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "ERK / RSK (MAPK)", "entity": "erk-rsk-mapk" }, "effect": "inhibits", "type": "signal-relay", "directness": "indirect", "timescale": "hours", "compartment": "cytosol", "species": [ "human cells", "mouse" ], "mechanism": "A second feedback arm: inhibiting mTORC1 releases a PI3K-dependent brake and MAPK signalling goes up. Together with S6K1-IRS1 this is why single-agent mTOR inhibition tends to be met by compensatory growth signalling.", "mechanism_beginner": "Blocking mTORC1 can backfire by releasing a brake on a different growth pathway (MAPK) – one reason mTOR-blocking drugs alone often aren't enough.", "context": null, "boundary": "Single-study edge in this corpus.", "note": "CAR2008 was already in the corpus but carried no edge until 2026-07-29.", "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "established", "consensus": "established" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "CAR2008" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-MAPK.json" }, { "id": "MTORC1-MITO", "claim": "mTORC1 activates Mitochondrial biogenesis", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "Mitochondrial biogenesis", "entity": "mitochondrial-biogenesis" }, "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "hours", "compartment": "mito", "species": [ "mammalian cells" ], "mechanism": "mTORC1 raises mitochondrial output two ways: through a YY1-PGC-1alpha transcription complex, and by relieving 4E-BP so mitochondrial proteins get translated.", "mechanism_beginner": "mTORC1 boosts the cell's mitochondria – its power plants – two ways at once: through a gene-activating complex, and by freeing up 4E-BP.", "context": null, "boundary": "Shown in cultured cells and skeletal muscle (CUN2007) and mammalian cell lines (MOR2013). One organismal result points the other way: adipose-specific Raptor deletion raised mitochondrial respiration (POL2008), see MTORC1-OXPHOS.", "note": null, "contested": false, "confidence": { "mechanistic": "medium", "human_relevance": "plausible", "consensus": "emerging" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "CUN2007", "MOR2013" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-MITO.json" }, { "id": "MTORC1-NUCL", "claim": "mTORC1 activates Nucleotide synthesis", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "Nucleotide synthesis", "entity": "nucleotide-synthesis" }, "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "hours", "compartment": "cytosol", "species": [ "mammalian cells" ], "mechanism": "mTORC1 couples nucleotide supply to demand - it turns on purine synthesis through the mitochondrial tetrahydrofolate cycle so a dividing cell can actually copy its DNA.", "mechanism_beginner": "mTORC1 turns on the machinery for building DNA/RNA building blocks, so a growing cell can actually copy its DNA.", "context": null, "boundary": null, "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Direct biochemical", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "VAL2017", "BEN2016" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-NUCL.json" }, { "id": "MTORC1-PROSTATE", "claim": "mTORC1 activates Prostate cancer", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "Prostate cancer", "entity": "prostate-cancer" }, "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": [ "mouse" ], "mechanism": "Blocking mTOR reversed Akt-driven pre-cancerous prostate lesions in mice, showing the growth was mTORC1-dependent and reversible.", "mechanism_beginner": "Blocking mTOR reversed early, pre-cancerous prostate changes in mice caused by an overactive growth signal.", "context": null, "boundary": "Scope: the lesion was prostatic intraepithelial neoplasia, a pre-cancerous stage, driven by transgenic human AKT1 in mice, and the drug (RAD001) inhibits mTORC1 allosterically. Not a demonstration in established prostate cancer.", "note": null, "contested": false, "confidence": { "mechanistic": "medium", "human_relevance": "plausible", "consensus": "emerging" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "A", "label": "Animal model" }, "supporting": [ "MAJ2004" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-PROSTATE.json" }, { "id": "MTORC1-RCC", "claim": "mTORC1 activates Renal cell carcinoma (RCC)", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "Renal cell carcinoma (RCC)", "entity": "renal-cell-carcinoma-rcc" }, "effect": "activates", "type": "association", "directness": "unresolved", "timescale": "chronic", "compartment": "outcome", "species": [ "human" ], "mechanism": "Renal cancers frequently carry lesions that leave mTORC1 constitutively active - which is why this tissue responds to mTOR inhibitors at all, and why an exceptional responder could be traced to TSC1 loss.", "mechanism_beginner": "Many kidney cancers carry mutations that leave mTORC1 stuck \"on\" – that's why this cancer type responds to mTOR-blocking drugs at all, though it doesn't prove mTORC1 causes the cancer.", "context": null, "boundary": "Correlative plus one n-of-1 genomic case (IYE2012); not a demonstration that mTORC1 activation initiates RCC.", "note": "Replaces TUMOR-RCC, which asserted 'Tumor growth activates RCC' - a category error, since RCC is an instance of tumour growth, not a downstream target.", "contested": false, "confidence": { "mechanistic": "low", "human_relevance": "established", "consensus": "emerging" }, "evidence": { "kind": "Correlative", "strongest": { "code": "H", "label": "Human study" }, "supporting": [ "IYE2012", "MOT2008", "HUD2007" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-RCC.json" }, { "id": "MTORC1-S6K1", "claim": "mTORC1 activates S6K1", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "S6K1", "entity": "s6k1" }, "effect": "activates", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": [ "mammalian cells" ], "mechanism": "mTORC1 phosphorylates S6K1, switching on the translation machinery. This is the classic rapamycin-sensitive output and the readout most papers actually measure.", "mechanism_beginner": "mTORC1 switches on S6K1, which turns on the cell's protein-building machinery – the classic effect most studies of this drug class measure.", "context": "Standard mTORC1 readout, but a readout is not the whole output. S6K1 phosphorylation is fully rapamycin-sensitive while 4E-BP1 is not, so 'mTORC1 activity' measured by S6K1 alone systematically overstates how much rapamycin inhibits mTORC1.", "boundary": "Caution: p-S6K is a proxy, not the phenotype. Many 'mTORC1 activity' claims rest on this single band.", "note": "Worth flagging on the page: readout != outcome.", "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Direct biochemical", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "BUR1998", "CHU1992", "HOL2005" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-S6K1.json" }, { "id": "MTORC1-SENESCENCE", "claim": "mTORC1 activates Senescence-associated secretory phenotype (SASP)", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "Senescence-associated secretory phenotype (SASP)", "entity": "senescence-associated-secretory-phenotype-sasp" }, "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "days", "compartment": "outcome", "species": [ "mammalian cells" ], "mechanism": "mTORC1 sustains the inflammatory secretory output of cells that are already senescent, by promoting IL1A translation. Inhibiting it quietens that output without reversing the proliferative arrest.", "mechanism_beginner": "mTORC1 keeps old, \"senescent\" cells pumping out inflammatory signals, and blocking it calms that output down. It does not turn healthy cells senescent, and it does not make senescent cells young again.", "context": null, "boundary": "Single-study edge in this corpus, and a scoped one: LAB2015 measures the secretome of senescent cells, not whether mTORC1 drives cells into senescence. That is why this arrow lands on the secretory programme and not on senescence itself.", "note": "Thin - one supporting study.", "contested": false, "confidence": { "mechanistic": "medium", "human_relevance": "plausible", "consensus": "emerging" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "LAB2015" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-SENESCENCE.json" }, { "id": "MTORC1-SREBP", "claim": "mTORC1 activates SREBP1 / SREBP2", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "SREBP1 / SREBP2", "entity": "srebp1-srebp2" }, "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "hours", "compartment": "cytosol", "species": [ "mammalian cells" ], "mechanism": "mTORC1 drives the SREBP transcription factors, which turn on the genes for making fat and cholesterol - growth needs membrane, not just protein.", "mechanism_beginner": "mTORC1 switches on SREBP, the genes that build fat and cholesterol – a growing cell needs membrane material, not just protein.", "context": null, "boundary": null, "note": null, "contested": false, "confidence": { "mechanistic": "medium", "human_relevance": "plausible", "consensus": "emerging" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "POR2008", "PET2011" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-SREBP.json" }, { "id": "MTORC1-TFEB", "claim": "mTORC1 inhibits TFEB", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "TFEB", "entity": "tfeb" }, "effect": "inhibits", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": [ "mammalian cells" ], "mechanism": "Active mTORC1 phosphorylates TFEB right on the lysosomal surface, trapping it in the cytoplasm. Switch mTORC1 off and TFEB walks into the nucleus.", "mechanism_beginner": "Active mTORC1 tags TFEB and traps it outside the nucleus; switch mTORC1 off and TFEB moves in.", "context": "Substrate-selective. Depends on FLCN/FNIP RagC/D status, so mTORC1 can be active on S6K1 while not phosphorylating TFEB.", "boundary": "RagD specifically (more than RagC) promotes TFEB/TFE3 phosphorylation via tighter LAMTOR binding — GOL2022 shows this is paralogue-specific, not a generic Rag-dimer property.", "note": "Four independent studies - one of the best-supported output edges.", "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Direct biochemical", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "ROC2012", "SET2012", "MAR2012", "SET2011", "GOL2022" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-TFEB.json" }, { "id": "MTORC1-TUMOR", "claim": "mTORC1 activates Tumor growth", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "Tumor growth", "entity": "tumor-growth" }, "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": [ "mouse", "human cells" ], "mechanism": "Hyperactive mTORC1 reprograms translation toward a specific set of pro-growth and pro-metastasis mRNAs (HSI2012, prostate models) and couples nucleotide synthesis to demand, creating a targetable vulnerability in TSC-deficient cells (VAL2017).", "mechanism_beginner": "Hyperactive mTORC1 pushes cells to build a specific set of growth- and spread-promoting proteins – the tumour becomes hooked on that programme.", "context": null, "boundary": "Context-dependent: shown in genetically driven mouse tumour models and cancer cell lines with hyperactive mTORC1 (PTEN loss, TSC loss), not as a general property of tumours.", "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "established", "consensus": "established" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "HSI2010", "HSI2012", "VAL2017" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-TUMOR.json" }, { "id": "MTORC1-ULK1", "claim": "mTORC1 inhibits ULK1", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "ULK1", "entity": "ulk1" }, "effect": "inhibits", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": [ "mammalian cells" ], "mechanism": "Active mTORC1 phosphorylates ULK1 at an inhibitory site, holding autophagy shut while nutrients are plentiful.", "mechanism_beginner": "Active mTORC1 tags ULK1 to hold it back, keeping the cell's self-cleanup process (autophagy) switched off while nutrients are plentiful.", "context": null, "boundary": null, "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Direct biochemical", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "HOS2009", "GAN2009", "KIM2011", "NAZ2013" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-ULK1.json" }, { "id": "PRAS40-MTORC1", "claim": "PRAS40 inhibits mTORC1", "source": { "name": "PRAS40", "entity": "pras40" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "inhibits", "type": "competitive-inhibition", "directness": "direct", "timescale": "seconds", "compartment": "lyso", "species": [ "mammalian cells" ], "mechanism": "Unphosphorylated PRAS40 sits in the substrate groove of mTORC1 and blocks it - a built-in plug.", "mechanism_beginner": "Untagged PRAS40 sits inside mTORC1 and blocks it, like a built-in plug.", "context": null, "boundary": null, "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Structural", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "SAN2007", "YAN2017" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/PRAS40-MTORC1.json" }, { "id": "RAG-MTORC1", "claim": "Rag GTPases recruits mTORC1", "source": { "name": "Rag GTPases", "entity": "rag-gtpases" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "recruits", "type": "recruitment", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": [ "human cells" ], "mechanism": "The active Rag dimer grabs Raptor and physically drags mTORC1 to the lysosomal surface. This is a relocation, not an activation - the kinase is moved to where its activator waits.", "mechanism_beginner": "The switched-on Rag proteins grab mTORC1 and drag it to the lysosome. This moves it into place; it doesn't turn it on by itself.", "context": null, "boundary": "Rag paralogues are not interchangeable: RagC/D sets substrate specificity downstream (RagD favors TFEB/TFE3 phosphorylation via tighter LAMTOR binding, while both Rags are involved for non-lysosomal substrates like S6K), and RagA/B sets the response to amino acid withdrawal (RagB-expressing cells keep mTORC1 lysosomal and active even when starved) — GOL2022.", "note": "The conceptual crux of the whole route: teach recruitment vs activation as two separate ideas.", "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "established", "consensus": "established" }, "evidence": { "kind": "Direct biochemical", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "SAN2008", "SAN2010", "LAW2018", "GOL2022" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/RAG-MTORC1.json" }, { "id": "RAPTOR-MTORC1", "claim": "Raptor required-for mTORC1", "source": { "name": "Raptor", "entity": "raptor" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "required-for", "type": "complex-assembly", "directness": "direct", "timescale": "constitutive", "compartment": "cytosol", "species": [ "mammalian cells" ], "mechanism": "Raptor is the subunit that defines mTORC1 and presents substrates to the kinase.", "mechanism_beginner": "Raptor is the piece that makes mTORC1 what it is, and hands it the targets it needs to act on.", "context": null, "boundary": null, "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Direct biochemical", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "HARA2002", "KIM2002" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/RAPTOR-MTORC1.json" }, { "id": "RHEB-MTORC1", "claim": "Rheb activates mTORC1", "source": { "name": "Rheb", "entity": "rheb" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "activates", "type": "allosteric-activation", "directness": "direct", "timescale": "seconds", "compartment": "lyso", "species": [ "mammalian cells" ], "mechanism": "GTP-loaded Rheb binds mTORC1 at the lysosome and physically re-shapes its active site into the working conformation.", "mechanism_beginner": "Switched-on Rheb docks onto mTORC1 and physically reshapes it into its working form – the actual \"on\" switch.", "context": "Rheb must be GTP-loaded and co-located with mTORC1. Rheb is also distributed across the ER and Golgi, and which pool supplies the activating Rheb is unresolved.", "boundary": null, "note": "Convergence point: the amino-acid route delivers mTORC1 here, the growth-factor route delivers Rheb. Both required.", "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Structural", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "INOK2003", "SAU2003", "YAN2017" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/RHEB-MTORC1.json" }, { "id": "SALR-MTORC1", "claim": "Spalt-related (Salr) inhibits mTORC1", "source": { "name": "Spalt-related (Salr)", "entity": "spalt-related-salr" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "inhibits", "type": "signal-relay", "directness": "unresolved", "timescale": "hours", "compartment": "cytosol", "species": [ "fly" ], "mechanism": "Salr suppresses mTORC1-driven growth downstream of stress signalling.", "mechanism_beginner": "This stress-induced protein suppresses mTORC1-driven growth once stress signalling turns it on.", "context": null, "boundary": null, "note": null, "contested": false, "confidence": { "mechanistic": "low", "human_relevance": "untested", "consensus": "emerging" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "A", "label": "Animal model" }, "supporting": [ "DEN2026" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/SALR-MTORC1.json" }, { "id": "TEM-MTORC1", "claim": "Temsirolimus inhibits mTORC1", "source": { "name": "Temsirolimus", "entity": "temsirolimus" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "inhibits", "type": "allosteric-inhibition", "directness": "indirect", "timescale": "hours", "compartment": "lyso", "species": [ "human" ], "mechanism": "Temsirolimus is the intravenous rapamycin analogue, and, to our knowledge, the first mTOR inhibitor to show an overall-survival benefit in a randomised trial.", "mechanism_beginner": "Temsirolimus is the IV version of rapamycin, and the first mTOR-blocking drug shown to help patients live longer in a controlled trial.", "context": null, "boundary": null, "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "established", "consensus": "established" }, "evidence": { "kind": "Pharmacological", "strongest": { "code": "H", "label": "Human study" }, "supporting": [ "HUD2007" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/TEM-MTORC1.json" }, { "id": "TSC-MTORC1", "claim": "TSC1/TSC2 inhibits mTORC1", "source": { "name": "TSC1/TSC2", "entity": "tsc1-tsc2" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "inhibits", "type": "signal-relay", "directness": "indirect", "timescale": "seconds", "compartment": "lyso", "species": [ "human", "mammalian cells" ], "mechanism": "The TSC complex is the pathway's main tumour suppressor. Inherit one broken copy and lesions grow wherever the second copy is lost - the clearest human evidence that mTORC1 activity drives tissue overgrowth.", "mechanism_beginner": "The TSC brake is the pathway's main tumour-suppressor. Inherit one broken copy of the gene and growths appear wherever the second copy is also lost. (This arrow skips a step for simplicity – TSC actually acts through Rheb first.)", "context": "Deliberately compressed: TSC acts on Rheb, never on mTORC1. Kept as one link so the overview reads cleanly.", "boundary": null, "note": "This is the edge that turns the biochemistry into a disease.", "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "established", "consensus": "established" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "H", "label": "Human study" }, "supporting": [ "TEE2003", "INOK2003", "KRU2010" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/TSC-MTORC1.json" }, { "id": "RAPA-MTORC1", "claim": "Rapamycin inhibits mTORC1", "source": { "name": "Rapamycin", "entity": "rapamycin" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "inhibits", "type": "allosteric-inhibition", "directness": "indirect", "timescale": "minutes", "compartment": "lyso", "species": [ "human cells" ], "mechanism": "Rapamycin inhibits mTORC1 only as a complex with FKBP12: the pair docks on the FRB domain beside the active site and blocks some substrates but not all, so S6K1 phosphorylation collapses while much of 4E-BP1 phosphorylation persists.", "mechanism_beginner": "Rapamycin, carried by its helper protein FKBP12, jams part of mTORC1 – it blocks some of what mTORC1 does but not all of it.", "context": null, "boundary": "Directness is graded indirect because the mechanism requires FKBP12, as for everolimus and the bi-sterics. Acute effect only; the chronic effect on mTORC2 is the separate RAPA-MTORC2 edge.", "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Structural", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "CHU1992", "BRO1994", "SAB1994", "SAB1995", "CHO1996" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/RAPA-MTORC1.json" }, { "id": "GLN-MTORC1-ARF1", "claim": "Glutamine activates mTORC1", "source": { "name": "Glutamine", "entity": "glutamine" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "activates", "type": "signal-relay", "directness": "unresolved", "timescale": "minutes", "compartment": "cytosol", "species": [ "mammalian cells" ], "mechanism": "A second and contested way in: JEW2015 reports that glutamine activates mTORC1 without the Rag GTPases, through Arf1, and that leucine and glutamine therefore do not share one entry point. If it holds, Rag-dependent lysosomal recruitment is not the only route to the kinase.", "mechanism_beginner": "Some experiments say glutamine has a second way in that skips the Rag proteins entirely. If that is right, the lysosome story is not the whole story – which is a big claim resting on thin evidence.", "context": null, "boundary": "Cell-type dependent and not uniformly reproduced across labs. The Rag-dependent route is the separate GLN-RAG edge; neither edge should be read as covering the other.", "note": null, "contested": true, "confidence": { "mechanistic": "low", "human_relevance": "untested", "consensus": "contested" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "JEW2015" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/GLN-MTORC1-ARF1.json" }, { "id": "LOAD-MTORC1", "claim": "Resistance exercise / mechanical load activates mTORC1", "source": { "name": "Resistance exercise / mechanical load", "entity": "resistance-exercise-mechanical-load" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "hours", "compartment": "lyso", "species": [ "human", "mouse" ], "mechanism": "Mechanical loading raises mTORC1 signalling in skeletal muscle. Rapamycin given to human volunteers blocks the contraction-induced increase in muscle protein synthesis, placing mTORC1 causally between the load and the response.", "mechanism_beginner": null, "context": null, "boundary": "Compressed: load reaches mTORC1 through several routes, only some of which need IGF-1, and the map draws one arrow. The human evidence establishes that mTORC1 is required, not which upstream route carries the signal.", "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "established", "consensus": "established" }, "evidence": { "kind": "Pharmacological", "strongest": { "code": "H", "label": "Human study" }, "supporting": [ "DRU2009", "BOD2001" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/LOAD-MTORC1.json" }, { "id": "CR-MTORC1", "claim": "Fasting / caloric restriction inhibits mTORC1", "source": { "name": "Fasting / caloric restriction", "entity": null }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "inhibits", "type": "signal-relay", "directness": "indirect", "timescale": "chronic", "compartment": "lyso", "species": [ "mouse" ], "mechanism": "Reduced nutrient and energy availability lowers mTORC1 signalling through the amino-acid and energy arms simultaneously – the sensors detect scarcity, and AMPK detects the falling energy charge.", "mechanism_beginner": null, "context": null, "boundary": "Supporting evidence here is thinner than the claim's reputation. ROM2016 (two-year caloric restriction is tolerable in non-obese humans) and MAT2017 (rhesus survival) were removed as support in the 2026-09-21 audit because neither measured mTORC1; they belong to the CR-LONGEVITY edge, not to this one. SOL2014 found macronutrient RATIO mattered more than total intake in mice, so 'caloric restriction' may be the wrong variable name.", "note": null, "contested": false, "confidence": { "mechanistic": "medium", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "A", "label": "Animal model" }, "supporting": [ "SOL2014" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/CR-MTORC1.json" }, { "id": "TORIN-MTORC1", "claim": "ATP-competitive mTOR inhibitors inhibits mTORC1", "source": { "name": "ATP-competitive mTOR inhibitors", "entity": "atp-competitive-mtor-inhibitors" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "inhibits", "type": "competitive-inhibition", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": [ "mammalian cells" ], "mechanism": "Occupies the mTOR active site in competition with ATP, so inhibition does not depend on obstructing substrate access and is not partial in the way rapalog inhibition is.", "mechanism_beginner": null, "context": null, "boundary": "Cell-line pharmacology. Clinical development of this class has been limited by toxicity attributed to simultaneous mTORC2 inhibition, which is precisely what the bi-steric design tries to avoid.", "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Pharmacological", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "THO2009", "FEL2009", "CHR2009" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/TORIN-MTORC1.json" }, { "id": "BISTERIC-MTORC1", "claim": "Bi-steric mTORC1-selective inhibitors inhibits mTORC1", "source": { "name": "Bi-steric mTORC1-selective inhibitors", "entity": "bi-steric-mtorc1-selective-inhibitors" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "inhibits", "type": "competitive-inhibition", "directness": "indirect", "timescale": "hours", "compartment": "lyso", "species": [ "human" ], "mechanism": "A bivalent molecule engages an FKBP12-dependent site and the active site simultaneously, producing deeper mTORC1 inhibition than a rapalog while sparing mTORC2.", "mechanism_beginner": null, "context": null, "boundary": "Phase 1 in advanced solid tumours – a safety and pharmacodynamic result, not an efficacy verdict. Directness is graded indirect because, like rapalogs, the mechanism requires FKBP12. Consensus is emerging: one trial, newest evidence in the corpus.", "note": null, "contested": false, "confidence": { "mechanistic": "medium", "human_relevance": "established", "consensus": "emerging" }, "evidence": { "kind": "Pharmacological", "strongest": { "code": "H", "label": "Human study" }, "supporting": [ "SCH2025" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/BISTERIC-MTORC1.json" }, { "id": "MITODYS-MTORC1", "claim": "Mitochondrial dysfunction inhibits mTORC1", "source": { "name": "Mitochondrial dysfunction", "entity": "mitochondrial-dysfunction" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "inhibits", "type": "signal-relay", "directness": "indirect", "timescale": "hours", "compartment": "cytosol", "species": [ "human cells" ], "mechanism": "Genome-wide CRISPR screens identify at least two parallel relays carrying mitochondrial dysfunction to mTORC1: AMPK, and the heme-regulated inhibitor HRI acting through the integrated stress response.", "mechanism_beginner": "When mitochondria – the cell's power plants – are damaged, at least two separate alarm signals reach mTORC1 to shut it down.", "context": null, "boundary": "CRISPR screening in cell lines; the relative weight of the AMPK and HRI arms in tissue is untested.", "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "emerging" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "CON2021" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MITODYS-MTORC1.json" }, { "id": "MTORC1-OXPHOS", "claim": "mTORC1 activates Oxidative phosphorylation", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "Oxidative phosphorylation", "entity": "oxidative-phosphorylation" }, "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "hours", "compartment": "mito", "species": [ "mammalian cells" ], "mechanism": "mTORC1 raises mitochondrial respiratory capacity through a YY1–PGC-1α transcriptional programme and through 4E-BP-dependent translation of respiratory components.", "mechanism_beginner": "mTORC1 boosts how much energy mitochondria can produce, through both gene activation and protein-building. One mouse experiment points the other way – removing mTORC1 from fat tissue RAISED respiration – so this direction is not settled in a living animal.", "context": null, "boundary": "Effect size varies strongly by tissue; the transcriptional and translational arms have not been cleanly separated in vivo. OVERLAP (audit 2026-09-04): this edge and MTORC1-MITO assert overlapping biology from overlapping citations (CUN2007, MOR2013) at different tiers and different consensus levels. Read them together; they are not independent support.", "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "CUN2007", "MOR2013" ], "conflicting": [ "POL2008" ] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-OXPHOS.json" }, { "id": "MTORC1-PGC1A", "claim": "mTORC1 activates PGC-1α / YY1", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "PGC-1α / YY1", "entity": "pgc-1alpha-yy1" }, "effect": "activates", "type": "binding", "directness": "direct", "timescale": "hours", "compartment": "nucleus", "species": [ "mammalian cells" ], "mechanism": "mTOR interacts with YY1 and is required for the YY1–PGC-1α complex to drive mitochondrial gene expression; rapamycin lowers both the transcripts and oxygen consumption.", "mechanism_beginner": "mTOR works together with a gene-activating team to switch on mitochondrial genes – a rare example of this pathway acting inside the nucleus rather than at the cell's outer edges. The direct interaction rests on a single study in this Atlas.", "context": null, "boundary": "Single-study support in this corpus for the direct interaction; the downstream respiratory phenotype is better replicated than the binding itself.", "note": null, "contested": false, "confidence": { "mechanistic": "high", "human_relevance": "plausible", "consensus": "emerging" }, "evidence": { "kind": "Direct biochemical", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "CUN2007" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-PGC1A.json" }, { "id": "MTORC1-ROS", "claim": "mTORC1 activates Reactive oxygen species", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "Reactive oxygen species", "entity": "reactive-oxygen-species" }, "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "days", "compartment": "mito", "species": [ "mouse" ], "mechanism": "Unleashing mTORC1 by deleting TSC1 drives quiescent haematopoietic stem cells into cycle, raises mitochondrial biogenesis and floods them with ROS; an antioxidant rescues self-renewal.", "mechanism_beginner": "Switching mTORC1 on too much pushes resting stem cells to start dividing and floods them with reactive, damaging molecules; giving them antioxidants restores their normal function.", "context": null, "boundary": "Demonstrated in haematopoietic stem cells, where quiescence is the baseline state. Cell types that are already cycling need not behave this way.", "note": null, "contested": false, "confidence": { "mechanistic": "medium", "human_relevance": "plausible", "consensus": "established" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "A", "label": "Animal model" }, "supporting": [ "CHE2008" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-ROS.json" }, { "id": "ROS-MTORC1", "claim": "Reactive oxygen species activates mTORC1", "source": { "name": "Reactive oxygen species", "entity": "reactive-oxygen-species" }, "target": { "name": "mTORC1", "entity": "mtorc1" }, "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "minutes", "compartment": "cytosol", "species": [ "cell line" ], "mechanism": "Oxidative stress activates a redox-sensitive PI3K–Akt–mTORC1–eIF4A cascade that selectively promotes cap-dependent translation of P-glycoprotein.", "mechanism_beginner": "Oxidative damage can itself switch on mTORC1 through a chain of signals, closing a feedback loop that can turn a brief stress into a lasting one.", "context": null, "boundary": "One cell-line study in a multidrug-resistance context; whether the loop runs in normal physiology at these ROS levels is untested.", "note": null, "contested": false, "confidence": { "mechanistic": "medium", "human_relevance": "untested", "consensus": "emerging" }, "evidence": { "kind": "Direct biochemical", "strongest": { "code": "M", "label": "Molecular — cells, biochemistry, structure" }, "supporting": [ "JIN2026" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/ROS-MTORC1.json" }, { "id": "MTORC1-HIF1A", "claim": "mTORC1 activates HIF-1α", "source": { "name": "mTORC1", "entity": "mtorc1" }, "target": { "name": "HIF-1α", "entity": "hif-1alpha" }, "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "hours", "compartment": "nucleus", "species": [ "mouse" ], "mechanism": "mTOR inhibition reverses Akt-driven prostate intraepithelial neoplasia partly through HIF-1-dependent pathways, placing HIF-1α downstream of mTORC1 in this setting.", "mechanism_beginner": "In one specific setting (prostate cells), mTORC1 turns on a factor usually associated with low oxygen – here it's mTORC1 driving it, not the other way around.", "context": null, "boundary": "Mouse prostate model with pharmacological mTOR inhibition; HIF-1α is one of several pathways implicated in the same experiment.", "note": null, "contested": false, "confidence": { "mechanistic": "medium", "human_relevance": "plausible", "consensus": "emerging" }, "evidence": { "kind": "Genetic epistasis", "strongest": { "code": "A", "label": "Animal model" }, "supporting": [ "MAJ2004" ], "conflicting": [] }, "reviewed": "2026-07-29", "updated": "2026-07-29", "api_url": "https://mtor-atlas.org/api/v1/relations/MTORC1-HIF1A.json" } ] } }