[ { "id": "4EBP1-EIF4E", "source": "4E-BP1", "source_id": "4e-bp1", "target": "eIF4E", "target_id": "eif4e", "effect": "inhibits", "type": "competitive-inhibition", "directness": "direct", "timescale": "seconds", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "Unphosphorylated 4E-BP1 clamps onto eIF4E and stops it assembling the cap-binding complex. mTORC1 phosphorylates 4E-BP1 to release that grip - so the brake on translation is released, not the accelerator pressed.", "mechanism_beginner": "Untagged 4E-BP1 clamps onto eIF4E and blocks it; mTORC1 tags 4E-BP1 to make it let go – releasing a brake, not pressing an accelerator.", "boundary": "Biochemical and cell-culture evidence (in vitro assays, mammalian and mouse cells, plus one review). It establishes the binding switch itself. It does not measure how much translation changes in a given tissue, in whole animals or in people.", "supporting_studies": "MAX2009;THO2012;SCH2003;FIN2002", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/4EBP1-EIF4E/" }, { "id": "4EBP1-LONGEVITY", "source": "4E-BP1", "source_id": "4e-bp1", "target": "Longevity", "target_id": "longevity", "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "fly", "mechanism": "Keeping 4E-BP active extends lifespan under dietary restriction in flies, by enhancing mitochondrial activity. One of the few places where a single downstream node, not the whole pathway, carries the lifespan effect.", "mechanism_beginner": "Keeping 4E-BP switched on extends lifespan in fruit flies on a restricted diet, by protecting their mitochondria.", "boundary": "Fly only, and only under dietary restriction - the effect was not seen on a full diet.", "supporting_studies": "ZID2009", "conflicting_studies": "", "human_relevance": "untested", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/4EBP1-LONGEVITY/" }, { "id": "4EBP1-MITO", "source": "4E-BP1", "source_id": "4e-bp1", "target": "Mitochondrial biogenesis", "target_id": "mitochondrial-biogenesis", "effect": "context-dependent", "type": "functional-consequence", "directness": "indirect", "timescale": "hours", "compartment": "mito", "species": "mammalian cells", "mechanism": "In mammalian cells (MOR2013) 4E-BPs repress translation of nucleus-encoded mitochondrial mRNAs, so mTORC1 raises mitochondrial output by inhibiting them; this arm is less rapamycin-sensitive than the S6K arm. In flies on dietary restriction (ZID2009) upregulated 4E-BP instead enhances translation of mitochondrial respiratory mRNAs. The sign depends on organism and nutrient state, so it is drawn as conditional.", "mechanism_beginner": "The 4E-BP branch helps set how many mitochondrial proteins get built. In mammalian cells it holds them back; in fruit flies on a restricted diet it boosts them, so the direction depends on the organism and the diet.", "boundary": "Scope: mammalian cells, MOR2013. The sign holds where 4E-BP represses translation of nuclear-encoded mitochondrial mRNAs (TFAM, mitochondrial ribosomal proteins), which is why this branch survives rapamycin better than the S6K arm. It does NOT hold universally across species and nutrient states: in Drosophila under dietary restriction, ZID2009 reports that 4E-BP ENHANCES mitochondrial activity, and that this is how it extends lifespan. Treat the mammalian-cell direction as scoped, not general.", "supporting_studies": "MOR2013", "conflicting_studies": "ZID2009", "human_relevance": "untested", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/4EBP1-MITO/" }, { "id": "AKT-PRAS40", "source": "Akt/PKB", "source_id": "akt-pkb", "target": "PRAS40", "target_id": "pras40", "effect": "inhibits", "type": "phosphorylation", "directness": "direct", "timescale": "seconds", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "Akt phosphorylates PRAS40, which then gets sequestered away from mTORC1 - a second, parallel way insulin lifts a brake.", "mechanism_beginner": "Akt tags PRAS40, which then gets pulled away from mTORC1 – a second way insulin releases a brake.", "boundary": "Three 2007 studies in cultured mammalian cells. Not tested in whole animals or in people, and how much this branch adds beside Akt's route through TSC2 is not measured.", "supporting_studies": "SAN2007;VAN2007;OSH2007", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/AKT-PRAS40/" }, { "id": "AKT-TSC", "source": "Akt/PKB", "source_id": "akt-pkb", "target": "TSC1/TSC2", "target_id": "tsc1-tsc2", "effect": "inhibits", "type": "phosphorylation", "directness": "direct", "timescale": "seconds", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "Akt phosphorylates TSC2, disabling the complex. Growth-factor signalling works by removing a brake, not by pressing an accelerator.", "mechanism_beginner": "Akt tags TSC2 to disable it. Growth signals work by releasing a brake, not by pressing a gas pedal.", "boundary": "In mouse liver, Akt phosphorylation of TSC2 is the main route by which insulin switches on mTORC1, but feeding activates hepatic mTORC1 without it; that response needs dietary protein instead (KAL2026). The biochemical mechanism itself was shown in cultured human cells (INO2002).", "supporting_studies": "INO2002;KAL2026;LAP2026;MAN2002;POT2002", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/AKT-TSC/" }, { "id": "AMPK-MITOPHAGY", "source": "AMPK", "source_id": "ampk", "target": "Mitophagy", "target_id": "mitophagy", "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "hours", "compartment": "mito", "species": "mammalian cells, C. elegans, mouse", "mechanism": "AMPK can promote the clearance of damaged mitochondria, in part by phosphorylating ULK1: cells whose ULK1 cannot be phosphorylated by AMPK show defective mitophagy under starvation. How much AMPK contributes depends on the cell type and on the kind of energy stress.", "mechanism_beginner": "The cell's energy sensor can help clear out damaged mitochondria, partly by switching on an autophagy starter kinase. How much it matters depends on the cell and on the kind of stress.", "boundary": "Two studies of different kinds: EGA2010 (cells and C. elegans, AMPK-site mutant of ULK1) and ZHU2026 (mouse toxicology model, where LKB1/AMPK loss also went with mitochondrial DNA leakage and liver inflammation; that downstream link is shown only there). The upstream step is disputed: PAR2023 (Park, Lee and Kim, Nat Commun 2023, PMID 37225695, in this corpus) reports that under glucose starvation and mitochondrial energy stress AMPK restrains ULK1 activation and autophagy induction; see AMPK-ULK1, where it is recorded as the conflicting study. PAR2023 measured ULK1 activity, bulk autophagy and aggrephagy rather than mitophagy itself, so it bears on the upstream step and not directly on the mitophagy readout here.", "supporting_studies": "EGA2010;ZHU2026", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/AMPK-MITOPHAGY/" }, { "id": "AMPK-MTORC1", "source": "AMPK", "source_id": "ampk", "target": "mTORC1", "target_id": "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.", "boundary": "Cell biochemistry in human and mouse cells (GWI2008) plus one study in aged mice (YAN2026B). Direct Raptor phosphorylation is shown in cells; how much it adds beside the TSC route in living tissue, and in people, is not shown.", "supporting_studies": "GWI2008;YAN2026B", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/AMPK-MTORC1/" }, { "id": "AMPK-TSC", "source": "AMPK", "source_id": "ampk", "target": "TSC1/TSC2", "target_id": "tsc1-tsc2", "effect": "activates", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "When energy runs low, AMPK phosphorylates TSC2 and strengthens the brake on Rheb.", "mechanism_beginner": "When energy is low, AMPK tags TSC2 and makes the brake on Rheb stronger.", "boundary": "Mammalian cell biochemistry (INO2003, INO2006). Not tested in whole animals or in people by the cited studies.", "supporting_studies": "INO2003;INO2006;BUD2008", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/AMPK-TSC/" }, { "id": "AMPK-ULK1", "source": "AMPK", "source_id": "ampk", "target": "ULK1", "target_id": "ulk1", "effect": "activates", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "AMPK phosphorylates ULK1 at sites distinct from mTORC1's inhibitory S757 site. The classic reading is that low energy therefore switches autophagy on directly, not only by releasing the mTORC1 brake; that reading is now disputed (see boundary).", "mechanism_beginner": "AMPK also tags ULK1 directly. The long-standing view is that this switches cleanup on; newer work suggests that during a sharp energy crisis AMPK instead holds ULK1 back while protecting it, so the direction is now debated.", "boundary": "Contested direction. EGA2010 and KIM2011 report activating phosphorylation. PAR2023 (Park, Lee and Kim, Nat Commun 2023, PMID 37225695) reports that under glucose starvation and mitochondrial energy stress AMPK inhibits ULK1 activation and autophagy induction while protecting the ULK1 machinery from degradation. Which effect dominates appears to depend on the kind and depth of the energy stress.", "supporting_studies": "EGA2010;KIM2011;DAL2016", "conflicting_studies": "PAR2023", "human_relevance": "plausible", "consensus": "contested", "curation_status": "Contested", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/AMPK-ULK1/" }, { "id": "ARG-CASTOR1", "source": "Arginine", "source_id": "arginine", "target": "CASTOR1", "target_id": "castor1", "effect": "inhibits", "type": "binding", "directness": "direct", "timescale": "seconds", "compartment": "cytosol", "species": "human cells", "mechanism": "Cytosolic arginine binds CASTOR1 and breaks its grip on GATOR2 - the same trick as leucine/Sestrin2, but for a different amino acid.", "mechanism_beginner": "Arginine sticks to CASTOR1 the same way leucine sticks to Sestrin2 – the same trick, for a different amino acid.", "boundary": "Human cells and structural work (CHA2016, SAX2016, VAL2025, JAN2025). The 2025 structures show how arginine binding changes CASTOR1 so that it lets go of GATOR2. Shows how arginine is sensed in cells and in purified proteins. Whether this sensor matters for arginine supply in a whole animal or a person is not tested here.", "supporting_studies": "CHA2016;SAX2016;VAL2025;JAN2025", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/ARG-CASTOR1/" }, { "id": "CASTOR1-GATOR2", "source": "CASTOR1", "source_id": "castor1", "target": "GATOR2", "target_id": "gator2", "effect": "inhibits", "type": "binding", "directness": "direct", "timescale": "seconds", "compartment": "cytosol", "species": "human cells", "mechanism": "Arginine-free CASTOR1 binds GATOR2 and inhibits it, so the pathway stays off until arginine is available.", "mechanism_beginner": "Without arginine, CASTOR1 holds onto GATOR2 and keeps the pathway switched off.", "boundary": "Human cell biochemistry and structure (CHA2016, SAX2016), plus 2025 cryo-EM structures of CASTOR1 bound to GATOR2 (VAL2025, JAN2025). The binding is shown in cells and in purified proteins; there is no whole-animal or human test in the cited studies.", "supporting_studies": "CHA2016;SAX2016;VAL2025;JAN2025", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/CASTOR1-GATOR2/" }, { "id": "DEPTOR-MTOR", "source": "DEPTOR", "source_id": "deptor", "target": "mTOR", "target_id": "mtor", "effect": "inhibits", "type": "binding", "directness": "direct", "timescale": "constitutive", "compartment": "cytosol", "species": "human cells", "mechanism": "DEPTOR sits on mTOR and damps both complexes; myeloma cells overexpress it and depend on that damping.", "mechanism_beginner": "DEPTOR sits on mTOR and dampens both complexes; some cancer cells (myeloma) make extra DEPTOR and come to depend on that damping.", "boundary": "One study in human cancer cell lines (PET2009), centred on myeloma. Not replicated in this corpus and not shown in other cell types, in animals or in patients.", "supporting_studies": "PET2009", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/DEPTOR-MTOR/" }, { "id": "EIF4E-TRANSL", "source": "eIF4E", "source_id": "eif4e", "target": "Protein synthesis", "target_id": "protein-synthesis", "effect": "activates", "type": "functional-consequence", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "Free eIF4E recruits the ribosome to the mRNA cap. This is the step that actually turns a growth signal into new protein.", "mechanism_beginner": "Freed eIF4E brings the ribosome to the mRNA – the step that actually turns a growth signal into new protein.", "boundary": "Biochemical and cell-based evidence (mouse cells with ribosome profiling, mouse models with human prostate cancer data in one study) plus a review. How much a given tissue depends on eIF4E-driven translation is not settled by these sources.", "supporting_studies": "MAX2009;HSI2012;THO2012", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/EIF4E-TRANSL/" }, { "id": "ERK-TSC", "source": "ERK / RSK (MAPK)", "source_id": "erk-rsk-mapk", "target": "TSC1/TSC2", "target_id": "tsc1-tsc2", "effect": "inhibits", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "ERK phosphorylates TSC2 and inactivates the TSC complex, so Ras-MAPK growth signalling converges on the same brake that Akt releases. This is the third upstream arm alongside PI3K/Akt and AMPK, and clinically it is a route to mTORC1 activation that PI3K inhibitors do not close.", "mechanism_beginner": "A separate growth pathway also disables the TSC brake – a third route into mTORC1 that drugs blocking only PI3K/Akt can't shut down.", "boundary": "Single-study edge in this corpus; Roux 2004 describes the parallel RSK arm and is not yet held.", "supporting_studies": "MA2005", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/ERK-TSC/" }, { "id": "EVE-BREAST", "source": "Everolimus", "source_id": "everolimus", "target": "Breast cancer", "target_id": "breast-cancer", "effect": "inhibits", "type": "clinical-outcome", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "human", "mechanism": "BOLERO-2: adding everolimus to hormone therapy roughly doubled progression-free survival in hormone-receptor-positive advanced breast cancer.", "mechanism_beginner": "Adding everolimus to hormone therapy roughly doubled the time before certain advanced breast cancers got worse.", "boundary": "Progression-free survival, in combination with exemestane - overall survival was not significantly improved.", "supporting_studies": "BAS2012;PIC2014", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/EVE-BREAST/" }, { "id": "EVE-IMMUNE", "source": "Everolimus", "source_id": "everolimus", "target": "Immune function", "target_id": "immune-function", "effect": "context-dependent", "type": "clinical-outcome", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "human", "mechanism": "Dose and schedule set the direction here, not the target. Intermittent low-dose everolimus improved influenza vaccine responses in older adults (MAN2014), while continuous transplant-level dosing of the same drug class is immunosuppressive. A larger phase 3 trial of a different mTOR inhibitor, RTB101 (an ATP-competitive PI3K/mTOR inhibitor), did not reduce respiratory illness (MAN2021), although it still switched on antiviral genes. The edge carries a conditional sign because the supported claim is regimen-specific rather than a net benefit to immune function.", "mechanism_beginner": "At a low, occasional dose, an mTOR-blocking drug helped older people respond better to a flu vaccine. At the high continuous dose used after transplants, mTOR inhibitors damp the immune system down. A larger phase 3 trial of a DIFFERENT mTOR inhibitor (RTB101, which blocks the kinase itself rather than working like rapamycin) found no reduction in respiratory illness – so what this arrow means depends on the dose, the schedule and the drug.", "boundary": "Dose-dependent and duration-dependent: this is not the immunosuppressive regimen. The corpus supports an improved vaccine response under one regimen, not improved immune function in general. MAN2021 is recorded as conflicting for two reasons, and the earlier wording here got the first one wrong. Its phase 3 arm tested RTB101 monotherapy - a different drug, ATP-competitive rather than rapamycin-like - and found no reduction in clinically symptomatic respiratory illness. But the same paper's phase 2b part 2 DID include everolimus: 115 participants were randomised to RTB101 10 mg plus everolimus 0.1 mg daily, and that arm did not reach significance in the first prespecified analysis of the primary endpoint. So the randomised everolimus-containing evidence in MAN2021 points away from benefit as well, at a different dose and in a different population from MAN2014, rather than being irrelevant to this edge. Note also that the positive RTB101 10 mg result in that paper comes from a second prespecified analysis pooling parts 1 and 2, not from the first.", "supporting_studies": "MAN2014", "conflicting_studies": "MAN2021", "human_relevance": "established", "consensus": "contested", "curation_status": "Contested", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/EVE-IMMUNE/" }, { "id": "EVE-LAM", "source": "Everolimus", "source_id": "everolimus", "target": "Renal angiomyolipoma", "target_id": "renal-angiomyolipoma", "effect": "inhibits", "type": "clinical-outcome", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "human", "mechanism": "EXIST-2 tested everolimus against renal angiomyolipoma in patients with tuberous sclerosis or sporadic LAM, and shrank those lesions by >=50% in 42% versus 0% on placebo.", "mechanism_beginner": "In another trial, everolimus shrank kidney growths in patients with tuberous sclerosis or a related lung disease, working in 42% of patients versus 0% on placebo.", "boundary": "Scope: the endpoint was the kidney lesion, not LAM lung disease, which is why this arrow lands on the angiomyolipoma and not on LAM. The evidence that mTOR inhibition treats the lung disease itself is the MILES trial with sirolimus - see the RAPA-LAM edge.", "supporting_studies": "BIS2013;GAO2026B", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/EVE-LAM/" }, { "id": "EVE-MTORC1", "source": "Everolimus", "source_id": "everolimus", "target": "mTORC1", "target_id": "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.", "boundary": "Clinical evidence from phase 3 trials of everolimus in specific diseases (kidney cancer, breast cancer, pancreatic neuroendocrine tumours, TSC and LAM) at the doses used for those diseases. It does not speak to low-dose use in healthy ageing.", "supporting_studies": "MOT2008;YAO2011;BAS2012;KRU2010;BIS2013;IYE2012;MEI2008", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/EVE-MTORC1/" }, { "id": "EVE-PNET", "source": "Everolimus", "source_id": "everolimus", "target": "Pancreatic neuroendocrine tumor", "target_id": "pancreatic-neuroendocrine-tumor", "effect": "inhibits", "type": "clinical-outcome", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "human", "mechanism": "RADIANT-3: progression-free survival more than doubled in advanced pancreatic neuroendocrine tumours.", "mechanism_beginner": "In a trial, everolimus more than doubled the time before advanced pancreatic neuroendocrine tumours got worse.", "boundary": "One phase 3 trial (RADIANT-3, n=410) in advanced pancreatic neuroendocrine tumours. The result applies to that disease, stage and dose, and it is a progression-free survival result.", "supporting_studies": "YAO2011", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/EVE-PNET/" }, { "id": "EVE-RCC", "source": "Everolimus", "source_id": "everolimus", "target": "Renal cell carcinoma (RCC)", "target_id": "renal-cell-carcinoma-rcc", "effect": "inhibits", "type": "clinical-outcome", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "human", "mechanism": "RECORD-1: everolimus roughly doubled progression-free survival after other targeted therapy failed.", "mechanism_beginner": "In a clinical trial, everolimus roughly doubled the time before advanced kidney cancer got worse, after other treatments had stopped working.", "boundary": "Second-line setting, after VEGF-targeted therapy - not first-line.", "supporting_studies": "MOT2008", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/EVE-RCC/" }, { "id": "EVE-TSC", "source": "Everolimus", "source_id": "everolimus", "target": "Tuberous sclerosis complex", "target_id": "tuberous-sclerosis-complex", "effect": "inhibits", "type": "clinical-outcome", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "human", "mechanism": "EXIST trials: everolimus shrank the brain tumours (SEGA) and kidney lesions of tuberous sclerosis - treating the pathway the mutation switches on, rather than a downstream symptom. The gene defect itself remains.", "mechanism_beginner": "In patients with the genetic disease tuberous sclerosis, everolimus shrank both brain and kidney tumours. It works one step downstream of the mutation: it replaces the brake the mutation removed, so the tumours shrink while the drug is given and regrow when it stops. The mutation itself is untouched.", "boundary": "Lesions regrow when the drug is stopped - this is suppression, not cure.", "supporting_studies": "KRU2010;BIS2013;GAO2026B", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/EVE-TSC/" }, { "id": "FKBP12-MTORC1", "source": "FKBP12", "source_id": "fkbp12", "target": "mTORC1", "target_id": "mtorc1", "effect": "binds", "type": "binding", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": "rat and bovine brain (protein purification); rodent and T cells; cryo-EM of human mTORC1", "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.", "boundary": "Biochemical and structural work on rat and bovine brain extracts, rodent and T cells, and a cryo-EM structure of human mTORC1. It defines how the drug-bound complex docks. FKBP12 alone does not inhibit mTORC1, and effects in whole animals are carried by the rapamycin edges, not this one.", "supporting_studies": "SAB1994;SAB1995;CHU1992;BRO1994;AYL2015;YIP2010", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/FKBP12-MTORC1/" }, { "id": "FLCN-RAG", "source": "FLCN / FNIP1/2", "source_id": "flcn-fnip1-2", "target": "Rag GTPases", "target_id": "rag-gtpases", "effect": "activates", "type": "gap-activity", "directness": "direct", "timescale": "seconds", "compartment": "lyso", "species": "human cells", "mechanism": "FLCN-FNIP is the GAP for RagC/D: it makes RagC/D hydrolyse its bound GTP, which puts that half of the Rag dimer into the GDP-bound state. 'Activates' on this edge means exactly that: FLCN-FNIP sets the nucleotide state of RagC/D. It does not switch on every Rag. The dimer can hold mTORC1 only when both halves are in the right state (RagA/B GTP-bound and RagC/D GDP-bound), and other factors act on the RagA/B half. Its direct effect is SUBSTRATE-SPECIFIC: it gates TFEB and TFE3 phosphorylation, while canonical outputs like S6K1 and 4E-BP1 largely carry on without it in the short term.", "mechanism_beginner": "FLCN helps set the other half of the Rag pair (RagC/D) into its working shape: it makes RagC/D break down its bound GTP, the cell's energy-carrying molecule. So 'activates' here means it sets the state of that one half, not that it switches on every Rag. Its direct job is mainly to control one group of outputs (TFEB and TFE3) rather than the whole pathway, but in kidney and lung, losing FLCN can still end up over-activating mTORC1 through a feedback loop.", "boundary": "FLCN's direct effect is substrate-specific: losing it blocks mTORC1 phosphorylation of TFEB/TFE3 while leaving S6K1 and 4E-BP1 largely intact in the short term (NAP2020). That is not the whole of Birt-Hogg-Dube, though. Constitutively active TFEB/TFE3 drive a feedback loop that hyperactivates mTORC1, and in kidney and lung that mTORC1 hyperactivation is itself a key driver of cyst and tumour formation (Di Malta 2023, EMBO Mol Med, PMID 36987696; Ferniani 2026, FER2026 in corpus; Cao 2026, JCI, PMID 41697734, 3 BHD patient lungs + mouse). So the regulation is tissue- and time-dependent, not a flat absence of hyperactivation.", "supporting_studies": "LAW2019;SHE2019;NAP2020", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/FLCN-RAG/" }, { "id": "GATOR1-RAG", "source": "GATOR1", "source_id": "gator1", "target": "Rag GTPases", "target_id": "rag-gtpases", "effect": "inhibits", "type": "gap-activity", "directness": "direct", "timescale": "seconds", "compartment": "lyso", "species": "human cells", "mechanism": "GATOR1 acts as a GAP: it forces RagA/B to hydrolyse GTP, flipping the Rag heterodimer into the inactive shape that cannot hold mTORC1.", "mechanism_beginner": "GATOR1 forces the Rag proteins into their \"off\" shape, so they can no longer hold onto mTORC1.", "boundary": "Human cell biochemistry with cancer genomics (BAR2013) and a cryo-EM structure (SHE2018). GAP activity is shown on purified and cellular Rags; the cited studies do not test it in whole animals or in people.", "supporting_studies": "BAR2013;SHE2018", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/GATOR1-RAG/" }, { "id": "GATOR2-GATOR1", "source": "GATOR2", "source_id": "gator2", "target": "GATOR1", "target_id": "gator1", "effect": "inhibits", "type": "binding", "directness": "direct", "timescale": "seconds", "compartment": "lyso", "species": "human cells", "mechanism": "Released GATOR2 suppresses GATOR1 - a double negative. Two brakes in series is why the sensors can flip mTORC1 on so sharply.", "mechanism_beginner": "Everyone agrees GATOR2 holds GATOR1 back when amino acids are around. Exactly how it does it is not settled by the work this Atlas holds, and the gap is left visible on purpose.", "boundary": "The epistasis is solid. VAL2022 resolved GATOR2's architecture by cryo-EM - a 1.1 MDa cage - and mapped where the sensors dock, but exactly how GATOR2 suppresses GATOR1's GAP activity is still not settled.", "supporting_studies": "BAR2013;PAR2014;VAL2022", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/GATOR2-GATOR1/" }, { "id": "GLN-RAG", "source": "Glutamine", "source_id": "glutamine", "target": "Rag GTPases", "target_id": "rag-gtpases", "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "minutes", "compartment": "lyso", "species": "human cells", "mechanism": "Glutamine burned through glutaminolysis raises alpha-ketoglutarate, which promotes RagB GTP loading and mTORC1 translocation to the lysosome. This edge asserts the Rag-dependent route only.", "mechanism_beginner": "Glutamine can switch on mTORC1 partly just by being burned for fuel: burning it makes a molecule that helps the Rag proteins pull mTORC1 to the lysosome.", "boundary": "Cell-type dependent, and deliberately narrow: the separate claim that glutamine can reach mTORC1 without the Rags is carried by its own edge rather than folded in here.", "supporting_studies": "DUR2012", "conflicting_studies": "", "human_relevance": "untested", "consensus": "emerging", "curation_status": "Contested", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/GLN-RAG/" }, { "id": "GRB10-IGF1", "source": "Grb10", "source_id": "grb10", "target": "Growth hormone / IGF-1 axis", "target_id": "growth-hormone-igf-1-axis", "effect": "inhibits", "type": "signal-relay", "directness": "indirect", "timescale": "hours", "compartment": "pm", "species": "mammalian cells", "mechanism": "Stabilised Grb10 damps insulin/IGF-1 receptor signalling. This is one of two feedback arms behind the paradox that blocking mTORC1 raises Akt activity; the other is the S6K1-IRS-1 loop.", "mechanism_beginner": "Grb10 dampens insulin/IGF-1 signalling – which is why blocking mTOR can paradoxically make Akt more active.", "boundary": "Two mammalian cell studies (HSU2011, YUX2011). The feedback is shown in cultured cells. Its size in living tissue and in people, and how it compares with the S6K1-IRS-1 loop, are not measured.", "supporting_studies": "HSU2011;YUX2011", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/GRB10-IGF1/" }, { "id": "HYPOXIA-REDD1", "source": "Hypoxia", "source_id": "hypoxia", "target": "REDD1 (DDIT4)", "target_id": "redd1-ddit4", "effect": "activates", "type": "transcriptional", "directness": "indirect", "timescale": "hours", "compartment": "nucleus", "species": "mammalian cells", "mechanism": "Low oxygen induces REDD1 transcriptionally over hours, slower than AMPK. REDD1 protein is short-lived, so the signal lasts only as long as hypoxia keeps the gene switched on.", "mechanism_beginner": "Low oxygen switches on the gene for REDD1 over hours - slower than AMPK. REDD1 protein is short-lived, so the signal lasts only while low oxygen keeps the gene on.", "boundary": "Single-study edge in this corpus.", "supporting_studies": "BRU2004", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/HYPOXIA-REDD1/" }, { "id": "IGF1-PI3K", "source": "Growth hormone / IGF-1 axis", "source_id": "growth-hormone-igf-1-axis", "target": "PI3K", "target_id": "pi3k", "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "seconds", "compartment": "pm", "species": "mammalian cells", "mechanism": "IGF-1 docks on the IGF-1 receptor, which recruits IRS proteins and switches on PI3K to make the lipid messenger PIP3. Growth hormone does not use this receptor: it signals through its own receptor and JAK2/STAT5b, and reaches this arm mostly by inducing hepatic IGF-1. The node is drawn as one axis because the Atlas's lifespan evidence comes from interventions that lower the whole axis at once.", "mechanism_beginner": "IGF-1 latches onto its own receptor and switches on PI3K, which builds a signalling lipid. Growth hormone works one step further back: it does not land on this receptor itself, it makes the liver release IGF-1, which then does. Insulin takes a receptor of its own into the same arm.", "boundary": "Compressed on purpose: growth hormone and IGF-1 are one node here, but they are not one molecule and they do not share a receptor. GH signals GHR-JAK2-STAT5b and acts on this arm largely by inducing hepatic IGF-1; patients with a homozygous STAT5b mutation have GH insensitivity with low IGF-1 and low IGFBP-3 (Kofoed 2003, PMID 13679528, outside this corpus). The dwarf-mouse lifespan evidence on this axis lowers GH and IGF-1 together, so it does not tell the two apart. Insulin enters the same arm through its own receptor and is drawn separately (INS-PI3K).", "supporting_studies": "CAN2002;ROM2001", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/IGF1-PI3K/" }, { "id": "IRS1-PI3K", "source": "IRS-1 / IRS-2", "source_id": "irs-1-irs-2", "target": "PI3K", "target_id": "pi3k", "effect": "activates", "type": "recruitment", "directness": "direct", "timescale": "seconds", "compartment": "pm", "species": "mammalian cells", "mechanism": "IRS proteins are the adaptors that carry the signal from the insulin/IGF-1 receptor to PI3K. Deplete them and the receptor is still there but the wire is cut.", "mechanism_beginner": "IRS proteins carry the signal from the insulin receptor to PI3K; without them, the receptor is still there but the wire connecting it is cut.", "boundary": "Cell studies (TSC1/TSC2-null mouse cells and human cells) plus a review. An adaptor relationship shown in cultured cells; differences between IRS-1 and IRS-2 by tissue are not resolved by these sources.", "supporting_studies": "HAR2004;CAN2002", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/IRS1-PI3K/" }, { "id": "ISR-SALR", "source": "Integrated stress response", "source_id": "integrated-stress-response", "target": "Spalt-related (Salr)", "target_id": "spalt-related-salr", "effect": "activates", "type": "transcriptional", "directness": "indirect", "timescale": "hours", "compartment": "nucleus", "species": "fly", "mechanism": "The integrated stress response switches on Salr, a growth inhibitor - a route into mTORC1 that bypasses TSC and AMPK entirely.", "mechanism_beginner": "The cell's stress-response system switches on a growth-blocking gene – a route to shutting down mTORC1 that skips right past TSC and AMPK.", "boundary": "Fly only, and newly reported.", "supporting_studies": "DEN2026", "conflicting_studies": "", "human_relevance": "untested", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/ISR-SALR/" }, { "id": "KICSTOR-GATOR1", "source": "KICSTOR", "source_id": "kicstor", "target": "GATOR1", "target_id": "gator1", "effect": "required-for", "type": "recruitment", "directness": "direct", "timescale": "constitutive", "compartment": "lyso", "species": "human cells", "mechanism": "KICSTOR is the dock that holds GATOR1 on the lysosomal surface. Without it, GATOR1 cannot reach its target and nutrient control of mTORC1 is lost.", "mechanism_beginner": "KICSTOR works like a docking clamp that holds GATOR1 in place on the lysosome; without it, GATOR1 can't reach its target.", "boundary": "Mammalian cell genetics (WOL2017, PEN2017). The dependency is shown in cultured cells; whole-animal and human relevance are not tested in the cited work.", "supporting_studies": "WOL2017;PEN2017", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/KICSTOR-GATOR1/" }, { "id": "LARS-RAG", "source": "LARS (leucyl-tRNA synthetase)", "source_id": "lars-leucyl-trna-synthetase", "target": "Rag GTPases", "target_id": "rag-gtpases", "effect": "activates", "type": "gap-activity", "directness": "unresolved", "timescale": "seconds", "compartment": "lyso", "species": "human cells", "mechanism": "In this model LARS acts as a GAP for RagD, doing for the RagC/D half what FLCN does - an alternative route from leucine to the Rags.", "mechanism_beginner": "In that model, this enzyme flips the other Rag protein into its working shape – an alternative route from leucine to the Rags.", "boundary": "Human cell biochemistry only, and cell-type dependence was never mapped. The reaction it claims - GAP activity on the RagC/D half - is the same reaction this Atlas assigns to FLCN, and the two assignments have never been reconciled head-to-head. Read together with LEU-LARS: if the upstream leucine-sensing claim does not hold, this edge loses its input.", "supporting_studies": "HAN2012", "conflicting_studies": "", "human_relevance": "untested", "consensus": "contested", "curation_status": "Contested", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/LARS-RAG/" }, { "id": "LEU-LARS", "source": "Leucine", "source_id": "leucine", "target": "LARS (leucyl-tRNA synthetase)", "target_id": "lars-leucyl-trna-synthetase", "effect": "activates", "type": "binding", "directness": "unresolved", "timescale": "seconds", "compartment": "cytosol", "species": "human cells", "mechanism": "A competing model: the enzyme that loads leucine onto tRNA doubles as the leucine sensor, binding free leucine directly.", "mechanism_beginner": "One competing idea: the enzyme that loads leucine onto its transport molecule for protein-building doubles as the leucine sensor.", "boundary": "Proposed before the Sestrin2 model and never cleanly reconciled with it.", "supporting_studies": "HAN2012", "conflicting_studies": "", "human_relevance": "untested", "consensus": "contested", "curation_status": "Contested", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/LEU-LARS/" }, { "id": "LEU-SESN2", "source": "Leucine", "source_id": "leucine", "target": "Sestrin2", "target_id": "sestrin2", "effect": "inhibits", "type": "binding", "directness": "direct", "timescale": "seconds", "compartment": "cytosol", "species": "human cells; rat", "mechanism": "Leucine binds a pocket inside Sestrin2 with roughly 20 uM affinity - close to the concentration at which cells actually feel leucine coming and going. The bound sensor can no longer hold GATOR2, so leucine effectively switches the brake off.", "mechanism_beginner": "Leucine sticks to a pocket inside Sestrin2 and makes it let go of the next protein in line – that's how the cell notices leucine is around.", "boundary": "Affinity was measured in vitro; whether the same 20 uM setpoint holds in tissues with different leucine transport is untested. VAL2025 (2025 cryo-EM) shows the leucine-induced shape change in Sestrin2 that releases GATOR2, again in purified protein and cultured cells. SHIM2026 is a 2026 rat study (dexamethasone-induced muscle atrophy, not an ageing model) with human myotubes; it tests a leucine-mimetic prodrug and supports Sestrin2-dependent mTORC1 activation, not the 20 uM leucine setpoint.", "supporting_studies": "WOL2015;SAX2015;SHIM2026;VAL2025", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/LEU-SESN2/" }, { "id": "LKB1-AMPK", "source": "LKB1 (STK11)", "source_id": "lkb1-stk11", "target": "AMPK", "target_id": "ampk", "effect": "activates", "type": "phosphorylation", "directness": "direct", "timescale": "seconds", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "LKB1 is the main kinase that primes AMPK, phosphorylating AMPK-alpha directly on Thr172; in LKB1-null cells AMPK no longer responds to energy stress (SHW2004). It is not the only upstream kinase: CaMKK2 phosphorylates the same site when calcium rises, and LKB1-deficient cells keep some basal AMPK activity (Hawley 2005, PMID 16054095; Woods 2005, PMID 16054096; outside this corpus).", "mechanism_beginner": "LKB1 is the main switch that turns AMPK on when energy runs low; in cells without it, AMPK no longer responds to low energy. A second kinase can still switch AMPK on when calcium rises, so AMPK is not completely silent.", "boundary": "Canonical step, established in LKB1-null cells and in vitro kinase assays (SHW2004). Coded M – molecular – because that is what the supporting evidence is: cell and in vitro biochemistry, not an organismal phenotype.", "supporting_studies": "SHW2004;COR2004", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/LKB1-AMPK/" }, { "id": "LYSO-MTORC1", "source": "Lysosome", "source_id": "lysosome", "target": "mTORC1", "target_id": "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. SAN2010 showed what happens when you take the first step away: anchoring mTORC1 to the lysosome permanently makes the pathway amino-acid insensitive and independent of Rag and Ragulator, but still dependent on Rheb. Recruitment and activation are two steps, and that experiment separates them. The requirement is stated for this route, not for every pool of mTOR in the cell.", "mechanism_beginner": "In the amino-acid route, mTORC1 has to travel to the lysosome before it can work, because its activator Rheb waits there. Getting it there and switching it on are two different steps: when researchers glued mTORC1 to the lysosome so it no longer had to be delivered, amino acids stopped making any difference, but the activator was still needed.", "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.", "supporting_studies": "SAN2010;ZON2011;FER2024;KOR2011;CUI2025", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/LYSO-MTORC1/" }, { "id": "METFORMIN-AMPK", "source": "Metformin", "source_id": "metformin", "target": "AMPK", "target_id": "ampk", "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "minutes", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "Metformin shifts the cell's energy balance and AMPK switches on - the route it is usually credited to, and why it keeps appearing next to rapamycin in longevity discussions.", "mechanism_beginner": "Metformin shifts the cell's energy balance and switches AMPK on – its best-known route to affecting this pathway.", "boundary": "How much of metformin's effect actually runs through AMPK is disputed: it still suppresses hepatic gluconeogenesis in AMPK-null and LKB1-null mouse liver (FOR2010) and still inhibits mTORC1 in AMPK-null cells (KAL2010). See the parallel METFORMIN-MTORC1 edge.", "supporting_studies": "ZHO2001;PEA2009", "conflicting_studies": "KAL2010", "human_relevance": "plausible", "consensus": "contested", "curation_status": "Contested", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/METFORMIN-AMPK/" }, { "id": "METFORMIN-MTORC1", "source": "Metformin", "source_id": "metformin", "target": "mTORC1", "target_id": "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 separate route that doesn't need AMPK – a route often left out of the simple \"metformin works via AMPK\" story. This was shown in cells and mice, often at doses higher than patients take, and how much each route matters in people is not known.", "boundary": "Runs in parallel with METFORMIN-AMPK, not instead of it. The relative weight of the two routes in humans is unresolved.", "supporting_studies": "KAL2010", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "contested", "curation_status": "Contested", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/METFORMIN-MTORC1/" }, { "id": "MLST8-MTORC2", "source": "mLST8", "source_id": "mlst8", "target": "mTORC2", "target_id": "mtorc2", "effect": "required-for", "type": "complex-assembly", "directness": "direct", "timescale": "constitutive", "compartment": "cytosol", "species": "mouse", "mechanism": "mLST8 is dispensable for mTORC1 in vivo but essential for mTORC2 - a rare clean genetic separation of the two complexes.", "mechanism_beginner": "This protein isn't needed for mTORC1 in a living animal, but mTORC2 can't work without it – a clean genetic way to tell the two complexes apart.", "boundary": "Knockout mice (GUE2006) and human cell biochemistry (KIM2003). The separation of the two complexes is shown in mouse tissue; whether it holds in human tissue is not tested by these studies.", "supporting_studies": "GUE2006;KIM2003", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MLST8-MTORC2/" }, { "id": "MTOR-MTORC2", "source": "mTOR", "source_id": "mtor", "target": "mTORC2", "target_id": "mtorc2", "effect": "required-for", "type": "complex-assembly", "directness": "direct", "timescale": "constitutive", "compartment": "cytosol", "species": "human cells; yeast", "mechanism": "mTORC2 is built around the same mTOR kinase as mTORC1 - the partner subunits, not the catalytic core, are what make the two complexes different.", "mechanism_beginner": "mTORC2 is built from the very same mTOR enzyme as mTORC1 – it's the partner proteins around it that make the two complexes different.", "boundary": "Cryo-EM structures of the complex from human cells and yeast (CHE2018, SCA2020, STU2018, KAR2017). Structural evidence shows how the complex is built, not how often or where it forms in living tissue.", "supporting_studies": "CHE2018;SCA2020;STU2018;KAR2017", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTOR-MTORC2/" }, { "id": "MTORC1-4EBP1", "source": "mTORC1", "source_id": "mtorc1", "target": "4E-BP1", "target_id": "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.", "boundary": "Cell and in vitro evidence (human and mouse cells, with C. elegans RNAi in one study). Rapamycin blocks this phosphorylation only partly, and individual sites differ in how sensitive they are (KAN2013). Not shown in people by these studies.", "supporting_studies": "BUR1998;HARA2002;FEL2009;GIN1999;KAN2013;HAR1998;BRU1997;NOJ2003;SAT2010", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-4EBP1/" }, { "id": "MTORC1-GRB10", "source": "mTORC1", "source_id": "mtorc1", "target": "Grb10", "target_id": "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.", "boundary": "Two mammalian cell studies (HSU2011, YUX2011). Cell culture only; not tested in whole animals or in people.", "supporting_studies": "HSU2011;YUX2011", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-GRB10/" }, { "id": "MTORC1-LONGEVITY", "source": "mTORC1", "source_id": "mtorc1", "target": "Longevity", "target_id": "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 best-replicated anti-ageing effects in laboratory animals. In mice, how big the effect is depends on sex, strain, diet and when treatment starts, and it has not been shown in people.", "boundary": "No human hard-endpoint evidence. This is the Atlas's flagged 'human endpoint desert'.", "supporting_studies": "HAR2009;LAM2012;ROB2012;VEL2003;HAN2008;POW2006;WAN2026", "conflicting_studies": "", "human_relevance": "untested", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-LONGEVITY/" }, { "id": "MTORC1-MAPK", "source": "mTORC1", "source_id": "mtorc1", "target": "ERK / RSK (MAPK)", "target_id": "erk-rsk-mapk", "effect": "inhibits", "type": "signal-relay", "directness": "indirect", "timescale": "hours", "compartment": "cytosol", "species": "patient tumour biopsies (RAD001); mouse; human cells", "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.", "boundary": "Single-study edge in this corpus. CAR2008 includes tumour biopsies from patients with advanced solid tumours treated with RAD001 (everolimus), in which MAPK activation depended on the dosing schedule, plus a mouse prostate cancer model, xenografts and cell lines.", "supporting_studies": "CAR2008", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-MAPK/" }, { "id": "MTORC1-MITO", "source": "mTORC1", "source_id": "mtorc1", "target": "Mitochondrial biogenesis", "target_id": "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.", "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.", "supporting_studies": "CUN2007;MOR2013;BEN2008", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-MITO/" }, { "id": "MTORC1-NUCL", "source": "mTORC1", "source_id": "mtorc1", "target": "Nucleotide synthesis", "target_id": "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.", "boundary": "Cancer cell and mammalian cell studies, including xenograft tumours (VAL2017, BEN2016, ALI2022). The evidence comes mostly from dividing or tumour cells; whether non-dividing tissues use the same route is not shown.", "supporting_studies": "VAL2017;BEN2016;ALI2022", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-NUCL/" }, { "id": "MTORC1-PROSTATE", "source": "mTORC1", "source_id": "mtorc1", "target": "Prostate cancer", "target_id": "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.", "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. Mouse only in this corpus. Not a demonstration in established prostate cancer.", "supporting_studies": "MAJ2004", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-PROSTATE/" }, { "id": "MTORC1-RCC", "source": "mTORC1", "source_id": "mtorc1", "target": "Renal cell carcinoma (RCC)", "target_id": "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. In two phase III trials in metastatic RCC, temsirolimus extended overall survival versus interferon alfa in poor-prognosis patients (HUD2007), and everolimus extended progression-free survival versus placebo after VEGF-targeted therapy (MOT2008). That the tumour responds to the drug is not the same as mTORC1 initiating the cancer.", "mechanism_beginner": "Many kidney cancers carry changes that leave mTORC1 stuck \"on\", which is why this cancer responds to mTOR-blocking drugs at all. In one large trial, people with advanced kidney cancer lived longer on temsirolimus; in another, everolimus slowed the cancer's growth for a few months. Responding to the drug is not proof that mTORC1 started the cancer.", "boundary": "Correlative, plus two randomised human trials showing the tumour responds to mTOR inhibitors: overall survival in poor-prognosis first-line RCC with temsirolimus (HUD2007), progression-free survival only after VEGF-targeted therapy with everolimus (MOT2008). This is response to treatment, not a demonstration that mTORC1 activation initiates RCC. The bladder-cancer responder case IYE2012 was removed from this edge on 2026-10-09 as a citation-population mismatch (it describes bladder, not kidney).", "supporting_studies": "MOT2008;HUD2007", "conflicting_studies": "", "human_relevance": "established", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-RCC/" }, { "id": "MTORC1-S6K1", "source": "mTORC1", "source_id": "mtorc1", "target": "S6K1", "target_id": "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.", "boundary": "Caution: p-S6K is a proxy, not the phenotype. Many 'mTORC1 activity' claims rest on this single band.", "supporting_studies": "BUR1998;CHU1992;HOL2005;KAN2013;HAR1998;NOJ2003;POD2001;JEF1997;RAO2010", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-S6K1/" }, { "id": "MTORC1-SENESCENCE", "source": "mTORC1", "source_id": "mtorc1", "target": "Senescence-associated secretory phenotype (SASP)", "target_id": "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 without making those cells young again. Whether mTORC1 also helps push cells into senescence in the first place is a separate question this arrow does not answer.", "boundary": "Three studies, all in cells or a rat disease model. LAB2015 and NAR2011 measure the secretory output of cells that are already senescent (IL1A translation; IL-6/IL-8 production fuelled by mTOR at the TASCC). CHEN2026C (human disc cells, rat needle-puncture model) shows mTORC1 hyperactivation after TSC2 loss together with senescence and SASP, both blocked by rapamycin - a disease-model result, not a general demonstration that mTORC1 drives cells into senescence. That is why this arrow lands on the secretory programme and not on senescence itself.", "supporting_studies": "LAB2015;CHEN2026C;NAR2011;WAN2017", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-SENESCENCE/" }, { "id": "MTORC1-SREBP", "source": "mTORC1", "source_id": "mtorc1", "target": "SREBP1 / SREBP2", "target_id": "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.", "boundary": "Mammalian cell studies (POR2008, PET2011) and an emerging rather than settled consensus. Cultured cells; the size of the effect in whole animals and in people is not measured by these studies. KID2013 adds primary mouse T cells: rapamycin blocked SREBP processing and nuclear entry after T-cell activation, and Scap-deleted T cells could not raise sterol synthesis. Still no human tissue data.", "supporting_studies": "POR2008;PET2011;DUV2010;KID2013", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-SREBP/" }, { "id": "MTORC1-TFEB", "source": "mTORC1", "source_id": "mtorc1", "target": "TFEB", "target_id": "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.", "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.", "supporting_studies": "ROC2012;SET2012;MAR2012;SET2011;GOL2022;CUI2023;MAR2013", "conflicting_studies": "ZHANG2026;PEN2011", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-TFEB/" }, { "id": "MTORC1-TUMOR", "source": "mTORC1", "source_id": "mtorc1", "target": "Tumor growth", "target_id": "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": "In mouse tumour models and cancer cells where the pathway is already over-active, hyperactive mTORC1 pushes cells to build a specific set of growth- and spread-promoting proteins, and the tumour becomes dependent on that programme.", "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. OKI2021 (mouse AML) is not cited as support: mTORC1 activity fell as the leukaemia progressed and rose during the chemotherapy response, so it bears on when to inhibit mTORC1, not on mTORC1 driving growth.", "supporting_studies": "HSI2010;HSI2012;VAL2017;INO2006;FER2026;NES2001;POD2001", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-TUMOR/" }, { "id": "MTORC1-ULK1", "source": "mTORC1", "source_id": "mtorc1", "target": "ULK1", "target_id": "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.", "boundary": "Mammalian and human/mouse cell studies (HOS2009, GAN2009, KIM2011, NAZ2013). Cell-culture biochemistry; the whole-animal and human consequence is not shown by these sources.", "supporting_studies": "HOS2009;GAN2009;KIM2011;NAZ2013", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-ULK1/" }, { "id": "MTORC2-ACTIN", "source": "mTORC2", "source_id": "mtorc2", "target": "Actin cytoskeleton", "target_id": "actin-cytoskeleton", "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "minutes", "compartment": "cytosol", "species": "mammalian cells; yeast", "mechanism": "One of the first functions assigned to mTORC2 was shaping the cell's skeleton. In yeast it was the original TOR2 phenotype; in mammalian cells it showed that the second complex is acutely rapamycin-insensitive.", "mechanism_beginner": "mTORC2's first known job was shaping the cell's internal skeleton. It was found in yeast first, as the original TOR2 phenotype, and then in mammalian cells - where it stood out precisely because rapamycin didn't block it.", "boundary": "Mammalian cells, yeast, Drosophila and conditional Rictor-knockout mice (JAC2004, SAR2004, LOE2002, HUA2013). The cytoskeleton phenotype was defined in cell lines and yeast; its role in intact tissue is less tested.", "supporting_studies": "JAC2004;SAR2004;LOE2002;HUA2013", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC2-ACTIN/" }, { "id": "MTORC2-AKT", "source": "mTORC2", "source_id": "mtorc2", "target": "Akt/PKB", "target_id": "akt-pkb", "effect": "activates", "type": "phosphorylation", "directness": "direct", "timescale": "seconds", "compartment": "pm", "species": "mammalian cells", "mechanism": "mTORC2 puts the second, activating phosphate on Akt (Ser473). This is the step rapamycin eventually breaks, and a major reason, in mice, that chronic rapamycin impairs glucose tolerance (LAM2012).", "mechanism_beginner": "mTORC2 adds the final activating tag to Akt – the same step that long-term use of the drug rapamycin eventually disrupts. In mice, that disruption is a major reason long-term rapamycin raises blood sugar.", "boundary": "Mammalian cell studies, cancer cells and one mouse and rat liver study (ARI2015). Ser473 phosphorylation is shown in cells. The glucose consequence of losing it comes from mouse work (LAM2012) and has not been measured in people.", "supporting_studies": "JAC2006;FRI2006;YAN2006;LIU2015;ROD2011;ARI2015;GAN2011;FAC2008;HAG2012", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC2-AKT/" }, { "id": "MTORC2-INSULINRES", "source": "mTORC2", "source_id": "mtorc2", "target": "Insulin resistance", "target_id": "insulin-resistance", "effect": "inhibits", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "mouse", "mechanism": "Losing mTORC2 uncouples Akt from insulin signalling and produces glucose intolerance - and this is separable from the lifespan benefit.", "mechanism_beginner": "Losing mTORC2 disconnects Akt from insulin signalling and can cause blood-sugar problems – a separate effect from any lifespan benefit.", "boundary": "In mice, intermittent dosing largely spared glucose tolerance while keeping mTORC1 inhibition (ARR2015); not tested against this endpoint in humans.", "supporting_studies": "LAM2012;ARR2015", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC2-INSULINRES/" }, { "id": "MTORC2-LIPID", "source": "mTORC2", "source_id": "mtorc2", "target": "Lipid synthesis", "target_id": "lipid-synthesis", "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "mouse", "mechanism": "In an mTOR-driven mouse liver model that progresses from steatosis to hepatocellular carcinoma, hepatic mTORC2 promoted de novo fatty-acid, sphingolipid and cardiolipin synthesis, and blocking lipid synthesis prevented the tumours.", "mechanism_beginner": "mTORC2 also drives fat-making, which is one of the ways it is thought to help tumours grow. The cause-and-effect part was shown in mice; in people with liver cancer, the study only found that more fat-making went together with higher mTORC2 activity.", "boundary": "The causal part comes from mouse liver: one liver tumour model (GUR2017) that progresses from steatosis to hepatocellular carcinoma, and liver-specific Rictor knockout in otherwise normal mice (HAG2012), where loss of mTORC2 lowered lipogenesis through Akt and SREBP1c. GUR2017 also reports that in human HCC, increased lipogenesis correlated with elevated mTORC2 activity: correlative human data, not a test of this step. Not established as a general mTORC2 function outside liver.", "supporting_studies": "GUR2017;HAG2012", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC2-LIPID/" }, { "id": "MTORC2-PROSTATE", "source": "mTORC2", "source_id": "mtorc2", "target": "Prostate cancer", "target_id": "prostate-cancer", "effect": "required-for", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "mouse", "mechanism": "Prostate cancer driven by Pten loss needs mTORC2 to develop; normal prostate does not. A real therapeutic window, at least in mice.", "mechanism_beginner": "Prostate tumours caused by losing a specific tumour-suppressor gene (Pten) need mTORC2 to develop – normal prostate tissue doesn't, at least in mice.", "boundary": "Single-study edge in this corpus (GUE2009). Shown in Pten-null mouse prostate only: mTORC2 (Rictor) is required for tumours to develop in that genetic background, while normal prostate epithelium is not dependent on it. Mouse only - not tested in another species in this corpus, and not shown in human prostate cancer.", "supporting_studies": "GUE2009", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC2-PROSTATE/" }, { "id": "MTORC2-SGK1", "source": "mTORC2", "source_id": "mtorc2", "target": "SGK1", "target_id": "sgk1", "effect": "activates", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "SGK1 is a second mTORC2 substrate alongside Akt, and it carries some of the functions usually credited to Akt.", "mechanism_beginner": "SGK1 is a second target of mTORC2 alongside Akt, and it shares some of Akt's jobs.", "boundary": "Single-study edge in this corpus.", "supporting_studies": "GAR2008", "conflicting_studies": "", "human_relevance": "established", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC2-SGK1/" }, { "id": "PDCD4-TRANSL", "source": "PDCD4", "source_id": "pdcd4", "target": "Protein synthesis", "target_id": "protein-synthesis", "effect": "inhibits", "type": "functional-consequence", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "PDCD4 blocks the eIF4A helicase, so mRNAs with structured 5' ends cannot be unwound and translated.", "mechanism_beginner": "PDCD4 jams a helper enzyme so some mRNAs can't be unwound and read.", "boundary": "SUZ2008 shows by structure and binding assays that PDCD4 binds the N-terminal domain of eIF4A and displaces eIF4G and RNA, which is the step asserted here. Cell-level evidence that PDCD4 loss changes translation of structured mRNAs is not in this corpus.", "supporting_studies": "SUZ2008", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/PDCD4-TRANSL/" }, { "id": "PI3K-AKT", "source": "PI3K", "source_id": "pi3k", "target": "Akt/PKB", "target_id": "akt-pkb", "effect": "activates", "type": "recruitment", "directness": "indirect", "timescale": "seconds", "compartment": "pm", "species": "mammalian cells", "mechanism": "PIP3 pulls Akt to the membrane, where it gets phosphorylated and activated.", "mechanism_beginner": "That lipid pulls Akt to the cell membrane, where it gets switched on.", "boundary": "Mammalian cell study (LIU2015) plus a review (CAN2002). Cell biochemistry; not tested in whole animals or in people by the cited sources.", "supporting_studies": "CAN2002;LIU2015", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/PI3K-AKT/" }, { "id": "PI3K-MTORC2", "source": "PI3K", "source_id": "pi3k", "target": "mTORC2", "target_id": "mtorc2", "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "seconds", "compartment": "pm", "species": "mammalian cells", "mechanism": "PIP3 made by PI3K binds SIN1 and releases its hold on the kinase site - so growth-factor signalling switches mTORC2 on, not only mTORC1.", "mechanism_beginner": "The same lipid signal that switches Akt on also switches mTORC2 on – so growth-factor signals hit both complexes.", "boundary": "Growth-factor dependence of mTORC2 assembly and activity, shown in mammalian cells. The ribosome requirement (ZIN2011) means the readout is not a clean separation of PI3K input from translational state.", "supporting_studies": "LIU2015;ZIN2011;DAL2012;GAN2011", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/PI3K-MTORC2/" }, { "id": "PRAS40-MTORC1", "source": "PRAS40", "source_id": "pras40", "target": "mTORC1", "target_id": "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.", "boundary": "Human cell biochemistry and a cryo-EM structure (SAN2007, YAN2017). Shows the plug mechanism in cells and in structure; its effect in whole animals and in people is not tested here.", "supporting_studies": "SAN2007;YAN2017", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/PRAS40-MTORC1/" }, { "id": "PTEN-PI3K", "source": "PTEN", "source_id": "pten", "target": "PI3K", "target_id": "pi3k", "effect": "inhibits", "type": "functional-consequence", "directness": "indirect", "timescale": "seconds", "compartment": "pm", "species": "mouse", "mechanism": "PTEN erases PIP3, undoing PI3K. Losing PTEN is one of the commonest ways a tumour leaves this whole axis switched on without an upstream signal.", "mechanism_beginner": "PTEN erases the lipid signal that PI3K makes. Losing PTEN is one of the most common ways cancers keep this whole pathway switched on without any signal from outside.", "boundary": "The arrow is drawn PTEN -> PI3K for readability, but PTEN does not act on the PI3K enzyme. It dephosphorylates PIP3, PI3K's lipid product, so the effect on PI3K signalling is indirect and the edge is a compressed one whose hidden intermediate is PIP3. The canonical biochemical demonstration (Maehama & Dixon, J Biol Chem 1998, PMID 9593664) sits outside this corpus: purified recombinant PTEN dephosphorylates PtdIns(3,4,5)P3 specifically at position 3, and in the same paper PTEN overexpression reduced insulin-induced PIP3 without affecting insulin-induced PI3K activation. The cancer-genetics support in-corpus is mouse (GUE2009).", "supporting_studies": "GUE2009", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/PTEN-PI3K/" }, { "id": "RAG-MTORC1", "source": "Rag GTPases", "source_id": "rag-gtpases", "target": "mTORC1", "target_id": "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.", "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.", "supporting_studies": "SAN2008;SAN2010;LAW2018;GOL2022;EFE2012;CUI2025;NAR2011;KIM2008;ANA2019;KIM2012", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/RAG-MTORC1/" }, { "id": "RAGULATOR-RAG", "source": "Ragulator", "source_id": "ragulator", "target": "Rag GTPases", "target_id": "rag-gtpases", "effect": "activates", "type": "scaffolding", "directness": "direct", "timescale": "constitutive", "compartment": "lyso", "species": "human cells", "mechanism": "Ragulator does two jobs on the Rags. It tethers the Rag heterodimer to the lysosomal surface, and it acts as an unusual exchange factor: first reported as a GEF for RagA/B (BAR2012), its exchange activity was later placed on RagC, where releasing GTP unlocks the inactive state (SHE2018B). Loading RagA with GTP is done by arginine-bound SLC38A9 (see SLC38A9-RAG).", "mechanism_beginner": "Ragulator anchors the Rag proteins to the lysosome and also helps flip them into their \"on\" shape, together with a second protein, SLC38A9. Both jobs are shown in biochemical experiments.", "boundary": "Human cells, Drosophila and purified recombinant proteins (BAR2012, SAN2010, SHE2018B). The exchange activity was first assigned to RagA/B and later to RagC, so the exact step is still being refined. Whole-animal and human relevance are not tested here.", "supporting_studies": "BAR2012;SAN2010;SHE2018B", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/RAGULATOR-RAG/" }, { "id": "RAPA-FKBP12", "source": "Rapamycin", "source_id": "rapamycin", "target": "FKBP12", "target_id": "fkbp12", "effect": "binds", "type": "binding", "directness": "direct", "timescale": "seconds", "compartment": "cytosol", "species": "human cells", "mechanism": "Rapamycin is not an ordinary inhibitor: it first binds the small protein FKBP12, and only the two-part complex is the real drug.", "mechanism_beginner": "Rapamycin doesn't work alone – it first has to team up with a helper protein called FKBP12.", "boundary": "X-ray crystallography and in vitro work on bovine, rat and mouse material (CHO1996, BRO1994, SAB1995). Describes drug binding in purified systems; it says nothing about dose or effect in patients.", "supporting_studies": "CHO1996;BRO1994;SAB1995", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/RAPA-FKBP12/" }, { "id": "RAPA-LAM", "source": "Rapamycin", "source_id": "rapamycin", "target": "Lymphangioleiomyomatosis", "target_id": "lymphangioleiomyomatosis", "effect": "inhibits", "type": "clinical-outcome", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "human", "mechanism": "The MILES trial: sirolimus stabilised lung function (FEV1) in lymphangioleiomyomatosis while patients took it, and decline resumed after stopping. This - not the everolimus angiomyolipoma trial - is the evidence that mTOR inhibition treats LAM lung disease.", "mechanism_beginner": "In a clinical trial, rapamycin stabilised lung function in a rare lung disease while patients kept taking it – the decline came back once they stopped.", "boundary": "Benefit is suppressive: lung function declined again after withdrawal.", "supporting_studies": "MCC2011", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/RAPA-LAM/" }, { "id": "RAPA-LONGEVITY", "source": "Rapamycin", "source_id": "rapamycin", "target": "Longevity", "target_id": "longevity", "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "mouse", "mechanism": "Rapamycin extends lifespan in genetically heterogeneous mice even when started late in life - one of the most influential results in the geroscience arm of this Atlas.", "mechanism_beginner": "Rapamycin makes mice live longer, even when given late in life – the single biggest result behind the whole \"this pathway and ageing\" idea.", "boundary": "Mouse only. No human lifespan or healthspan endpoint exists; EVERLAST has no results yet. BIT2016 shows a non-continuous schedule can still extend post-treatment life expectancy, but the result is dose- and route-specific: in the 8 mg/kg/day intraperitoneal arm males gained +60% post-treatment life expectancy (p=0.02) while females showed no survival benefit (p=0.261) and a shift toward aggressive haematopoietic cancers (16/16 vs 6/12, p=0.002); in the same paper's 126 ppm dietary encapsulated-rapamycin arm survival rose significantly in BOTH sexes, with a Cox model finding no evidence that sex modified the treatment effect (p=0.904). Cite the arm, not just the paper. ARR2016: an intermittent regimen (2 mg/kg every 5 days) started as late as 20 months of age extended lifespan in female C57BL/6J mice; the abstract reports the effect in females only.", "supporting_studies": "HAR2009;BIT2016;KHA2014;CHE2009;ARR2016;ANI2011", "conflicting_studies": "", "human_relevance": "untested", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/RAPA-LONGEVITY/" }, { "id": "RAPA-MTORC2", "source": "Rapamycin", "source_id": "rapamycin", "target": "mTORC2", "target_id": "mtorc2", "effect": "inhibits", "type": "complex-assembly", "directness": "indirect", "timescale": "chronic", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "Rapamycin does not touch mTORC2 in the short term - but over days it traps free mTOR and prevents new mTORC2 from being assembled.", "mechanism_beginner": "Rapamycin doesn't touch mTORC2 right away, but over days it stops new mTORC2 from being built.", "boundary": "Strictly time- and cell-type-dependent: absent acutely, present after prolonged exposure, and the sensitivity varies between cell lines. LAM2012 shows the same loss of mTORC2 signalling in mouse liver in vivo, so this is not a cell-culture-only phenomenon. Treating this edge as unconditional is a common error.", "supporting_studies": "SAR2006;LAM2012", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/RAPA-MTORC2/" }, { "id": "RAPTOR-MTORC1", "source": "Raptor", "source_id": "raptor", "target": "mTORC1", "target_id": "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.", "boundary": "Mostly cell and in vitro work (human cells, C. elegans RNAi, rodent cell lines). One muscle-specific knockout in mice (BEN2008) shows lifelong total loss, which is not the same as partial inhibition by a drug. Not tested in people.", "supporting_studies": "HARA2002;KIM2002;BEN2008;SEN2010;NOJ2003", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/RAPTOR-MTORC1/" }, { "id": "REDD1-TSC", "source": "REDD1 (DDIT4)", "source_id": "redd1-ddit4", "target": "TSC1/TSC2", "target_id": "tsc1-tsc2", "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "hours", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "REDD1 works through the TSC complex, not around it - hypoxia and growth factors therefore converge on the same brake.", "mechanism_beginner": "REDD1 acts through the TSC brake, so low oxygen and low growth-factor signals end up hitting the very same switch.", "boundary": "One study in mammalian cells (BRU2004). A single study, not replicated in this corpus, and not tested in whole animals or in people.", "supporting_studies": "BRU2004;DEY2008", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/REDD1-TSC/" }, { "id": "RHEB-MTORC1", "source": "Rheb", "source_id": "rheb", "target": "mTORC1", "target_id": "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.", "boundary": "Cryo-EM structures, in vitro biochemistry, Drosophila and one mouse study (INOK2003, SAU2003, YAN2017, CUI2025, DEL2011). Defines how Rheb activates mTORC1 in reconstituted and cellular systems; not measured directly in human tissue.", "supporting_studies": "INOK2003;SAU2003;YAN2017;CUI2025;DEL2011", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/RHEB-MTORC1/" }, { "id": "RICTOR-MTORC2", "source": "Rictor", "source_id": "rictor", "target": "mTORC2", "target_id": "mtorc2", "effect": "required-for", "type": "complex-assembly", "directness": "direct", "timescale": "constitutive", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "Rictor defines the second complex, mTORC2, which rapamycin does not block acutely.", "mechanism_beginner": "Rictor is what makes the second complex, mTORC2, distinct – and rapamycin doesn't block it right away.", "boundary": "Mammalian cells, Drosophila and conditional Rictor-knockout mice (SAR2004, JAC2004, HUA2013). Shows that the complex needs Rictor; relevance in human tissue is not tested by these studies.", "supporting_studies": "SAR2004;JAC2004;HUA2013;POL2015", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/RICTOR-MTORC2/" }, { "id": "S6K1-IRS1", "source": "S6K1", "source_id": "s6k1", "target": "IRS-1 / IRS-2", "target_id": "irs-1-irs-2", "effect": "inhibits", "type": "degradation", "directness": "direct", "timescale": "hours", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "One of the pathway's major negative feedback loops, and the best studied. Sustained S6K1 activity, as in obesity and nutrient excess, phosphorylates IRS-1 and represses its expression, so the insulin receptor can no longer signal to PI3K. This is a major reason blocking mTORC1 paradoxically RAISES Akt activity (the Grb10 arm adds to it). Rapalog-associated insulin resistance runs mainly through a different route, disruption of mTORC2 (LAM2012, in mice).", "mechanism_beginner": "This is one of the pathway's main self-limiting \"off switches\": strong, sustained S6K1 activity shuts down IRS-1, cutting the insulin signal off. That is how too much food can blunt the insulin signal. It also runs the other way: block mTOR and IRS-1 survives, so Akt can paradoxically become MORE active – which is why the insulin resistance seen on these drugs is blamed, on evidence from mice, on a different mechanism (loss of mTORC2), not on this loop.", "boundary": "Established in cells and mouse genetics. The size of this arm's contribution to rapalog dysglycaemia in humans, relative to mTORC2 loss, has not been apportioned.", "supporting_studies": "HAR2004;SHA2004;UMX2004;ORE2006", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/S6K1-IRS1/" }, { "id": "S6K1-LONGEVITY", "source": "S6K1", "source_id": "s6k1", "target": "Longevity", "target_id": "longevity", "effect": "inhibits", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "mouse", "mechanism": "Deleting S6K1 extends median lifespan in FEMALE mice (+19% in SEL2009); the effect was not significant in males. A separate study found that S6K1 loss protects against diet-induced obesity (UMX2004, which did not measure lifespan). Read the sex qualifier as part of the claim: this is the clearest evidence that one downstream branch, rather than mTORC1 as a whole, carries much of the ageing signal, and it is also the result whose qualifier is most often dropped in retelling.", "mechanism_beginner": "Removing S6K1 makes FEMALE mice live longer (about a fifth longer) and resist obesity. In male mice the same change did not significantly extend life – that difference is part of the result, not a footnote. Still strong evidence that one branch, not the whole pathway, drives much of the ageing effect.", "boundary": "Female mice only in SEL2009 - the lifespan extension was not significant in males.", "supporting_studies": "SEL2009", "conflicting_studies": "", "human_relevance": "untested", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/S6K1-LONGEVITY/" }, { "id": "S6K1-NUCL", "source": "S6K1", "source_id": "s6k1", "target": "Nucleotide synthesis", "target_id": "nucleotide-synthesis", "effect": "activates", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "S6K1 phosphorylates CAD, the enzyme that starts de novo pyrimidine synthesis - a direct line from growth signal to DNA building blocks.", "mechanism_beginner": "S6K1 switches on an enzyme that starts building the raw materials for DNA – a direct line from growth signal to DNA parts.", "boundary": "Mammalian cell studies including xenograft tumours (BEN2013, ROB2013, ALI2022). The evidence comes from cultured and tumour cells; whether non-dividing tissues use the same route is not shown.", "supporting_studies": "BEN2013;ROB2013;ALI2022", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/S6K1-NUCL/" }, { "id": "S6K1-PDCD4", "source": "S6K1", "source_id": "s6k1", "target": "PDCD4", "target_id": "pdcd4", "effect": "inhibits", "type": "degradation", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "S6K1 tags PDCD4 for destruction. PDCD4 is itself a translation inhibitor, so removing it is a second, parallel way mTORC1 lifts a brake on protein synthesis.", "mechanism_beginner": "S6K1 marks PDCD4, itself a brake on protein-building, for destruction – a second way mTORC1 releases the brake.", "boundary": "Single-study edge in this corpus.", "supporting_studies": "DOR2006", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/S6K1-PDCD4/" }, { "id": "SALR-MTORC1", "source": "Spalt-related (Salr)", "source_id": "spalt-related-salr", "target": "mTORC1", "target_id": "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.", "boundary": "One Drosophila study (DEN2026). Fly only and a single study; no mammalian or human data are cited for this edge.", "supporting_studies": "DEN2026", "conflicting_studies": "", "human_relevance": "untested", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/SALR-MTORC1/" }, { "id": "SAM-SAMTOR", "source": "S-adenosylmethionine (SAM)", "source_id": "s-adenosylmethionine-sam", "target": "SAMTOR", "target_id": "samtor", "effect": "inhibits", "type": "binding", "directness": "direct", "timescale": "seconds", "compartment": "cytosol", "species": "human cells", "mechanism": "S-adenosylmethionine, the cell's methyl-donor currency, binds SAMTOR and pulls it off GATOR1 - this is how methionine availability reaches mTORC1.", "mechanism_beginner": "SAM, a byproduct of methionine, binds SAMTOR and pulls it away from GATOR1 – the proposed way the cell senses how much methionine it has. Worked out in cells; whether this sensor is what matters in a whole animal has not been shown.", "boundary": "Single-study edge. Needs independent replication before it is treated as established.", "supporting_studies": "GU2017", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/SAM-SAMTOR/" }, { "id": "SAMTOR-GATOR1", "source": "SAMTOR", "source_id": "samtor", "target": "GATOR1", "target_id": "gator1", "effect": "activates", "type": "binding", "directness": "direct", "timescale": "seconds", "compartment": "lyso", "species": "human cells", "mechanism": "Methionine-starved SAMTOR binds the GATOR1-KICSTOR complex and helps it keep mTORC1 off.", "mechanism_beginner": "When methionine is low, SAMTOR teams up with GATOR1 to help keep mTORC1 switched off.", "boundary": "One biochemical study in human cells (GU2017). A single study in cell culture; the consensus is emerging, not settled.", "supporting_studies": "GU2017", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/SAMTOR-GATOR1/" }, { "id": "SESN2-AGING", "source": "Sestrin2", "source_id": "sestrin2", "target": "Age-related pathology", "target_id": "age-related-pathology", "effect": "inhibits", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "fly", "mechanism": "Losing Drosophila Sestrin produces fat accumulation, mitochondrial dysfunction, muscle degeneration and cardiac malfunction, all prevented by inhibiting TOR or activating AMPK. Sestrin therefore limits age-associated pathology in the fly.", "mechanism_beginner": "The only case in this atlas linking a nutrient sensor to ageing of a whole animal: fruit flies without this sensor build up fat and develop muscle and heart problems, and blocking this pathway or switching on AMPK prevents it. So the sensor holds age-related damage back. Watch what was measured – how sick the flies got, not how long they lived.", "boundary": "Fly only, and the readout is age-related pathology: survival was never measured. No mammalian sensor-to-ageing evidence exists in this corpus.", "supporting_studies": "LEE2010", "conflicting_studies": "", "human_relevance": "untested", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/SESN2-AGING/" }, { "id": "SESN2-GATOR2", "source": "Sestrin2", "source_id": "sestrin2", "target": "GATOR2", "target_id": "gator2", "effect": "inhibits", "type": "binding", "directness": "direct", "timescale": "seconds", "compartment": "cytosol", "species": "human cells", "mechanism": "When leucine is scarce, free Sestrin2 clamps onto GATOR2 and blocks it, keeping the whole pathway switched off.", "mechanism_beginner": "When there's no leucine, Sestrin2 grabs onto GATOR2 and holds the whole growth pathway shut.", "boundary": "Mammalian cell studies (CHA2014, PAR2014, WOL2015) and a cryo-EM structure of the Sestrin2-GATOR2 complex (VAL2025). Shows leucine sensing in cultured cells and where the sensor docks on GATOR2; the importance of this sensor in whole animals and people is not tested by these studies.", "supporting_studies": "CHA2014;PAR2014;WOL2015;VAL2025", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/SESN2-GATOR2/" }, { "id": "SIN1-MTORC2", "source": "SIN1 / MAPKAP1", "source_id": "sin1-mapkap1", "target": "mTORC2", "target_id": "mtorc2", "effect": "required-for", "type": "complex-assembly", "directness": "direct", "timescale": "constitutive", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "SIN1 holds the complex together and positions the substrate; without it mTORC2 cannot phosphorylate Akt.", "mechanism_beginner": "SIN1 holds mTORC2 together and positions its target – without it, mTORC2 can't switch Akt on.", "boundary": "Mammalian cell studies and a cryo-EM structure (JAC2006, FRI2006, YAN2006, STU2018). Cell and structural evidence; not tested in people by these sources.", "supporting_studies": "JAC2006;FRI2006;YAN2006;STU2018", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/SIN1-MTORC2/" }, { "id": "SLC38A9-RAG", "source": "SLC38A9", "source_id": "slc38a9", "target": "Rag GTPases", "target_id": "rag-gtpases", "effect": "activates", "type": "binding", "directness": "direct", "timescale": "seconds", "compartment": "lyso", "species": "human cells", "mechanism": "SLC38A9 sits in the lysosomal membrane and reads arginine on the inside. Arginine-bound SLC38A9 acts as an exchange factor that loads RagA with GTP, switching the Rag dimer on (SHE2018B); it also pumps essential amino acids, including leucine, back out into the cytosol.", "mechanism_beginner": "SLC38A9 sits in the lysosome's wall, senses arginine inside, and then flips RagA into its \"on\" shape, telling the Rag proteins there's enough.", "boundary": "Mammalian cell studies and purified-protein work (REB2015, WAN2015, JUN2015, WYA2017, SHE2018B). Cell and biochemical evidence; whole-animal and human relevance are not tested here.", "supporting_studies": "REB2015;WAN2015;JUN2015;WYA2017;SHE2018B", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/SLC38A9-RAG/" }, { "id": "SREBP-LIPID", "source": "SREBP1 / SREBP2", "source_id": "srebp1-srebp2", "target": "Lipid synthesis", "target_id": "lipid-synthesis", "effect": "activates", "type": "transcriptional", "directness": "direct", "timescale": "hours", "compartment": "nucleus", "species": "mammalian cells", "mechanism": "SREBP1 is the main transcriptional switch for de novo lipogenesis, and SREBP2 for cholesterol synthesis.", "mechanism_beginner": "SREBP is the master switch for making new fat from scratch.", "boundary": "Mammalian cell studies and a review (POR2008, PET2011, SHI2014). SREBP's role in lipid synthesis rests on cell-based work and does not measure it in people.", "supporting_studies": "POR2008;PET2011;SHI2014;DUV2010;KID2013", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/SREBP-LIPID/" }, { "id": "STRESS-AMPK", "source": "Energy & cellular stress", "source_id": "energy-cellular-stress", "target": "AMPK", "target_id": "ampk", "effect": "activates", "type": "allosteric-activation", "directness": "direct", "timescale": "seconds", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "AMPK does not read ATP directly - it reads the ratio of AMP and ADP to ATP. As ATP is consumed, AMP and ADP accumulate and bind the gamma subunit, which is the actual switch: it activates AMPK allosterically and protects the activating Thr172 phosphate from removal. AMPK is the cell's low-fuel sensor, and mTORC1 is one of the first things it shuts off.", "mechanism_beginner": "When the cell's fuel runs low, AMPK switches on – it's the cell's low-battery alarm, and one of the first things it does is shut mTORC1 off.", "boundary": "XIA2011 (crystal structure and biochemistry of mammalian AMPK) demonstrates that AMP binding to the gamma regulatory domain promotes phosphorylation and protects against dephosphorylation, and that ADP binds too. GWI2008 and ZHO2001 show downstream consequences. DEM2026 (IDH3 and citrate in AML stem cells) does not test AMP/ADP binding; its place on this edge needs the curator's decision.", "supporting_studies": "GWI2008;ZHO2001;DEM2026;XIA2011", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/STRESS-AMPK/" }, { "id": "STRESS-TSC", "source": "Energy & cellular stress", "source_id": "energy-cellular-stress", "target": "TSC1/TSC2", "target_id": "tsc1-tsc2", "effect": "recruits", "type": "translocation", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": "mammalian cells", "mechanism": "Many different stresses do the same physical thing: they drag TSC2 onto the lysosome, right where Rheb is. That relocation, not a change in TSC2 amount, is the switch.", "mechanism_beginner": "Different kinds of stress all do the same physical thing: they drag TSC2 over to the lysosome, right next to Rheb. Moving it there is the switch, not making more of it.", "boundary": "Mammalian cell studies (DEM2016, MEN2014). Relocation of TSC2 to the lysosome is shown in cultured cells under several stresses; not tested in tissue or in people.", "supporting_studies": "DEM2016;MEN2014", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/STRESS-TSC/" }, { "id": "TBC1D7-TSC", "source": "TBC1D7", "source_id": "tbc1d7", "target": "TSC1/TSC2", "target_id": "tsc1-tsc2", "effect": "required-for", "type": "complex-assembly", "directness": "direct", "timescale": "constitutive", "compartment": "cytosol", "species": "human cells", "mechanism": "TBC1D7 is the third, often-forgotten subunit of the TSC complex; losing it weakens the brake without removing it.", "mechanism_beginner": "TBC1D7 is a smaller, easy-to-miss third piece of the TSC brake; losing it weakens the brake without removing it.", "boundary": "One study in human cells (DIB2012). A single study; consequences beyond cell-level complex assembly are not tested in whole animals or in people.", "supporting_studies": "DIB2012", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TBC1D7-TSC/" }, { "id": "TEM-MTORC1", "source": "Temsirolimus", "source_id": "temsirolimus", "target": "mTORC1", "target_id": "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, as far as we know, the first mTOR-blocking drug shown to help patients live longer in a controlled trial (in advanced kidney cancer).", "boundary": "HUD2007 shows the clinical effect (overall survival in poor-prognosis metastatic kidney cancer). It did not measure mTORC1 activity; that temsirolimus inhibits mTORC1 rests on the FKBP12-dependent mechanism it shares with rapamycin.", "supporting_studies": "HUD2007", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TEM-MTORC1/" }, { "id": "TEM-RCC", "source": "Temsirolimus", "source_id": "temsirolimus", "target": "Renal cell carcinoma (RCC)", "target_id": "renal-cell-carcinoma-rcc", "effect": "inhibits", "type": "clinical-outcome", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "human", "mechanism": "In poor-prognosis renal cancer, temsirolimus improved overall survival against interferon - the hardest endpoint there is.", "mechanism_beginner": "In hard-to-treat kidney cancer, temsirolimus helped patients live longer compared with an older drug.", "boundary": "Poor-prognosis patients specifically; the combination arm did not beat temsirolimus alone.", "supporting_studies": "HUD2007", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TEM-RCC/" }, { "id": "TFEB-AUTOPHAGY", "source": "TFEB", "source_id": "tfeb", "target": "Autophagy", "target_id": "autophagy", "effect": "activates", "type": "transcriptional", "directness": "direct", "timescale": "hours", "compartment": "nucleus", "species": "mammalian cells", "mechanism": "In the nucleus TFEB switches on a whole gene programme for autophagy and for building new lysosomes - the cell's recycling capacity, not just a single step.", "mechanism_beginner": "Once inside the nucleus, TFEB switches on a whole set of genes for cleanup and for building new lysosomes.", "boundary": "Human and mouse cell studies (SET2011, ROC2012, SET2012). The gene programme is shown in cells; its contribution to autophagy in living tissue and in people is not measured here.", "supporting_studies": "SET2011;ROC2012;SET2012", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TFEB-AUTOPHAGY/" }, { "id": "TRANSL-MUSCLE", "source": "Protein synthesis", "source_id": "protein-synthesis", "target": "Muscle growth", "target_id": "muscle-growth", "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "days", "compartment": "outcome", "species": "mouse; mouse myotubes", "mechanism": "Sustained protein synthesis is what physically builds muscle; in mice, Akt/mTOR signalling is necessary and sufficient for hypertrophy (BOD2001). In people, blocking mTOR blunts the short-term rise in muscle protein synthesis after exercise (DRU2009); whether that changes how much muscle is gained over months was not measured.", "mechanism_beginner": "Ongoing protein-building is what physically builds muscle; in mice, the signals that drive it are needed for muscle growth and are enough to cause it. In people, blocking mTOR blunts the rise in muscle protein-building after a single bout of exercise, but how much muscle is gained over months under the drug was not measured.", "boundary": "Mouse (BOD2001) and cultured myotubes (ROM2001). The human study DRU2009 is cited on the step before this one (LOAD-MTORC1): rapamycin blocked the rise in muscle protein synthesis 1-2 h after one bout of contractions (and also blocked ERK1/2). It did not measure muscle growth, so it is not evidence for this arrow.", "supporting_studies": "BOD2001;ROM2001", "conflicting_studies": "LAP2026", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TRANSL-MUSCLE/" }, { "id": "TSC-MTORC1", "source": "TSC1/TSC2", "source_id": "tsc1-tsc2", "target": "mTORC1", "target_id": "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.)", "boundary": "Human cell lines, Drosophila, mouse and cell studies, one open-label human trial (KRU2010) and human disease genetics. The human evidence comes from disease caused by TSC loss, not from healthy tissue.", "supporting_studies": "TEE2003;INOK2003;KRU2010;CHEN2026C;ZHANG2026;DEM2014;SEN2010;GAO2002;TEE2002;KWI2002;DEY2008;POL2015;TSA2012;BAT2013;ZEN2008", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TSC-MTORC1/" }, { "id": "TSC-RHEB", "source": "TSC1/TSC2", "source_id": "tsc1-tsc2", "target": "Rheb", "target_id": "rheb", "effect": "inhibits", "type": "gap-activity", "directness": "direct", "timescale": "seconds", "compartment": "lyso", "species": "mammalian cells", "mechanism": "TSC2 is a GAP for Rheb: it forces Rheb to hydrolyse its GTP, switching it off. This is the single step where the tumour-suppressor function lives.", "mechanism_beginner": "TSC2 forces Rheb to switch itself off – the one step where TSC acts as a tumour-suppressing brake.", "boundary": "In vitro, Drosophila and mammalian cell biochemistry (INOK2003, GAR2003). GAP activity is shown in cells and in vitro; not measured in human tissue by these sources.", "supporting_studies": "INOK2003;GAR2003", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TSC-RHEB/" }, { "id": "ULK1-AMPK", "source": "ULK1", "source_id": "ulk1", "target": "AMPK", "target_id": "ampk", "effect": "inhibits", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": "mammalian cells", "mechanism": "ULK1 phosphorylates AMPK back, damping the signal that activated it - a negative feedback loop that stops autophagy running away.", "mechanism_beginner": "ULK1 tags AMPK back and calms it down – a feedback loop that keeps cleanup from running out of control.", "boundary": "One study in human cells and mouse (LOF2011). A single study. The feedback loop is shown in cell models, and the relation in the other direction (AMPK-ULK1) is contested.", "supporting_studies": "LOF2011", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/ULK1-AMPK/" }, { "id": "ULK1-AUTOPHAGY", "source": "ULK1", "source_id": "ulk1", "target": "Autophagy", "target_id": "autophagy", "effect": "activates", "type": "functional-consequence", "directness": "direct", "timescale": "minutes", "compartment": "autophagy", "species": "mammalian cells", "mechanism": "Freed ULK1 nucleates the autophagosome - the self-eating programme that recycles damaged parts and is the leading candidate mechanism for mTOR inhibition's benefits.", "mechanism_beginner": "Freed ULK1 kicks off autophagy – the cell's recycling programme, and the leading idea for why blocking this pathway might be beneficial.", "boundary": "Mammalian cell studies (GAN2009, HOS2009, EGA2010). Autophagosome initiation is shown in cultured cells. Whether autophagy carries the benefits of mTOR inhibition in whole animals is not tested by these sources.", "supporting_studies": "GAN2009;HOS2009;EGA2010;CHA2007;RUS2013", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/ULK1-AUTOPHAGY/" }, { "id": "VATPASE-RAGULATOR", "source": "v-ATPase", "source_id": "v-atpase", "target": "Ragulator", "target_id": "ragulator", "effect": "required-for", "type": "binding", "directness": "direct", "timescale": "constitutive", "compartment": "lyso", "species": "human cells", "mechanism": "The lysosome's proton pump talks to Ragulator from the inside out: amino acids inside the lysosome change v-ATPase, which changes Ragulator, which changes the Rags.", "mechanism_beginner": "The lysosome's acid pump senses amino acids from the inside and passes that information out to Ragulator, which passes it on to the Rag proteins.", "boundary": "The 'inside-out' model requires amino acids to accumulate inside the lysosome first; how they get there for every amino acid is not fully mapped.", "supporting_studies": "ZON2011;BAR2012", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/VATPASE-RAGULATOR/" }, { "id": "RAPA-MTORC1", "source": "Rapamycin", "source_id": "rapamycin", "target": "mTORC1", "target_id": "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.", "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.", "supporting_studies": "CHU1992;BRO1994;SAB1994;SAB1995;CHO1996;MEI2008;KAN2013;FIN2002;BRU1997;SAT2010;YIP2010;RAO2010;MAR2014;BAT2013", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/RAPA-MTORC1/" }, { "id": "GLN-MTORC1-ARF1", "source": "Glutamine", "source_id": "glutamine", "target": "mTORC1", "target_id": "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.", "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.", "supporting_studies": "JEW2015", "conflicting_studies": "", "human_relevance": "untested", "consensus": "contested", "curation_status": "Contested", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/GLN-MTORC1-ARF1/" }, { "id": "LOAD-MTORC1", "source": "Resistance exercise / mechanical load", "source_id": "resistance-exercise-mechanical-load", "target": "mTORC1", "target_id": "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": "Working a muscle raises mTORC1 activity in it. When volunteers took rapamycin, the rise in muscle protein building after exercise was blocked, so in people, and not only in cell dishes, mTORC1 sits between the effort and the response. The map draws one arrow, but load reaches mTORC1 by several routes, and this result does not show which one carries the signal.", "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.", "supporting_studies": "DRU2009;BOD2001", "conflicting_studies": "", "human_relevance": "established", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/LOAD-MTORC1/" }, { "id": "CR-MTORC1", "source": "Fasting / caloric restriction", "source_id": "caloric-restriction", "target": "mTORC1", "target_id": "mtorc1", "effect": "inhibits", "type": "signal-relay", "directness": "indirect", "timescale": "chronic", "compartment": "lyso", "species": "mouse", "mechanism": "Reduced nutrient and energy availability is expected to lower mTORC1 through the amino-acid and energy arms at once - the sensors detect scarcity and AMPK detects the falling energy charge. Note what supports that expectation here, because it is less than the claim's reputation suggests. No study in this corpus measures mTORC1 under fasting or energy restriction. The single supporting study, SOL2014, fed mice ad libitum across 25 diets and concluded that the macronutrient RATIO, not caloric intake, set lifespan and cardiometabolic health; the mTOR link in it is a correlation between a lower protein-to-carbohydrate ratio and lower hepatic mTOR activation. So the supported variable is dietary protein, not calories, and the measurement is associative rather than interventional.", "mechanism_beginner": "Eating less is expected to turn mTORC1 down, because the cell's fuel and amino-acid sensors both report scarcity. But this has not been measured here. The one study behind this arrow let mice eat freely on 25 different diets and found that the ratio of protein to carbohydrate, not the number of calories, went with health and lifespan, and lower-protein diets went with lower mTOR activity in the liver. So what has support is eating less protein, not eating less, and it is a correlation, not a test.", "boundary": "Supporting evidence 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. That leaves SOL2014, which is an ad-libitum 25-diet study whose own title states that the ratio of macronutrients, not caloric intake, dictates the outcome, and whose mTOR observation is correlative and confined to liver. Re-audit 2026-10-10: consensus was downgraded from established to emerging and the evidence kind from genetic epistasis to correlative, because neither matched what SOL2014 actually did. The edge is retained because the mechanistic expectation is sound and well motivated by the sensor arms, but it is an expectation, not a measured result in this corpus. 2026-10-18: YIL2012 added. In mouse intestine, calorie restriction lowered mTORC1 activity in Paneth cells, and rapamycin or Paneth-cell genetics reproduced the stem-cell effect, so the corpus now has one direct mTORC1 measurement under restriction. It is a single tissue in mice and does not show the same in people.", "supporting_studies": "SOL2014;YIL2012", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/CR-MTORC1/" }, { "id": "CR-LONGEVITY", "source": "Fasting / caloric restriction", "source_id": "caloric-restriction", "target": "Longevity", "target_id": "longevity", "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "rhesus; mouse", "mechanism": "Caloric restriction improved health and survival in rhesus monkeys (MAT2017). In mice fed one of 25 diets ad libitum, lowering calories by diluting the food did not extend lifespan, while a lower protein-to-carbohydrate ratio did (SOL2014). That study is carried as conflicting evidence on which variable matters: calories, or protein.", "mechanism_beginner": "Eating less improved health and survival in monkeys. But in mice that could eat as much as they wanted, cutting calories by watering down the food did not make them live longer; eating less protein compared with carbohydrate did. So whether it is the calories or the protein that counts is still open.", "boundary": "No human lifespan data exists. Effect direction is reproducible across several species; effect size and even the responsible variable (calories versus composition) are not settled.", "supporting_studies": "MAT2017", "conflicting_studies": "SOL2014", "human_relevance": "untested", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/CR-LONGEVITY/" }, { "id": "TORIN-MTORC1", "source": "ATP-competitive mTOR inhibitors", "source_id": "atp-competitive-mtor-inhibitors", "target": "mTORC1", "target_id": "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": "Torin sits in the spot where mTOR holds its energy molecule ATP, so it shuts the kinase down whatever the kinase is about to modify. Rapamycin leaves part of mTORC1's work running; Torin does not, which is how researchers learned how much rapamycin had been missing. This comes from cell-culture work, not from patients.", "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.", "supporting_studies": "THO2009;FEL2009;CHR2009;JAN2010;ROD2011;GAR2009;MAR2014", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TORIN-MTORC1/" }, { "id": "TORIN-MTORC2", "source": "ATP-competitive mTOR inhibitors", "source_id": "atp-competitive-mtor-inhibitors", "target": "mTORC2", "target_id": "mtorc2", "effect": "inhibits", "type": "competitive-inhibition", "directness": "direct", "timescale": "minutes", "compartment": "pm", "species": "mammalian cells", "mechanism": "The same active site is present in both complexes, so an ATP-competitive inhibitor cannot distinguish them.", "mechanism_beginner": "mTORC1 and mTORC2 use the same ATP-binding pocket, so a drug that blocks the pocket hits both and cannot choose. That is thought to explain why this class of drugs causes more metabolic and immune side effects than rapamycin-type drugs, but the size of that effect has only been seen in cell studies and has not been measured in patients.", "boundary": "Explains the metabolic and immunological toxicity of this class relative to rapalogs; the magnitude in patients is not established from these cell-line studies.", "supporting_studies": "THO2009;FEL2009;JAN2010;ROD2011;GAR2009", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TORIN-MTORC2/" }, { "id": "BISTERIC-MTORC1", "source": "Bi-steric mTORC1-selective inhibitors", "source_id": "bi-steric-mtorc1-selective-inhibitors", "target": "mTORC1", "target_id": "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": "A two-part drug grips mTORC1 at two places at once, which blocks it more completely than rapamycin-type drugs. So far only a first safety trial in people with advanced tumours has reported on it.", "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.", "supporting_studies": "SCH2025", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/BISTERIC-MTORC1/" }, { "id": "TFEB-LYSOBIO", "source": "TFEB", "source_id": "tfeb", "target": "Lysosomal biogenesis", "target_id": "lysosomal-biogenesis", "effect": "activates", "type": "transcriptional", "directness": "direct", "timescale": "hours", "compartment": "nucleus", "species": "human cells; mouse cells", "mechanism": "Nuclear TFEB switches on the lysosomal and autophagy gene programme as a single coordinated module, expanding the lysosomal compartment.", "mechanism_beginner": "In the nucleus, TFEB switches on a whole gene package for cleanup and for building new lysosomes.", "boundary": "Transcriptional output measured as gene expression and lysosomal markers; how much the compartment actually expands varies with cell type and starvation depth.", "supporting_studies": "SET2011;ROC2012;SAR2009;PEN2011", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TFEB-LYSOBIO/" }, { "id": "LYSOBIO-LYSOSOME", "source": "Lysosomal biogenesis", "source_id": "lysosomal-biogenesis", "target": "Lysosome", "target_id": "lysosome", "effect": "activates", "type": "functional-consequence", "directness": "direct", "timescale": "hours", "compartment": "lyso", "species": "mammalian cells", "mechanism": "A larger, renewed lysosomal compartment changes the platform on which mTORC1 is regulated – the return leg of the lysosome-to-nucleus circuit.", "mechanism_beginner": "More, fresher lysosomes change the very platform that controls mTORC1 – closing a loop back to where the signal started.", "boundary": "SET2012 establishes lysosome-to-nucleus signalling via mTOR and TFEB; the quantitative effect of compartment size on mTORC1 output is not resolved.", "supporting_studies": "SET2012;SET2011", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/LYSOBIO-LYSOSOME/" }, { "id": "MITODYS-MTORC1", "source": "Mitochondrial dysfunction", "source_id": "mitochondrial-dysfunction", "target": "mTORC1", "target_id": "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.", "boundary": "CRISPR screening in cell lines; the relative weight of the AMPK and HRI arms in tissue is untested.", "supporting_studies": "CON2021", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MITODYS-MTORC1/" }, { "id": "MTORC1-OXPHOS", "source": "mTORC1", "source_id": "mtorc1", "target": "Oxidative phosphorylation", "target_id": "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.", "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.", "supporting_studies": "CUN2007;MOR2013;SCH2006", "conflicting_studies": "POL2008", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-OXPHOS/" }, { "id": "MTORC1-PGC1A", "source": "mTORC1", "source_id": "mtorc1", "target": "PGC-1α / YY1", "target_id": "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.", "boundary": "Single-study support in this corpus for the direct interaction; the downstream respiratory phenotype is better replicated than the binding itself.", "supporting_studies": "CUN2007", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-PGC1A/" }, { "id": "MTORC1-ROS", "source": "mTORC1", "source_id": "mtorc1", "target": "Reactive oxygen species", "target_id": "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.", "boundary": "Demonstrated in haematopoietic stem cells, where quiescence is the baseline state. Cell types that are already cycling need not behave this way.", "supporting_studies": "CHE2008", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-ROS/" }, { "id": "ROS-MTORC1", "source": "Reactive oxygen species", "source_id": "reactive-oxygen-species", "target": "mTORC1", "target_id": "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.", "boundary": "One cell-line study in a multidrug-resistance context; whether the loop runs in normal physiology at these ROS levels is untested.", "supporting_studies": "JIN2026", "conflicting_studies": "", "human_relevance": "untested", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/ROS-MTORC1/" }, { "id": "MTORC2-MAM", "source": "mTORC2", "source_id": "mtorc2", "target": "MAM (ER–mitochondria contacts)", "target_id": "mam-ermitochondria-contacts", "effect": "activates", "type": "localisation", "directness": "direct", "timescale": "minutes", "compartment": "mito", "species": "mammalian cells", "mechanism": "mTORC2–Akt signalling localises to mitochondria-associated ER membranes and regulates mitochondrial physiology from there.", "mechanism_beginner": "mTORC2 signalling also happens at a specific contact point between mitochondria and another cell structure - a sign that this pathway works at more than one location in the cell, not only on the lysosome.", "boundary": "Biochemical fractionation and imaging in cell lines; the functional contribution relative to plasma-membrane mTORC2 is not quantified.", "supporting_studies": "BET2013", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC2-MAM/" }, { "id": "FOXO-LONGEVITY", "source": "FOXO1/3", "source_id": "foxo", "target": "Longevity", "target_id": "longevity", "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "C. elegans", "mechanism": "Genetic TORC1 inhibition in C. elegans extends lifespan through BOTH SKN-1/Nrf and DAF-16/FoxO, which activate protective genes and raise stress resistance. Rapamycin does NOT work the same way: it triggers a similar protective response but extends worm lifespan dependent on SKN-1 and NOT on DAF-16, apparently by interfering with TORC2 alongside TORC1 (ROB2012). This FoxO arrow therefore holds for the genetic arm, not for the drug.", "mechanism_beginner": "Part of how this pathway affects lifespan runs through stress-resistance genes switched on by FOXO – so far shown mainly in simple animals like worms, not yet in mammals.", "boundary": "An invertebrate result, and the two arms must not be merged. ROB2012's title reads 'TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO', but its own abstract splits them: the DAF-16/FoxO requirement belongs to genetic TORC1 inhibition, while the rapamycin effect is SKN-1-dependent and DAF-16-INDEPENDENT. Not shown in mammals in this corpus.", "supporting_studies": "ROB2012", "conflicting_studies": "", "human_relevance": "untested", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/FOXO-LONGEVITY/" }, { "id": "MTORC1-HIF1A", "source": "mTORC1", "source_id": "mtorc1", "target": "HIF-1α", "target_id": "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.", "boundary": "Mouse prostate model with pharmacological mTOR inhibition; HIF-1α is one of several pathways implicated in the same experiment. DUV2010 adds cultured-cell evidence (Tsc2-null fibroblasts with rapamycin) that mTORC1 drives HIF1α target genes such as glycolytic enzymes; still no human tissue data.", "supporting_studies": "MAJ2004;DUV2010", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-HIF1A/" }, { "id": "RAGULATOR-CGASSTING", "source": "Ragulator", "source_id": "ragulator", "target": "cGAS-STING pathway", "target_id": "cgas-sting-pathway", "effect": "inhibits", "type": "degradation", "directness": "direct", "timescale": "chronic", "compartment": "cytosol", "species": "mouse", "mechanism": "Lamtor5 binds cGAS directly and routes it for degradation through the ESCRT machinery, so the Ragulator subunit acts as a physical brake on the sensor itself. Age-related decline of Lamtor5 in macrophages leaves cGAS stabilised, and that is sufficient to unleash cGAS-mediated paracrine inflammatory signalling: transferring Lamtor5-deficient macrophages accelerates ageing in young mice, while restoring young macrophages, clearing senescent cells, or applying a small peptide that blocks the Lamtor5/cGAS interface alleviates the phenotype in aged mice.", "mechanism_beginner": "Lamtor5 belongs to Ragulator, the lysosome complex that switches mTORC1 on, but this link does not run through mTORC1 as far as the source shows. Lamtor5 grabs the inflammation sensor cGAS and sends it for disposal. When Lamtor5 falls with age in immune cells called macrophages, cGAS builds up and drives inflammation that spreads to neighbouring cells; in mice, moving such macrophages into young animals sped up their ageing. This is one mouse study, so it is not known whether the same happens in people, or whether mTORC1 plays any part.", "boundary": "One mouse study (LV2026), A - animal, and no human data for this link. The abstract reports no mTORC1 or mTORC2 measurement for the cGAS step, so whether mTORC1 signalling contributes at all is untested here rather than established. Macrophage-specific: the conditional knockout is myeloid, and the ageing phenotypes are read out at the organismal level, which is a long inferential chain from one protein interaction.", "supporting_studies": "LV2026", "conflicting_studies": "", "human_relevance": "untested", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/RAGULATOR-CGASSTING/" }, { "id": "CGASSTING-SENESCENCE", "source": "cGAS-STING pathway", "source_id": "cgas-sting-pathway", "target": "Cellular senescence", "target_id": "cellular-senescence", "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "days", "compartment": "outcome", "species": "mouse", "mechanism": "cGAS-STING activation in aged macrophages drives a paracrine inflammatory senescence programme that spreads the phenotype to neighbouring cells, contributing to systemic ageing.", "mechanism_beginner": "In aged immune cells called macrophages, cGAS-STING switches on an inflammatory programme that spreads to neighbouring cells, so the ageing effect does not stay in the cell where it started. This comes from a single mouse study, and whether the same spread happens in human tissue has not been tested.", "boundary": "Single mouse study; the human magnitude of this effect, and whether the same paracrine spread occurs in human tissue, are untested.", "supporting_studies": "LV2026", "conflicting_studies": "", "human_relevance": "untested", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/CGASSTING-SENESCENCE/" }, { "id": "ERK-NUCL", "source": "ERK / RSK (MAPK)", "source_id": "erk-rsk-mapk", "target": "Nucleotide synthesis", "target_id": "nucleotide-synthesis", "effect": "activates", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": "human cells; mouse xenograft", "mechanism": "ERK2 directly phosphorylates the purine-making enzyme PFAS within minutes, speeding de novo purine synthesis. This growth signal for DNA and RNA building blocks runs in parallel to mTORC1's own routes.", "mechanism_beginner": "ERK2 switches on an enzyme that makes purines.", "boundary": "Human cancer cell lines and xenograft tumours; ERK2, not ERK1; post-translational and parallel to mTORC1. Single study.", "supporting_studies": "ALI2020", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/ERK-NUCL/" }, { "id": "GHIGF1-LONGEVITY", "source": "Growth hormone / IGF-1 axis", "source_id": "growth-hormone-igf-1-axis", "target": "Longevity", "target_id": "longevity", "effect": "inhibits", "type": "functional-consequence", "directness": "indirect", "timescale": "chronic", "compartment": "outcome", "species": "mouse", "mechanism": "Growth hormone / IGF-1 signalling acts as a brake on lifespan: mice whose GH signalling is blocked, either lifelong or from middle age, live longer and are less frail in old age.", "mechanism_beginner": "Less growth-hormone signalling, longer life in mice.", "boundary": "Mouse only. A lifelong GH-receptor-antagonist transgenic (LIST2026; an earlier study of the same line did not detect extension) and a tamoxifen-inducible whole-body Ghr knockout started at 12 months (DUR2026). mTOR signalling was not measured in either, so the route through PI3K-Akt-mTOR is inferred, not shown here.", "supporting_studies": "LIST2026;DUR2026", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/GHIGF1-LONGEVITY/" }, { "id": "MTORC1-SAM", "source": "mTORC1", "source_id": "mtorc1", "target": "S-adenosylmethionine (SAM)", "target_id": "s-adenosylmethionine-sam", "effect": "activates", "type": "transcriptional", "directness": "indirect", "timescale": "hours", "compartment": "nucleus", "species": "human cells; mouse xenograft", "mechanism": "Active mTORC1, acting through the transcription factor c-MYC, raises production of MAT2A, the enzyme that makes SAM, so a growing cell makes more of its main methyl donor.", "mechanism_beginner": "mTORC1 tells the cell to make more SAM.", "boundary": "Human cell lines and mouse xenograft tumours; acts through c-MYC on MAT2A. Together with SAM-SAMTOR this forms a loop whose behaviour in normal tissue is untested. Single study.", "supporting_studies": "VIL2021", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-SAM/" }, { "id": "PDCD4-MTORC2", "source": "PDCD4", "source_id": "pdcd4", "target": "mTORC2", "target_id": "mtorc2", "effect": "inhibits", "type": "complex-assembly", "directness": "direct", "timescale": "minutes", "compartment": "cytosol", "species": "human cells; mouse", "mechanism": "PDCD4 binds the mTORC2 subunit Rictor through three basic residues, which stops mTORC2 from assembling properly and lowers its kinase activity.", "mechanism_beginner": "PDCD4 grabs Rictor and keeps mTORC2 from working.", "boundary": "Human NSCLC cell lines and mouse xenografts; not shown in normal tissue. Single study.", "supporting_studies": "WANG2026B", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/PDCD4-MTORC2/" }, { "id": "RAG-TSC", "source": "Rag GTPases", "source_id": "rag-gtpases", "target": "TSC1/TSC2", "target_id": "tsc1-tsc2", "effect": "recruits", "type": "recruitment", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": "mammalian cells", "mechanism": "When amino acids run out, the Rag GTPases also pull the TSC complex onto the lysosome, where it can switch Rheb off and help shut mTORC1 down.", "mechanism_beginner": "Without amino acids, the Rags bring the TSC brake to the lysosome.", "boundary": "Mammalian cell lines under acute amino-acid withdrawal; the contribution of this route in tissues is not established. Single study.", "supporting_studies": "DEM2014", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/RAG-TSC/" }, { "id": "ULK1-FNIP1", "source": "ULK1", "source_id": "ulk1", "target": "FLCN / FNIP1/2", "target_id": "flcn-fnip1-2", "effect": "inhibits", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": "human cells", "mechanism": "When lysosomes are stressed, ULK1 brought in by the adaptor TAX1BP1 (TAX1BP1-ULK1) phosphorylates FNIP1 at S296 on the lysosome. This switches the FLCN-FNIP complex off, so mTORC1 can no longer hold TFEB in the cytoplasm and TFEB moves into the nucleus. TBK1 does the same job on this route and has its own link (TBK1-FNIP1).", "mechanism_beginner": "ULK1 tags FNIP1, which turns FLCN off and lets TFEB escape mTORC1's grip.", "boundary": "Human cell lines and ATP6V1B2-mutant follicular lymphoma samples (ESP2026); a nutrient-independent lysosomal-stress route in which TBK1 is an alternative kinase. Single study, not yet replicated.", "supporting_studies": "ESP2026", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/ULK1-FNIP1/" }, { "id": "AKT-FOXO", "source": "Akt/PKB", "source_id": "akt-pkb", "target": "FOXO1/3", "target_id": "foxo", "effect": "inhibits", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "nucleus", "species": "mouse; mammalian cells", "mechanism": "Akt phosphorylates FOXO transcription factors and excludes them from the nucleus. Rictor or mLST8 deletion abolishes signalling to Akt–FOXO while sparing S6K1.", "mechanism_beginner": "Akt tags FOXO proteins and keeps them out of the nucleus; this specific link belongs to mTORC2, not mTORC1.", "boundary": "Mouse knockouts and cell lines; FOXO isoform contributions differ by tissue.", "supporting_studies": "GUE2006;JAC2006;BRU1999", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/AKT-FOXO/" }, { "id": "INS-PI3K", "source": "Insulin", "source_id": "insulin", "target": "PI3K", "target_id": "pi3k", "effect": "activates", "type": "signal-relay", "directness": "indirect", "timescale": "minutes", "compartment": "pm", "species": "human, mammalian cells, Drosophila", "mechanism": "Insulin binds the insulin receptor, which phosphorylates IRS proteins; those recruit PI3K, which makes PIP3 and so starts the arm that reaches mTORC1 through Akt. The step is also where the pathway's best-known feedback lands: S6K1 depletes IRS1/2 and the cell goes deaf to insulin (SHA2004).", "mechanism_beginner": "Insulin lands on its own receptor on the cell surface. The message is passed inward by IRS proteins to PI3K, which builds a signalling lipid, and that is the beginning of the route to mTORC1. This is also the step that breaks when the pathway is overactive for too long.", "boundary": "Insulin and IGF-1 share this receptor arm; growth hormone does not, and is kept separate for that reason. The amplitude and the time pattern of the insulin signal are not interchangeable: KUB2012 shows the AKT pathway multiplexes insulin's temporal pattern, so a single arrow understates what the cell reads. Cell and genetic work, plus human physiology for the insulin-resistance end of it.", "supporting_studies": "HAR2004;GAR2003;SAU2003;SAN2007;SHA2004", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/INS-PI3K/" }, { "id": "MTORC1-RIBOBIO", "source": "mTORC1", "source_id": "mtorc1", "target": "Ribosome biogenesis", "target_id": "ribosome-biogenesis", "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "hours", "compartment": "nucleus", "species": "budding yeast, human cells", "mechanism": "TORC1 activity tracks ribosome biogenesis: in budding yeast TORC1 and PKA activity towards ribosome biogenesis oscillates with the cell cycle (GUE2022), and in mammalian cells the translational programme mTORC1 controls is dominated by the ribosome's own components (HSI2012). The dependency also runs the other way: when ribosome biogenesis fails, mTOR inactivation is what lets cells survive it (FAN2026).", "mechanism_beginner": "A growing cell needs more ribosomes, not just busier ones, and mTORC1 has a say in how many get built. That was followed through the cell cycle in yeast, and in mammalian cells the programme mTORC1 controls turns out to be dominated by the ribosome's own parts. The link runs in both directions: block ribosome building and the cell turns mTOR down to cope.", "boundary": "The two polymerase steps that carry most of this output are NOT measured by any study in this corpus. mTOR controls rRNA transcription through RNA polymerase I via TIF-IA (Mayer 2004, PMID 15004009, outside this corpus) and tRNA and 5S transcription through RNA polymerase III via Maf1 (Shor 2010, PMID 20233713, outside this corpus). Until those are curated here the edge rests on a yeast cell-cycle study, a mammalian ribosome-profiling study and a reverse-direction survival study, so read it as the existence of the output rather than as its mechanism.", "supporting_studies": "GUE2022;HSI2012;FAN2026", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-RIBOBIO/" }, { "id": "MTORC1-TOPMRNA", "source": "mTORC1", "source_id": "mtorc1", "target": "5'TOP mRNA", "target_id": "5top-mrna", "effect": "activates", "type": "functional-consequence", "directness": "indirect", "timescale": "minutes", "compartment": "cytosol", "species": "human cells, Drosophila", "mechanism": "mTORC1 raises translation of the 5'TOP class of mRNAs, which encode ribosomal proteins and translation factors. Ribosome profiling showed the effect is selective rather than uniform: mTORC1 does not turn all translation up equally, it shifts which transcripts get translated.", "mechanism_beginner": "When mTORC1 is on, the cell does not simply make more of every protein. It preferentially makes the parts of its own protein-making machinery, from a particular class of messages marked at one end.", "boundary": "The selectivity is from ribosome profiling in cancer cell lines (HSI2012); the lifespan link is Drosophila only (WAN2026); PLEDGER2026 shows the same arm being repressed in chronically activated human CD8+ T cells. No human in vivo measurement of 5'TOP translation under an mTOR inhibitor in this corpus. Which of the 5'TOP transcripts matter for which phenotype is not resolved.", "supporting_studies": "HSI2012;WAN2026;PLEDGER2026;JEF1997", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "established", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MTORC1-TOPMRNA/" }, { "id": "CHOL-LYCHOS", "source": "Cholesterol", "source_id": "cholesterol", "target": "LYCHOS (GPR155)", "target_id": "lychos-gpr155", "effect": "activates", "type": "binding", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": "human cells", "mechanism": "Cholesterol binds the amino-terminal permease-like region of LYCHOS, and that is the step the sensing depends on: mutating the binding site impairs mTORC1 activation while leaving the protein in place (SHI2022). Occupancy switches LYCHOS into the state that holds GATOR1, so the sterol is read where it accumulates, on the lysosome, rather than at the cell surface.", "mechanism_beginner": "Cholesterol itself sticks to the sensor. That is what tells the sensor there is plenty about: break the spot where it sticks and the growth signal no longer goes through, even though the sensor is still there. The reading is taken at the lysosome, where cholesterol arrives, not at the outside of the cell.", "boundary": "Single-study edge in this corpus (SHI2022): human cell lines, photoaffinity and mutational biochemistry. The binding site was later resolved by cryo-EM outside this corpus (Bayly-Jones 2024, PMID 39358511; Zhao 2025, PMID 39824976; Li 2025, PMID 41058362). What is shown is that occupancy of the site is required for cholesterol-driven mTORC1 activation in cultured cells; no dose-response in tissue, no animal or human endpoint, and no measurement of how this route divides the signal with the SLC38A9-NPC1 complex (CAS2017).", "supporting_studies": "SHI2022", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/CHOL-LYCHOS/" }, { "id": "LYCHOS-GATOR1", "source": "LYCHOS (GPR155)", "source_id": "lychos-gpr155", "target": "GATOR1", "target_id": "gator1", "effect": "inhibits", "type": "binding", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": "human cells", "mechanism": "When lysosomal cholesterol is high, cholesterol binds the permease-like region of LYCHOS and LYCHOS binds GATOR1 through a conserved cytoplasm-facing loop. Sequestering GATOR1, which is the GTPase-activating protein for the Rag GTPases, keeps that brake off the Rags, so mTORC1 is recruited to the lysosome in a cholesterol- and Rag-dependent way. Mutating the cholesterol-binding site impairs mTORC1 activation (SHI2022).", "mechanism_beginner": "Cholesterol is a building block the cell needs to grow, so the lysosome keeps track of how much it has. When there is plenty, it sticks to a sensor protein called LYCHOS, which then holds on to GATOR1, the brake that would otherwise stop mTORC1 being pulled to the lysosome. Brake held out of the way, the growth switch gets to work.", "boundary": "Single-study edge in this corpus: human cell lines and biochemistry (SHI2022), with the binding interface supported by later cryo-EM structures outside this corpus (Bayly-Jones 2024, PMID 39358511; Zhao 2025, PMID 39824976). No animal or human endpoint, and no measurement of how much of lysosomal cholesterol sensing runs through this route as against the SLC38A9-NPC1 complex (CAS2017), which is a separate cholesterol input to the same machinery.", "supporting_studies": "SHI2022", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/LYCHOS-GATOR1/" }, { "id": "MET-PKM2", "source": "Methionine", "source_id": "methionine", "target": "PKM2", "target_id": "pkm2", "effect": "binds", "type": "binding", "directness": "direct", "timescale": "seconds", "compartment": "cytosol", "species": "human cells", "mechanism": "Free methionine binds PKM2 in a recognition pocket separate from its catalytic site. Binding does not inhibit PKM2 as an enzyme: the sensing works independently of its glycolytic activity. What changes is PKM2's interaction with GATOR2: when methionine is present, PKM2 stops restraining GATOR2 (the restraining step is the separate PKM2-GATOR2 edge), so methionine switches that brake off. The binding was captured in living human cells with a photoaffinity methionine analogue and confirmed biochemically. This reads methionine itself, unlike SAMTOR, which reads the metabolite SAM.", "mechanism_beginner": "Methionine sticks to PKM2. This does not switch the enzyme off; it just stops PKM2 from holding the brake on GATOR2. A second methionine detector next to SAMTOR.", "boundary": "One study in cultured human cells (SANG2026): photoaffinity chemoproteomics plus biochemical validation. No affinity measurement in tissue, no animal or human test, and not yet replicated by another group. The direction (methionine binding relieves PKM2's restraint on GATOR2) is taken from the authors' abstract; the full text was not accessible when this link was written.", "supporting_studies": "SANG2026", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/MET-PKM2/" }, { "id": "PKM2-GATOR2", "source": "PKM2", "source_id": "pkm2", "target": "GATOR2", "target_id": "gator2", "effect": "inhibits", "type": "binding", "directness": "unresolved", "timescale": "minutes", "compartment": "cytosol", "species": "human cells", "mechanism": "When methionine is scarce, PKM2 interacts with the GATOR2 complex and keeps it from relaying the 'nutrients present' signal, so mTORC1 stays off. The authors propose that stabilising the PKM2-GATOR2 interaction would mimic methionine starvation. Same double-negative logic as Sestrin2 for leucine and CASTOR1 for arginine.", "mechanism_beginner": "Without methionine, PKM2 holds GATOR2 back, so mTORC1 stays off.", "boundary": "One study in cultured human cells (SANG2026). Whether PKM2 binds GATOR2 directly or through another protein, and on which subunit, is not stated in the abstract, so the step is marked unresolved. Cell and chemoproteomic data do not show that this sensor matters for mTORC1 in a whole organism. Not yet replicated.", "supporting_studies": "SANG2026", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/PKM2-GATOR2/" }, { "id": "TAX1BP1-TBK1", "source": "TAX1BP1", "source_id": "tax1bp1", "target": "TBK1", "target_id": "tbk1", "effect": "recruits", "type": "recruitment", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": "human cells", "mechanism": "TAX1BP1 acts as the adaptor that brings TBK1 onto stressed lysosomes, putting the kinase next to its substrate FNIP1.", "mechanism_beginner": "TAX1BP1 brings the kinase TBK1 to the lysosome.", "boundary": "One study in human cell lines (ESP2026). Full text not accessible when this link was written; the adaptor role is taken from the authors' abstract.", "supporting_studies": "ESP2026", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TAX1BP1-TBK1/" }, { "id": "TAX1BP1-ULK1", "source": "TAX1BP1", "source_id": "tax1bp1", "target": "ULK1", "target_id": "ulk1", "effect": "recruits", "type": "recruitment", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": "human cells", "mechanism": "The same adaptor, TAX1BP1, can bring ULK1 instead of TBK1 to stressed lysosomes; either kinase then phosphorylates FNIP1.", "mechanism_beginner": "TAX1BP1 can bring ULK1 to the lysosome instead of TBK1.", "boundary": "One study in human cell lines (ESP2026). Which kinase dominates in which cell type is not stated in the abstract. Full text not accessible when this link was written.", "supporting_studies": "ESP2026", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TAX1BP1-ULK1/" }, { "id": "TBK1-FNIP1", "source": "TBK1", "source_id": "tbk1", "target": "FLCN / FNIP1/2", "target_id": "flcn-fnip1-2", "effect": "inhibits", "type": "phosphorylation", "directness": "direct", "timescale": "minutes", "compartment": "lyso", "species": "human cells", "mechanism": "On the stressed lysosome, TBK1 phosphorylates FNIP1 at S296. This switches the FLCN-FNIP complex off, so mTORC1 can no longer hold TFEB in the cytoplasm and TFEB moves into the nucleus. ULK1 can do the same (ULK1-FNIP1).", "mechanism_beginner": "TBK1 tags FNIP1, which turns FLCN off and lets TFEB escape mTORC1's grip.", "boundary": "Human cell lines and ATP6V1B2-mutant follicular lymphoma samples (ESP2026); a nutrient-independent lysosomal-stress route. Single study, not yet replicated.", "supporting_studies": "ESP2026", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/TBK1-FNIP1/" }, { "id": "VATPASE-TAX1BP1", "source": "v-ATPase", "source_id": "v-atpase", "target": "TAX1BP1", "target_id": "tax1bp1", "effect": "recruits", "type": "recruitment", "directness": "unresolved", "timescale": "minutes", "compartment": "lyso", "species": "human cells", "mechanism": "Lysosomal stress acting through the v-ATPase proton pump brings the adaptor TAX1BP1 to the lysosome, where it docks the kinases TBK1 and ULK1. Recurrent ATP6V1B2 mutations in this pump, found in follicular lymphoma, keep the route switched on. This route is independent of nutrients and runs in parallel to amino-acid signalling through the same pump.", "mechanism_beginner": "A stressed lysosome's proton pump calls in the helper protein TAX1BP1.", "boundary": "One study (ESP2026) in human cell lines and ATP6V1B2-mutant follicular lymphoma samples. How the v-ATPase recruits TAX1BP1 (direct contact or an intermediate) is not stated in the abstract, so the step is marked unresolved. Full text not accessible when this link was written.", "supporting_studies": "ESP2026", "conflicting_studies": "", "human_relevance": "plausible", "consensus": "emerging", "curation_status": "Proposed", "review_status": "unreviewed", "atlas_url": "https://mtor-atlas.org/relation/VATPASE-TAX1BP1/" } ]