mTORC1
mTOR Complex 1; regulates protein synthesis, autophagy, and growth in response to nutrients and growth factors.
The growth decision itself.
Coincidence detector: nutrients supply location via the Rags, growth factors supply activation via Rheb. Neither alone is sufficient – the single most important idea in the pathway.
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 13 |
| A | Animal model | 17 |
| M | Molecular — cells, biochemistry, structure | 38 |
| PP | Preprint, not peer-reviewed | 2 |
| R | Review — secondary literature, not a new result | 10 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | H | 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 GIL2026 Low-dose rapamycin in ME/CFS patients reduced fatigue symptoms, modulated purine biosynthesis via IMP dehydrogenase inhibition, reduced microglial inflammatory responses, and improved mitochondrial energy metabolism in a phase-II observational pilot study. |
| 2026 | H | EVERolimus effectiveness after proGREssion on ENdocrine therapy plus CDK4/6 inhibitor for ER-positive/HER2-negative advanced breast cancer: EVERGREEN study MAR2026 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. |
| 2025 | H | The Bi-steric, mTORC1-Selective Inhibitor, RMC-5552, in Advanced Solid Tumors: A Phase 1 Trial SCH2025 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. |
| 2021 | H | Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials MAN2021 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. |
| 2019 | H | Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial CHU2019 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 but tangible human evidence for rapamycin as an anti-aging agent. |
| 2018 | H | TORC1 inhibition enhances immune function and reduces infections in the elderly MAN2018 The strongest human evidence that mTOR inhibition can rejuvenate a specific function of aging - immunity. In 264 elderly people, a low-dose combination that selectively hits TORC1 significantly reduced infections over the following year and boosted antiviral gene expression and flu-vaccine response. The follow-up to Mannick 2014. |
| 2018 | H | A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort KRA2018 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. |
| 2013 | H | Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial BIS2013 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. |
| 2013 | H | 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 FRA2013 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. |
| 2012 | H | Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer (BOLERO-2) BAS2012 A phase 3 RCT (n=724) proving mTOR matters in a common cancer. When hormone-therapy stops working in breast cancer, it's partly because mTOR switches on. 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. |
| 2011 | H | Everolimus for advanced pancreatic neuroendocrine tumors (RADIANT-3) YAO2011 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. |
| 2011 | H | Efficacy and safety of sirolimus in lymphangioleiomyomatosis (MILES) MCC2011 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. |
| 2009 | H | Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis DRU2009 Rapamycin given before resistance exercise completely blocked the normal post-exercise increase in human muscle protein synthesis. |
| 2026 | A | Spalt-related is an inhibitor of mTORC1-mediated growth activated by the integrated stress response DEN2026 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 independently of AKT-FoxO signaling. |
| 2026 | A | SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation. YAN2026 SLC15A3-mediated dipeptide import sustains mTORC1 activation in B cell lymphomas, enabling resistance to antimetabolite chemotherapy; inhibiting SLC15A3 or mTORC1 restores drug sensitivity. |
| 2026 | A | Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERRα-dependent manner BCH2026 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. |
| 2023 | A | A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer MEN2023 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. |
| 2014 | A | The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice SOL2014 Lifespan and cardiometabolic health were determined not by caloric intake but by the protein:carbohydrate ratio; low protein ratio suppressed hepatic mTOR. |
| 2013 | A | Late-life rapamycin treatment reverses age-related heart dysfunction FLY2013 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) mice for 3 months improved aged heart function, reversing age-related cardiac changes via anti-hypertrophic and anti-inflammatory effects. Started late, still worked. |
| 2012 | A | Rapamycin slows aging in mice WIL2012 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. |
| 2012 | A | Chronic inhibition of mTOR by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice HAL2012 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. |
| 2010 | A | Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster BJE2010 Feeding rapamycin extended fly lifespan through autophagy and reduced translation, and worked even in flies already on a lifespan-maximizing diet. |
| 2010 | A | Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease SPI2010 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. |
| 2010 | A | Molecular interplay between mTOR, amyloid-beta, and Tau: effects on cognitive impairments CAC2010 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 shown to be required for the effect. |
| 2009 | A | Rapamycin fed late in life extends lifespan in genetically heterogeneous mice HAR2009 Rapamycin fed from 600 days of age extended median lifespan by 9-14% in both sexes. |
| 2009 | A | Ribosomal protein S6 kinase 1 signaling regulates mammalian life span SEL2009 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. |
| 2009 | A | 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila ZID2009 Connected the dots between diet, mTOR, and lifespan. Dietary restriction lowers mTOR activity, which frees up 4E-BP - and here 4E-BP 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. |
| 2008 | A | TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species CHE2008 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. |
| 2004 | A | Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway KAP2004 Genetically reducing TOR pathway activity extends fruit fly lifespan, overlapping with dietary restriction effects. |
| 2004 | A | Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease RAV2004 Rapamycin-induced autophagy cleared toxic clumped proteins and improved symptoms in fly and mouse models of Huntington's disease. |
| 2026 | R | Biological limits of lifespan extension: evidence for a shift from pathway leverage to system-level buffering across species PIR2026 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. |
| 2026 | M | FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer ULL2026 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. |
| 2026 | M | mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency FAN2026 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. |
| 2026 | M | Firefox, a protein encoded by circular RNA circPVT1, is essential for MYC-driven oncogenesis TIW2026 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. |
| 2026 | M | mTORC1 inhibition upregulates CD20 and enhances anti-CD20 antibody efficacy in B-cell precursor acute lymphoblastic leukemia DAB2026 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. |
| 2026 | M | Fluorescent protein ticker tape (FPTT): Multiplexed recording of transcriptional dynamics in living cells and in vivo WANG2026C 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. |
| 2026 | M | CASTOR1 regulates humoral immune responses and contributes to the pathogenesis of systemic lupus erythematosus KUS2026 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. |
| 2025 | R | mTORC1, the maestro of cell metabolism and growth HE2025 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. |
| 2024 | M | mTORC1 activity oscillates throughout the cell cycle, promoting mitotic entry and differentially influencing autophagy induction JOS2024 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. |
| 2020 | R | mTOR at the nexus of nutrition, growth, ageing and disease LIU2020 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. |
| 2017 | R | mTOR Signaling in Growth, Metabolism, and Disease SAX2017 Comprehensive synthesis of mTORC1/mTORC2 signaling, growth regulation, metabolism, and disease relevance. |
| 2017 | M | SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway GU2017 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. |
| 2017 | M | Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex HOW2017 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. |
| 2016 | M | The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway CHA2016 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. |
| 2016 | R | The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging KEN2016 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. |
| 2015 | M | Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway SAX2015 Solves the crystal structure of Sestrin2 bound to leucine, revealing the molecular pocket that lets it act as mTORC1's dedicated leucine sensor. |
| 2015 | M | mTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation LAB2015 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. |
| 2013 | M | A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1 BAR2013 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. |
| 2013 | R | mTOR is a key modulator of ageing and age-related disease JOH2013 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. |
| 2012 | M | A unifying model for mTORC1-mediated regulation of mRNA translation THO2012 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 resistant to mTOR inhibition - naming them the master effectors. |
| 2012 | M | The translational landscape of mTOR signalling steers cancer initiation and metastasis HSI2012 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. |
| 2012 | M | MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB MAR2012 Pinned down the direct mTORC1-TFEB link: 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. |
| 2012 | R | mTOR signaling in growth control and disease LAP2012 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. |
| 2011 | M | mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase ZON2011 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. |
| 2011 | M | TFEB links autophagy to lysosomal biogenesis SET2011 Established TFEB as the single master switch that coordinates the WHOLE recycling program - it turns on both autophagosome and lysosome genes at once during starvation. This is the transcription factor that the mTORC1 pathway keeps switched off when nutrients are plentiful (mechanism pinned down by companion papers). |
| 2011 | M | AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 KIM2011 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. |
| 2010 | M | Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids SAN2010 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. |
| 2010 | R | Extending healthy life span--from yeast to humans FON2010 The landmark synthesis showing that eating less (dietary restriction) and dialing down nutrient-sensing pathways - mTOR and growth hormone/IGF-1 - extend healthy lifespan by the SAME conserved mechanisms from yeast to monkeys to humans. This is the paper that frames why mTOR sits at the crossroads of diet and aging. |
| 2009 | M | The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment DEL2009 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. |
| 2009 | M | DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival PET2009 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. |
| 2009 | M | Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy HOS2009 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. |
| 2009 | M | An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1 THO2009 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. |
| 2009 | M | Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2 FEL2009 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. |
| 2009 | M | Rapamycin decelerates cellular senescence DEM2009 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. |
| 2008 | M | The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1 SAN2008 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. |
| 2008 | M | AMPK phosphorylation of raptor mediates a metabolic checkpoint GWI2008 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. |
| 2007 | R | Defining the role of mTOR in cancer GUE2007 Comprehensive review arguing mTOR signaling is commonly deregulated in human cancers, laying out the rationale for rapalog trials in oncology. |
| 2007 | M | PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase SAN2007 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. |
| 2007 | M | mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex CUN2007 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. |
| 2006 | R | Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition BLA2006 Proposes the 'hyperfunction theory' of aging: TOR signaling, useful in youth, stays switched on into old age and becomes actively damaging. |
| 2006 | M | 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 GUE2006 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. |
| 2003 | M | Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb TEE2003 TSC1-TSC2 acts as a GTPase-activating protein (GAP) for Rheb; when TSC is inactive, Rheb accumulates in its active GTP-bound form and directly activates mTORC1. |
| 2003 | M | GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR KIM2003 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. |
| 2003 | M | TSC2 mediates cellular energy response to control cell growth and survival INO2003 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). |
| 2002 | M | TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling INO2002 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. |
| 2002 | M | mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery KIM2002 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. |
| 2002 | M | Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action HARA2002 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. |
| 2001 | M | Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways ROM2001 Shows IGF-1 drives muscle fiber hypertrophy specifically through the Akt-mTOR pathway, establishing mTORC1 as a central node for muscle growth signaling. |
| 2026 | PP | ER-Lysosome Cholesterol Exchange Regulates Lysosomal Motility Through mTOR-Dependent LAMTOR1 Phosphorylation MUT2026 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. |
| 2024 | PP | Targeting mTOR restores tau-induced metabolic, mitochondrial, and cognitive deficits in a tauopathy mouse model TAN2024 In mice engineered to overexpress a phosphomimetic tau variant, one week of rapamycin reversed tau-driven mitochondrial dysfunction and rescued cognitive performance 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. |