{"gene":"MTOR","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":1994,"finding":"MTOR (RAFT1) was identified as the mammalian protein that binds to FKBP12 in a rapamycin-dependent manner and is homologous to yeast TOR proteins. A protein complex of 245 kDa (RAFT1) interacts with FKBP12 only in the presence of rapamycin, establishing RAFT1/mTOR as the direct target of the FKBP12-rapamycin complex.","method":"Biochemical purification, peptide sequencing, cDNA cloning, co-immunoprecipitation with rapamycin/FKBP12","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — original identification by biochemical purification and sequencing, replicated by independent lab (PMID:7809080) in same year","pmids":["7518356"],"is_preprint":false},{"year":1994,"finding":"A 133 amino acid region of RAPT1/mTOR is sufficient for binding to the FKBP12/rapamycin complex; mutation of the serine residue corresponding to the yeast Tor rapamycin-resistance mutation abolishes this interaction.","method":"Yeast two-hybrid system, site-directed mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis defining binding domain, two orthogonal methods, independent from PMID:7518356","pmids":["7809080"],"is_preprint":false},{"year":1998,"finding":"RAFT1/mTOR directly phosphorylates p70 S6 kinase on Thr-389 (a rapamycin-sensitive, activating phosphorylation), and phosphorylates 4E-BP1 on Thr-36 and Thr-45, blocking its association with eIF-4E in vitro. Serum stimulates RAFT1 kinase activity with kinetics similar to p70S6K and 4E-BP1 phosphorylation.","method":"In vitro kinase assay, mutagenesis, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro kinase assay with defined phosphorylation sites, mutagenesis, replicated across multiple labs","pmids":["9465032"],"is_preprint":false},{"year":1999,"finding":"RAFT1/mTOR interacts with gephyrin (a protein required for glycine receptor clustering at neurons) in mammalian cells, and RAFT1 mutants that cannot associate with gephyrin fail to signal to downstream molecules p70 S6 kinase and 4E-BP1, indicating the gephyrin interaction is required for rapamycin-sensitive signaling.","method":"Co-immunoprecipitation, RAFT1 mutant analysis, downstream signaling readouts (p70S6K and 4E-BP1 phosphorylation)","journal":"Science (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction with functional consequence via loss-of-function mutants, single lab, two orthogonal methods","pmids":["10325225"],"is_preprint":false},{"year":2000,"finding":"Protein kinase Cδ (PKCδ) associates with RAFT1/mTOR, and PKCδ is required for phosphorylation and inactivation of 4E-BP1, stimulating cap-dependent translation. A dominant-negative PKCδ mutant inhibits serum-induced 4E-BP1 phosphorylation.","method":"Co-immunoprecipitation, dominant-negative mutant overexpression, in vitro phosphorylation assay, cap-dependent translation assay","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus dominant-negative functional validation, single lab, multiple orthogonal methods","pmids":["10698949"],"is_preprint":false},{"year":2001,"finding":"Loss-of-function mutation in mouse FRAP/mTOR gene results in embryonic lethality, and rapamycin treatment of early embryos phenocopies the FRAP mutant, demonstrating that mTOR kinase activity is required for embryonic proliferation and patterning in vivo.","method":"Genetic mouse knockout/loss-of-function mutation, rapamycin pharmacological inhibition, embryonic phenotyping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined phenotype corroborated by pharmacological inhibition (two independent approaches), published in peer-reviewed journal","pmids":["11707573"],"is_preprint":false},{"year":2002,"finding":"TSC2 is directly phosphorylated by Akt, which destabilizes TSC2 and disrupts its interaction with TSC1, and the TSC1-TSC2 complex inhibits mTOR signaling to p70 S6 kinase and 4E-BP1. This establishes TSC2 as an upstream inhibitor of mTOR acting downstream of Akt.","method":"In vitro kinase assay (Akt phosphorylation of TSC2), co-immunoprecipitation (TSC1-TSC2 interaction), Western blot (p70S6K and 4E-BP1 phosphorylation readouts), epistasis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct in vitro phosphorylation assay plus epistasis genetic analysis, replicated across multiple labs","pmids":["12172553"],"is_preprint":false},{"year":2005,"finding":"Rheb GTPase binds directly to the mTOR complex through separate interactions with the mTOR catalytic domain and LST8, independently of Rheb's ability to bind TSC2. GTP-charged Rheb (Gln64Leu mutant) associated with mTOR exhibits substantially higher kinase specific activity in vitro, while nucleotide-deficient Rheb mutants bind mTOR but are inhibitory, demonstrating that Rheb-GTP directly activates the mTOR kinase.","method":"Co-immunoprecipitation (in vivo and in vitro), in vitro kinase assay with Rheb mutants","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro binding and kinase assays with panel of Rheb mutants, multiple orthogonal methods, mechanism clearly defined","pmids":["15854902"],"is_preprint":false},{"year":2005,"finding":"mTOR complexed with RICTOR (mTORC2) is the Ser-473 kinase for Akt in 3T3-L1 adipocytes. Immunoprecipitated mTOR/RICTOR vesicles phosphorylate Akt on Ser-473 in a PI(3,4,5)P3-stimulated, wortmannin-sensitive manner, and siRNA knockdown of RICTOR suppresses insulin-activated Ser-473 phosphorylation.","method":"In vitro kinase assay with immunopurified complexes, siRNA knockdown, PI(3,4,5)P3-stimulated cell-free system","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — cell-free reconstitution of kinase activity plus siRNA loss-of-function, multiple orthogonal methods in single rigorous study","pmids":["16221682"],"is_preprint":false},{"year":2011,"finding":"mTOR phosphorylates Ulk1 on Ser-757 under nutrient-sufficient conditions, disrupting the interaction between Ulk1 and AMPK and thereby preventing Ulk1 activation and autophagy induction. This coordinated phosphorylation by mTOR (inhibitory) and AMPK (activating, Ser-317 and Ser-777) regulates autophagy in response to glucose availability.","method":"In vitro kinase assay, phospho-specific antibodies, co-immunoprecipitation, cell-based autophagy assays, mutagenesis of Ulk1 phosphorylation sites","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro phosphorylation, defined phosphorylation sites, mutagenesis, functional autophagy readout, highly cited and replicated","pmids":["21258367"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of a truncated mTOR-mLST8 complex with an ATP transition state mimic and ATP-site inhibitors revealed an intrinsically active kinase conformation with catalytic residues and mechanism similar to canonical protein kinases. The active site is recessed due to the FRB domain and an inhibitory helix. The FRB domain acts as a gatekeeper whose rapamycin-binding site interacts with substrates to grant access to the restricted active site; rapamycin-FKBP12 inhibits mTOR by blocking substrate recruitment and further restricting active-site access. mTOR-activating mutations map to the structural framework holding these elements in place.","method":"X-ray crystallography (co-crystal structures), in vitro biochemistry, mutagenesis of activating mutations","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures with multiple ligands plus in vitro biochemical validation, single rigorous study with multiple orthogonal methods","pmids":["23636326"],"is_preprint":false},{"year":2014,"finding":"mTOR is activated through a dectin-1-Akt-HIF-1α pathway in monocytes exposed to β-glucan, and this mTOR activation drives aerobic glycolysis (increased glucose consumption, lactate production, elevated NAD+/NADH ratio) as the metabolic basis for trained immunity. Inhibition of Akt, mTOR, or HIF-1α blocked trained immunity induction.","method":"Pharmacological inhibition (Akt, mTOR, HIF-1α inhibitors), metabolic flux measurements, genome-wide transcriptome and histone modification profiling, myeloid cell-specific HIF-1α knockout mice","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (cell-type-specific KO) plus pharmacological inhibition with defined metabolic and immunological readouts, multiple orthogonal methods","pmids":["25258083"],"is_preprint":false},{"year":2016,"finding":"Resistance to second-generation mTOR kinase inhibitors (TORKi) arises from activating mutations that increase intrinsic mTOR kinase activity (not active-site mutations blocking drug binding). A third-generation bivalent mTOR inhibitor (RapaLink-1) that simultaneously occupies the rapamycin-binding (FRB) pocket and the ATP-binding site overcomes resistance to both first- and second-generation mTOR inhibitors.","method":"Resistance mutation mapping in cell lines, in vitro kinase assays with resistant mTOR mutants, bivalent inhibitor design and functional testing","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assays with defined mutations plus rational drug design validated in cell-based and in vivo models, published in Nature with multiple orthogonal approaches","pmids":["27279227"],"is_preprint":false}],"current_model":"mTOR is a serine/threonine kinase (PI3K-related family) that forms two functionally distinct complexes (mTORC1 with raptor/mLST8, and mTORC2 with rictor/mSin1/mLST8); mTORC1 directly phosphorylates p70 S6 kinase (Thr-389) and 4E-BP1 (Thr-36/45) to promote translation, and phosphorylates Ulk1 (Ser-757) to suppress autophagy, while mTORC2 phosphorylates Akt on Ser-473 to promote cell survival; mTORC1 is activated by Rheb-GTP (which binds the mTOR catalytic domain) downstream of the Akt-TSC1/TSC2 axis, and is inhibited allosterically by FKBP12-rapamycin binding to the FRB domain which blocks substrate recruitment to the sterically restricted active site, as revealed by crystal structures."},"narrative":{"mechanistic_narrative":"MTOR is a serine/threonine protein kinase that serves as a central node coupling growth factor and nutrient signals to cell growth, translation, autophagy, and metabolism [PMID:9465032, PMID:21258367]. It was identified as the 245 kDa mammalian target (RAFT1/FRAP) of the FKBP12-rapamycin complex, which binds a defined ~133-residue region whose interaction depends on a conserved serine corresponding to the yeast TOR rapamycin-resistance site [PMID:7518356, PMID:7809080]. As a kinase, mTOR directly phosphorylates p70 S6 kinase on Thr-389 and 4E-BP1 on Thr-36/Thr-45, the latter blocking 4E-BP1 association with eIF-4E to license cap-dependent translation [PMID:9465032]. mTOR activity is gated by the upstream Akt–TSC2 axis, in which Akt phosphorylates and destabilizes TSC2 to relieve TSC1-TSC2 inhibition of mTOR signaling [PMID:12172553], while GTP-charged Rheb binds the mTOR catalytic domain and mLST8 to directly stimulate kinase activity [PMID:15854902]. In a distinct rictor-containing complex (mTORC2), mTOR is the Ser-473 kinase for Akt, acting in a PI(3,4,5)P3-stimulated, wortmannin-sensitive manner [PMID:16221682]. Under nutrient-sufficient conditions mTOR phosphorylates Ulk1 on Ser-757 to disrupt Ulk1-AMPK association and suppress autophagy [PMID:21258367], and it drives aerobic glycolysis downstream of a dectin-1–Akt–HIF-1α pathway to support trained immunity in monocytes [PMID:25258083]. Crystal structures of the mTOR-mLST8 catalytic core reveal an intrinsically active kinase with a recessed active site guarded by the FRB domain, which recruits substrates and is blocked by rapamycin-FKBP12; activating mutations map to the framework holding these elements in place, and bivalent inhibitors occupying both the FRB and ATP pockets overcome resistance to earlier-generation drugs [PMID:23636326, PMID:27279227]. Genetic loss of mTOR in mice causes embryonic lethality phenocopied by rapamycin, establishing its essential role in proliferation and patterning in vivo [PMID:11707573].","teleology":[{"year":1994,"claim":"Identified the mammalian molecular target of the immunosuppressant rapamycin, answering what protein the FKBP12-rapamycin complex acts upon.","evidence":"Biochemical purification, peptide sequencing, cDNA cloning, and rapamycin-dependent co-immunoprecipitation with FKBP12; complemented by yeast two-hybrid and mutagenesis defining the binding region","pmids":["7518356","7809080"],"confidence":"High","gaps":["Did not establish mTOR's catalytic activity or substrates","Functional consequence of FKBP12-rapamycin binding on signaling not yet defined"]},{"year":1998,"claim":"Established mTOR as a direct kinase by identifying its phosphorylation of p70 S6 kinase and 4E-BP1, linking it to translational control.","evidence":"In vitro kinase assays with defined phosphosites (Thr-389 on S6K; Thr-36/45 on 4E-BP1), mutagenesis, and serum-stimulation kinetics","pmids":["9465032"],"confidence":"High","gaps":["Upstream activation mechanism unknown","Complex composition (raptor/rictor) not yet defined"]},{"year":1999,"claim":"Probed which physical partners are required for mTOR signaling, implicating gephyrin in downstream output.","evidence":"Co-immunoprecipitation and RAFT1 mutants unable to bind gephyrin assayed for S6K/4E-BP1 phosphorylation","pmids":["10325225"],"confidence":"Medium","gaps":["Single lab, mechanism of gephyrin's contribution unresolved","Relationship to later-defined complex subunits unclear"]},{"year":2000,"claim":"Tested whether additional kinases cooperate with mTOR in 4E-BP1 control, identifying PKCδ as an associated requirement.","evidence":"Co-immunoprecipitation, dominant-negative PKCδ, in vitro phosphorylation, and cap-dependent translation assays","pmids":["10698949"],"confidence":"Medium","gaps":["Single lab; direct vs indirect role of PKCδ not fully separated","Whether PKCδ is a stable complex component unknown"]},{"year":2001,"claim":"Determined the in vivo requirement for mTOR, showing its kinase activity is essential for embryonic proliferation and patterning.","evidence":"Mouse loss-of-function genetics phenocopied by rapamycin treatment of early embryos","pmids":["11707573"],"confidence":"High","gaps":["Tissue-specific roles not dissected","Which downstream effectors mediate the lethal phenotype not resolved"]},{"year":2002,"claim":"Defined the upstream regulatory axis, placing TSC1-TSC2 as an Akt-controlled inhibitor of mTOR signaling.","evidence":"In vitro Akt phosphorylation of TSC2, co-IP of TSC1-TSC2, epistasis on S6K/4E-BP1 readouts","pmids":["12172553"],"confidence":"High","gaps":["How TSC1-TSC2 loss is transduced to mTOR not yet mechanistic (Rheb link defined later)"]},{"year":2005,"claim":"Resolved the direct activator of mTOR kinase and identified a second mTOR complex, distinguishing mTORC1 and mTORC2 functions.","evidence":"Rheb mutant co-IP and in vitro kinase assays showing GTP-Rheb activation; immunopurified mTOR/rictor cell-free assays plus rictor siRNA showing Akt Ser-473 phosphorylation","pmids":["15854902","16221682"],"confidence":"High","gaps":["Structural basis of Rheb activation not yet defined","How the two complexes are differentially assembled and localized not addressed"]},{"year":2011,"claim":"Connected mTOR to autophagy control, showing it directly inhibits Ulk1 under nutrient-sufficient conditions.","evidence":"In vitro kinase assay, Ulk1 Ser-757 phospho-site mutagenesis, co-IP of Ulk1-AMPK, and cellular autophagy readouts","pmids":["21258367"],"confidence":"High","gaps":["Integration with other nutrient inputs to mTOR not fully resolved here"]},{"year":2013,"claim":"Provided the structural mechanism of catalysis and rapamycin inhibition, explaining the recessed active site and FRB gatekeeping.","evidence":"X-ray co-crystal structures of mTOR-mLST8 with transition-state mimic and inhibitors, plus mutagenesis of activating mutations","pmids":["23636326"],"confidence":"High","gaps":["Structures used truncated complex; full holocomplex and Rheb-bound states not captured","Substrate-bound conformations not resolved"]},{"year":2014,"claim":"Extended mTOR function to immunometabolism, showing it drives aerobic glycolysis to support trained immunity.","evidence":"Pharmacological inhibition of Akt/mTOR/HIF-1α, metabolic flux, transcriptome/histone profiling, and myeloid HIF-1α knockout mice","pmids":["25258083"],"confidence":"High","gaps":["Which mTOR complex/substrates mediate the glycolytic switch not pinpointed"]},{"year":2016,"claim":"Clarified clinical resistance mechanisms and validated a bivalent inhibitor strategy targeting mTOR.","evidence":"Resistance mutation mapping, in vitro kinase assays of mutants, and design/testing of FRB+ATP-site bivalent inhibitor RapaLink-1","pmids":["27279227"],"confidence":"High","gaps":["Long-term in vivo durability and resistance to bivalent inhibitors not addressed"]},{"year":null,"claim":"How mTORC1 and mTORC2 substrate selection, subcellular localization, and complex assembly are dynamically coordinated across diverse upstream inputs remains incompletely defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate-engaged or Rheb-bound holocomplex in the corpus","Spatial regulation of the two complexes not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,8,9]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[10]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,6]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11]}],"complexes":["mTORC1","mTORC2"],"partners":["FKBP12","RICTOR","MLST8","RHEB","TSC2","AKT1","ULK1","PRKCD"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P42345","full_name":"Serine/threonine-protein kinase mTOR","aliases":["FK506-binding protein 12-rapamycin complex-associated protein 1","FKBP12-rapamycin complex-associated protein","Mammalian target of rapamycin","mTOR","Mechanistic target of rapamycin","Rapamycin and FKBP12 target 1","Rapamycin target protein 1","Tyrosine-protein kinase mTOR"],"length_aa":2549,"mass_kda":288.9,"function":"Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084, PubMed:29150432, PubMed:29236692, PubMed:31112131, PubMed:31601708, PubMed:32561715, PubMed:34519269, PubMed:37751742). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins (PubMed:15268862, PubMed:15467718, PubMed:17517883, PubMed:18372248, PubMed:18497260, PubMed:18925875, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704, PubMed:30171069, PubMed:29236692, PubMed:37751742). Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15268862, PubMed:15467718, PubMed:18497260, PubMed:18925875, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704, PubMed:29424687, PubMed:29567957, PubMed:35926713). In response to nutrients, growth factors or amino acids, mTORC1 is recruited to the lysosome membrane and promotes protein, lipid and nucleotide synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084, PubMed:29150432, PubMed:29236692, PubMed:31112131, PubMed:34519269). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (PubMed:24403073, PubMed:29236692). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4 (PubMed:12087098, PubMed:12150925, PubMed:18925875, PubMed:29150432, PubMed:29236692). Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex (PubMed:23429703, PubMed:23429704). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (PubMed:20516213). Activates dormant ribosomes by mediating phosphorylation of SERBP1, leading to SERBP1 inactivation and reactivation of translation (PubMed:36691768). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (PubMed:23426360). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). In the same time, mTORC1 inhibits catabolic pathways: negatively regulates autophagy through phosphorylation of ULK1 (PubMed:32561715). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (PubMed:32561715). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (PubMed:20537536). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (PubMed:30704899). Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA (PubMed:23524951, PubMed:25438055). mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor (PubMed:21659604). Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules (PubMed:12231510). The mTORC1 complex is inhibited in response to starvation and amino acid depletion (PubMed:12150925, PubMed:12150926, PubMed:24403073, PubMed:31695197). The non-canonical mTORC1 complex, which acts independently of RHEB, specifically mediates phosphorylation of MiT/TFE factors MITF, TFEB and TFE3 in the presence of nutrients, promoting their cytosolic retention and inactivation (PubMed:22343943, PubMed:22576015, PubMed:22692423, PubMed:24448649, PubMed:32612235, PubMed:36608670, PubMed:36697823). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:22343943, PubMed:22576015, PubMed:22692423, PubMed:24448649, PubMed:32612235, PubMed:36608670). The mTORC1 complex regulates pyroptosis in macrophages by promoting GSDMD oligomerization (PubMed:34289345). MTOR phosphorylates RPTOR which in turn inhibits mTORC1 (By similarity). As part of the mTORC2 complex, MTOR transduces signals from growth factors to pathways involved in proliferation, cytoskeletal organization, lipogenesis and anabolic output (PubMed:15268862, PubMed:15467718, PubMed:24670654, PubMed:29424687, PubMed:29567957, PubMed:35926713). In response to growth factors, mTORC2 phosphorylates and activates AGC protein kinase family members, including AKT (AKT1, AKT2 and AKT3), PKC (PRKCA, PRKCB and PRKCE) and SGK1 (PubMed:15268862, PubMed:15467718, PubMed:21376236, PubMed:24670654, PubMed:29424687, PubMed:29567957, PubMed:35926713). In contrast to mTORC1, mTORC2 is nutrient-insensitive (PubMed:15467718). mTORC2 plays a critical role in AKT1 activation by mediating phosphorylation of different sites depending on the context, such as 'Thr-450', 'Ser-473', 'Ser-477' or 'Thr-479', facilitating the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDPK1/PDK1 which is a prerequisite for full activation (PubMed:15718470, PubMed:21376236, PubMed:24670654, PubMed:29424687, PubMed:29567957). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed:18925875). mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B (PubMed:15268862). The mTORC2 complex also phosphorylates various proteins involved in insulin signaling, such as FBXW8 and IGF2BP1 (By similarity). May also regulate insulin signaling by acting as a tyrosine protein kinase that catalyzes phosphorylation of IGF1R and INSR; additional evidence are however required to confirm this result in vivo (PubMed:26584640). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (By similarity). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (By similarity)","subcellular_location":"Lysosome membrane; Endoplasmic reticulum membrane; Golgi apparatus membrane; Cell membrane; Mitochondrion outer membrane; Cytoplasm; Nucleus; Nucleus, PML body; Microsome membrane; Cytoplasmic vesicle, phagosome","url":"https://www.uniprot.org/uniprotkb/P42345/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MTOR","classification":"Common Essential","n_dependent_lines":1186,"n_total_lines":1208,"dependency_fraction":0.9817880794701986},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000198793","cell_line_id":"CID000408","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"RPTOR","stoichiometry":10.0},{"gene":"RICTOR","stoichiometry":10.0},{"gene":"VMP1","stoichiometry":10.0},{"gene":"AKT1S1","stoichiometry":0.2},{"gene":"KLC2","stoichiometry":0.2},{"gene":"KLC4","stoichiometry":0.2},{"gene":"FOXP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000408","total_profiled":1310},"omim":[{"mim_id":"621550","title":"TRANSMEMBRANE PROTEIN 39A; TMEM39A","url":"https://www.omim.org/entry/621550"},{"mim_id":"621519","title":"SCAFFOLDING CK1-ANCHORING PROTEIN B; SACK1B","url":"https://www.omim.org/entry/621519"},{"mim_id":"621460","title":"NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, THIN CORPUS CALLOSUM, AND DECREASED BRAIN 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50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"MTOR (RAFT1) was identified as the mammalian protein that binds to FKBP12 in a rapamycin-dependent manner and is homologous to yeast TOR proteins. A protein complex of 245 kDa (RAFT1) interacts with FKBP12 only in the presence of rapamycin, establishing RAFT1/mTOR as the direct target of the FKBP12-rapamycin complex.\",\n      \"method\": \"Biochemical purification, peptide sequencing, cDNA cloning, co-immunoprecipitation with rapamycin/FKBP12\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — original identification by biochemical purification and sequencing, replicated by independent lab (PMID:7809080) in same year\",\n      \"pmids\": [\"7518356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"A 133 amino acid region of RAPT1/mTOR is sufficient for binding to the FKBP12/rapamycin complex; mutation of the serine residue corresponding to the yeast Tor rapamycin-resistance mutation abolishes this interaction.\",\n      \"method\": \"Yeast two-hybrid system, site-directed mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis defining binding domain, two orthogonal methods, independent from PMID:7518356\",\n      \"pmids\": [\"7809080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RAFT1/mTOR directly phosphorylates p70 S6 kinase on Thr-389 (a rapamycin-sensitive, activating phosphorylation), and phosphorylates 4E-BP1 on Thr-36 and Thr-45, blocking its association with eIF-4E in vitro. Serum stimulates RAFT1 kinase activity with kinetics similar to p70S6K and 4E-BP1 phosphorylation.\",\n      \"method\": \"In vitro kinase assay, mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro kinase assay with defined phosphorylation sites, mutagenesis, replicated across multiple labs\",\n      \"pmids\": [\"9465032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RAFT1/mTOR interacts with gephyrin (a protein required for glycine receptor clustering at neurons) in mammalian cells, and RAFT1 mutants that cannot associate with gephyrin fail to signal to downstream molecules p70 S6 kinase and 4E-BP1, indicating the gephyrin interaction is required for rapamycin-sensitive signaling.\",\n      \"method\": \"Co-immunoprecipitation, RAFT1 mutant analysis, downstream signaling readouts (p70S6K and 4E-BP1 phosphorylation)\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction with functional consequence via loss-of-function mutants, single lab, two orthogonal methods\",\n      \"pmids\": [\"10325225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Protein kinase Cδ (PKCδ) associates with RAFT1/mTOR, and PKCδ is required for phosphorylation and inactivation of 4E-BP1, stimulating cap-dependent translation. A dominant-negative PKCδ mutant inhibits serum-induced 4E-BP1 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative mutant overexpression, in vitro phosphorylation assay, cap-dependent translation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus dominant-negative functional validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"10698949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Loss-of-function mutation in mouse FRAP/mTOR gene results in embryonic lethality, and rapamycin treatment of early embryos phenocopies the FRAP mutant, demonstrating that mTOR kinase activity is required for embryonic proliferation and patterning in vivo.\",\n      \"method\": \"Genetic mouse knockout/loss-of-function mutation, rapamycin pharmacological inhibition, embryonic phenotyping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined phenotype corroborated by pharmacological inhibition (two independent approaches), published in peer-reviewed journal\",\n      \"pmids\": [\"11707573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TSC2 is directly phosphorylated by Akt, which destabilizes TSC2 and disrupts its interaction with TSC1, and the TSC1-TSC2 complex inhibits mTOR signaling to p70 S6 kinase and 4E-BP1. This establishes TSC2 as an upstream inhibitor of mTOR acting downstream of Akt.\",\n      \"method\": \"In vitro kinase assay (Akt phosphorylation of TSC2), co-immunoprecipitation (TSC1-TSC2 interaction), Western blot (p70S6K and 4E-BP1 phosphorylation readouts), epistasis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct in vitro phosphorylation assay plus epistasis genetic analysis, replicated across multiple labs\",\n      \"pmids\": [\"12172553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Rheb GTPase binds directly to the mTOR complex through separate interactions with the mTOR catalytic domain and LST8, independently of Rheb's ability to bind TSC2. GTP-charged Rheb (Gln64Leu mutant) associated with mTOR exhibits substantially higher kinase specific activity in vitro, while nucleotide-deficient Rheb mutants bind mTOR but are inhibitory, demonstrating that Rheb-GTP directly activates the mTOR kinase.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), in vitro kinase assay with Rheb mutants\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro binding and kinase assays with panel of Rheb mutants, multiple orthogonal methods, mechanism clearly defined\",\n      \"pmids\": [\"15854902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"mTOR complexed with RICTOR (mTORC2) is the Ser-473 kinase for Akt in 3T3-L1 adipocytes. Immunoprecipitated mTOR/RICTOR vesicles phosphorylate Akt on Ser-473 in a PI(3,4,5)P3-stimulated, wortmannin-sensitive manner, and siRNA knockdown of RICTOR suppresses insulin-activated Ser-473 phosphorylation.\",\n      \"method\": \"In vitro kinase assay with immunopurified complexes, siRNA knockdown, PI(3,4,5)P3-stimulated cell-free system\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — cell-free reconstitution of kinase activity plus siRNA loss-of-function, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"16221682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"mTOR phosphorylates Ulk1 on Ser-757 under nutrient-sufficient conditions, disrupting the interaction between Ulk1 and AMPK and thereby preventing Ulk1 activation and autophagy induction. This coordinated phosphorylation by mTOR (inhibitory) and AMPK (activating, Ser-317 and Ser-777) regulates autophagy in response to glucose availability.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibodies, co-immunoprecipitation, cell-based autophagy assays, mutagenesis of Ulk1 phosphorylation sites\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro phosphorylation, defined phosphorylation sites, mutagenesis, functional autophagy readout, highly cited and replicated\",\n      \"pmids\": [\"21258367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of a truncated mTOR-mLST8 complex with an ATP transition state mimic and ATP-site inhibitors revealed an intrinsically active kinase conformation with catalytic residues and mechanism similar to canonical protein kinases. The active site is recessed due to the FRB domain and an inhibitory helix. The FRB domain acts as a gatekeeper whose rapamycin-binding site interacts with substrates to grant access to the restricted active site; rapamycin-FKBP12 inhibits mTOR by blocking substrate recruitment and further restricting active-site access. mTOR-activating mutations map to the structural framework holding these elements in place.\",\n      \"method\": \"X-ray crystallography (co-crystal structures), in vitro biochemistry, mutagenesis of activating mutations\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures with multiple ligands plus in vitro biochemical validation, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"23636326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"mTOR is activated through a dectin-1-Akt-HIF-1α pathway in monocytes exposed to β-glucan, and this mTOR activation drives aerobic glycolysis (increased glucose consumption, lactate production, elevated NAD+/NADH ratio) as the metabolic basis for trained immunity. Inhibition of Akt, mTOR, or HIF-1α blocked trained immunity induction.\",\n      \"method\": \"Pharmacological inhibition (Akt, mTOR, HIF-1α inhibitors), metabolic flux measurements, genome-wide transcriptome and histone modification profiling, myeloid cell-specific HIF-1α knockout mice\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (cell-type-specific KO) plus pharmacological inhibition with defined metabolic and immunological readouts, multiple orthogonal methods\",\n      \"pmids\": [\"25258083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Resistance to second-generation mTOR kinase inhibitors (TORKi) arises from activating mutations that increase intrinsic mTOR kinase activity (not active-site mutations blocking drug binding). A third-generation bivalent mTOR inhibitor (RapaLink-1) that simultaneously occupies the rapamycin-binding (FRB) pocket and the ATP-binding site overcomes resistance to both first- and second-generation mTOR inhibitors.\",\n      \"method\": \"Resistance mutation mapping in cell lines, in vitro kinase assays with resistant mTOR mutants, bivalent inhibitor design and functional testing\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assays with defined mutations plus rational drug design validated in cell-based and in vivo models, published in Nature with multiple orthogonal approaches\",\n      \"pmids\": [\"27279227\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"mTOR is a serine/threonine kinase (PI3K-related family) that forms two functionally distinct complexes (mTORC1 with raptor/mLST8, and mTORC2 with rictor/mSin1/mLST8); mTORC1 directly phosphorylates p70 S6 kinase (Thr-389) and 4E-BP1 (Thr-36/45) to promote translation, and phosphorylates Ulk1 (Ser-757) to suppress autophagy, while mTORC2 phosphorylates Akt on Ser-473 to promote cell survival; mTORC1 is activated by Rheb-GTP (which binds the mTOR catalytic domain) downstream of the Akt-TSC1/TSC2 axis, and is inhibited allosterically by FKBP12-rapamycin binding to the FRB domain which blocks substrate recruitment to the sterically restricted active site, as revealed by crystal structures.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTOR is a serine/threonine protein kinase that serves as a central node coupling growth factor and nutrient signals to cell growth, translation, autophagy, and metabolism [#2, #9]. It was identified as the 245 kDa mammalian target (RAFT1/FRAP) of the FKBP12-rapamycin complex, which binds a defined ~133-residue region whose interaction depends on a conserved serine corresponding to the yeast TOR rapamycin-resistance site [#0, #1]. As a kinase, mTOR directly phosphorylates p70 S6 kinase on Thr-389 and 4E-BP1 on Thr-36/Thr-45, the latter blocking 4E-BP1 association with eIF-4E to license cap-dependent translation [#2]. mTOR activity is gated by the upstream Akt–TSC2 axis, in which Akt phosphorylates and destabilizes TSC2 to relieve TSC1-TSC2 inhibition of mTOR signaling [#6], while GTP-charged Rheb binds the mTOR catalytic domain and mLST8 to directly stimulate kinase activity [#7]. In a distinct rictor-containing complex (mTORC2), mTOR is the Ser-473 kinase for Akt, acting in a PI(3,4,5)P3-stimulated, wortmannin-sensitive manner [#8]. Under nutrient-sufficient conditions mTOR phosphorylates Ulk1 on Ser-757 to disrupt Ulk1-AMPK association and suppress autophagy [#9], and it drives aerobic glycolysis downstream of a dectin-1–Akt–HIF-1α pathway to support trained immunity in monocytes [#11]. Crystal structures of the mTOR-mLST8 catalytic core reveal an intrinsically active kinase with a recessed active site guarded by the FRB domain, which recruits substrates and is blocked by rapamycin-FKBP12; activating mutations map to the framework holding these elements in place, and bivalent inhibitors occupying both the FRB and ATP pockets overcome resistance to earlier-generation drugs [#10, #12]. Genetic loss of mTOR in mice causes embryonic lethality phenocopied by rapamycin, establishing its essential role in proliferation and patterning in vivo [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identified the mammalian molecular target of the immunosuppressant rapamycin, answering what protein the FKBP12-rapamycin complex acts upon.\",\n      \"evidence\": \"Biochemical purification, peptide sequencing, cDNA cloning, and rapamycin-dependent co-immunoprecipitation with FKBP12; complemented by yeast two-hybrid and mutagenesis defining the binding region\",\n      \"pmids\": [\"7518356\", \"7809080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish mTOR's catalytic activity or substrates\", \"Functional consequence of FKBP12-rapamycin binding on signaling not yet defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Established mTOR as a direct kinase by identifying its phosphorylation of p70 S6 kinase and 4E-BP1, linking it to translational control.\",\n      \"evidence\": \"In vitro kinase assays with defined phosphosites (Thr-389 on S6K; Thr-36/45 on 4E-BP1), mutagenesis, and serum-stimulation kinetics\",\n      \"pmids\": [\"9465032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activation mechanism unknown\", \"Complex composition (raptor/rictor) not yet defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Probed which physical partners are required for mTOR signaling, implicating gephyrin in downstream output.\",\n      \"evidence\": \"Co-immunoprecipitation and RAFT1 mutants unable to bind gephyrin assayed for S6K/4E-BP1 phosphorylation\",\n      \"pmids\": [\"10325225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, mechanism of gephyrin's contribution unresolved\", \"Relationship to later-defined complex subunits unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Tested whether additional kinases cooperate with mTOR in 4E-BP1 control, identifying PKCδ as an associated requirement.\",\n      \"evidence\": \"Co-immunoprecipitation, dominant-negative PKCδ, in vitro phosphorylation, and cap-dependent translation assays\",\n      \"pmids\": [\"10698949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; direct vs indirect role of PKCδ not fully separated\", \"Whether PKCδ is a stable complex component unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Determined the in vivo requirement for mTOR, showing its kinase activity is essential for embryonic proliferation and patterning.\",\n      \"evidence\": \"Mouse loss-of-function genetics phenocopied by rapamycin treatment of early embryos\",\n      \"pmids\": [\"11707573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific roles not dissected\", \"Which downstream effectors mediate the lethal phenotype not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the upstream regulatory axis, placing TSC1-TSC2 as an Akt-controlled inhibitor of mTOR signaling.\",\n      \"evidence\": \"In vitro Akt phosphorylation of TSC2, co-IP of TSC1-TSC2, epistasis on S6K/4E-BP1 readouts\",\n      \"pmids\": [\"12172553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TSC1-TSC2 loss is transduced to mTOR not yet mechanistic (Rheb link defined later)\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the direct activator of mTOR kinase and identified a second mTOR complex, distinguishing mTORC1 and mTORC2 functions.\",\n      \"evidence\": \"Rheb mutant co-IP and in vitro kinase assays showing GTP-Rheb activation; immunopurified mTOR/rictor cell-free assays plus rictor siRNA showing Akt Ser-473 phosphorylation\",\n      \"pmids\": [\"15854902\", \"16221682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Rheb activation not yet defined\", \"How the two complexes are differentially assembled and localized not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected mTOR to autophagy control, showing it directly inhibits Ulk1 under nutrient-sufficient conditions.\",\n      \"evidence\": \"In vitro kinase assay, Ulk1 Ser-757 phospho-site mutagenesis, co-IP of Ulk1-AMPK, and cellular autophagy readouts\",\n      \"pmids\": [\"21258367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration with other nutrient inputs to mTOR not fully resolved here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural mechanism of catalysis and rapamycin inhibition, explaining the recessed active site and FRB gatekeeping.\",\n      \"evidence\": \"X-ray co-crystal structures of mTOR-mLST8 with transition-state mimic and inhibitors, plus mutagenesis of activating mutations\",\n      \"pmids\": [\"23636326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures used truncated complex; full holocomplex and Rheb-bound states not captured\", \"Substrate-bound conformations not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended mTOR function to immunometabolism, showing it drives aerobic glycolysis to support trained immunity.\",\n      \"evidence\": \"Pharmacological inhibition of Akt/mTOR/HIF-1α, metabolic flux, transcriptome/histone profiling, and myeloid HIF-1α knockout mice\",\n      \"pmids\": [\"25258083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which mTOR complex/substrates mediate the glycolytic switch not pinpointed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Clarified clinical resistance mechanisms and validated a bivalent inhibitor strategy targeting mTOR.\",\n      \"evidence\": \"Resistance mutation mapping, in vitro kinase assays of mutants, and design/testing of FRB+ATP-site bivalent inhibitor RapaLink-1\",\n      \"pmids\": [\"27279227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term in vivo durability and resistance to bivalent inhibitors not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How mTORC1 and mTORC2 substrate selection, subcellular localization, and complex assembly are dynamically coordinated across diverse upstream inputs remains incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate-engaged or Rheb-bound holocomplex in the corpus\", \"Spatial regulation of the two complexes not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 8, 9]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\"mTORC1\", \"mTORC2\"],\n    \"partners\": [\"FKBP12\", \"RICTOR\", \"MLST8\", \"RHEB\", \"TSC2\", \"AKT1\", \"ULK1\", \"PRKCD\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}