{"gene":"RPTOR","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":2002,"finding":"Raptor forms a stoichiometric complex with mTOR; this association negatively regulates mTOR kinase activity under nutrient deprivation, while raptor is required for nutrient-stimulated signaling to S6K1, maintenance of cell size, and mTOR protein expression.","method":"Co-immunoprecipitation, mass spectrometry, RNAi knockdown, cell size measurements","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi phenotype, multiple orthogonal methods, replicated by independent lab in same issue (PMID:12150926)","pmids":["12150925","12150926"],"is_preprint":false},{"year":2002,"finding":"Raptor binds 4EBP1 and p70S6K and is required as a scaffold for mTOR-catalyzed phosphorylation of 4EBP1 in vitro; partial RNAi knockdown of raptor reduces mTOR-catalyzed 4EBP1 phosphorylation, and C. elegans raptor RNAi phenocopies Ce-TOR inactivation.","method":"In vitro kinase assay, Co-immunoprecipitation, RNAi in mammalian cells and C. elegans","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis support, RNAi in two organisms, independently replicated","pmids":["12150926"],"is_preprint":false},{"year":2003,"finding":"Raptor binds the TOS (TOR signaling) motif of p70S6K and 4EBP1; a point mutation in the 4EBP1 TOS motif abolishes raptor binding and eliminates mTOR-catalyzed 4EBP1 phosphorylation in vitro and in vivo, demonstrating raptor as the substrate-recruiting scaffold.","method":"Co-immunoprecipitation, site-directed mutagenesis, in vitro kinase assay, cell size measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis, replicated by independent lab (PMID:12747827)","pmids":["12604610","12747827"],"is_preprint":false},{"year":2003,"finding":"GbetaL (mLST8) binds the mTOR kinase domain and stabilizes the raptor–mTOR interaction; GbetaL stimulates mTOR kinase activity toward S6K1 and 4E-BP1, an effect reversed by stable raptor–mTOR association; nutrients and rapamycin regulate mTOR–raptor association only in complexes also containing GbetaL.","method":"Co-immunoprecipitation, in vitro kinase assay, RNAi, cell size measurement","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus Co-IP plus RNAi, single lab but multiple orthogonal methods","pmids":["12718876"],"is_preprint":false},{"year":2004,"finding":"Rictor defines a second mTOR complex (mTORC2) that does not contain raptor and is rapamycin-insensitive; raptor-containing mTORC1 regulates S6K1 while rictor-containing mTORC2 modulates PKCα phosphorylation and the actin cytoskeleton.","method":"Co-immunoprecipitation, mass spectrometry, RNAi, immunofluorescence","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi with defined phenotypes, independently replicated","pmids":["15268862"],"is_preprint":false},{"year":2004,"finding":"Rapamycin/FKBP12 complex inhibits mTOR function at least in part by dissociating raptor from mTOR both in vivo and directly in vitro; this dissociation uncouples mTOR from raptor-dependent substrates without altering intrinsic mTOR catalytic activity.","method":"Co-immunoprecipitation, in vitro binding assay, in vitro kinase assay","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution showing rapamycin-induced dissociation, confirmed in vivo, single lab","pmids":["15066126"],"is_preprint":false},{"year":2005,"finding":"The raptor–mTOR complex selectively phosphorylates rapamycin-sensitive forms of S6K1, while the rictor–mTOR complex phosphorylates rapamycin-resistant S6K1 mutants lacking the C-terminal domain; TOS motif-independent recognition is required for rictor-mTOR-mediated phosphorylation.","method":"In vitro kinase assay, Co-immunoprecipitation, mutant S6K1 constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with defined mutants, mechanistically discriminates the two complexes, single lab","pmids":["15809305"],"is_preprint":false},{"year":2005,"finding":"Redox state regulates the raptor–mTOR complex: oxidizing agents increase S6K1 phosphorylation and make it nutrient-insensitive, while the reducing agent BAL stabilizes mTOR–raptor interaction (mimicking nutrient deprivation) and inhibits S6K1 phosphorylation.","method":"Co-immunoprecipitation, immunoblot, pharmacological redox manipulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and signaling readouts, single lab, pharmacological tools only","pmids":["16183647"],"is_preprint":false},{"year":2006,"finding":"Raptor-dependent mTOR directly phosphorylates IRS-1 at Ser636/639; raptor binds IRS-1 directly and serves as a scaffold for this phosphorylation, providing a mechanism for mTOR-mediated negative feedback on PI3K/Akt signaling.","method":"Co-immunoprecipitation, RNAi knockdown, phospho-specific immunoblot, in vitro kinase assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding and in vitro phosphorylation demonstrated, RNAi confirmation, replicated in follow-up study (PMID:19561084)","pmids":["16354680","19561084"],"is_preprint":false},{"year":2006,"finding":"Raptor is ubiquitinated by the DDB1-CUL4 ubiquitin ligase complex; the deubiquitylase UCH-L1 disrupts this DDB1-CUL4–raptor complex, counteracts raptor ubiquitination, and leads to mTORC1 dissolution with secondary mTORC2 increase.","method":"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, Uchl1 transgenic and knockout mice","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vivo genetic models, multiple orthogonal methods, single lab","pmids":["23297343"],"is_preprint":false},{"year":2006,"finding":"Mice lacking raptor die early in embryonic development, establishing that mTORC1/raptor function is essential for early development; mLST8 is required only for mTORC2 (rictor-mTOR) signaling to Akt and PKCα, not for raptor-mTOR signaling to S6K1.","method":"Conditional gene knockout mice, immunoprecipitation, immunoblot","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic ablation in mice, multiple signaling readouts, replicated across raptor/rictor/mLST8 models","pmids":["17141160"],"is_preprint":false},{"year":2007,"finding":"Electron microscopy reconstruction revealed that yeast TOR1 N-terminal HEAT repeats form a curved tubular domain that associates with the C-terminal WD40 domain of KOG1/Raptor; the N terminus of KOG1 is proximal to the TOR kinase domain, supporting a substrate-delivery model.","method":"Single-particle electron microscopy, 3D reconstruction at 25 Å resolution","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural reconstruction of yeast ortholog, no mutagenesis validation, single lab","pmids":["17679098"],"is_preprint":false},{"year":2008,"finding":"AMPK directly phosphorylates raptor on Ser722 and Ser792 under energy stress; this phosphorylation induces 14-3-3 binding to raptor and is required for mTORC1 inhibition and cell-cycle arrest induced by energy stress.","method":"In vitro kinase assay, phospho-specific antibodies, Co-immunoprecipitation of 14-3-3, RNAi, phospho-mutant rescue experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation reconstituted, mutagenesis used, 14-3-3 binding consequence mapped, replicated by Van Nostrand et al. 2020 (PMID:32912901)","pmids":["18439900"],"is_preprint":false},{"year":2008,"finding":"The Rag GTPases interact with mTORC1 in an amino-acid-sensitive manner through raptor; GTP-loaded Rag promotes mTORC1 lysosomal/intracellular relocalization to activate mTOR without directly stimulating mTOR kinase activity.","method":"Co-immunoprecipitation, dominant-active/dominant-negative Rag constructs, immunofluorescence localization, RNAi","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — Rag–raptor interaction mapped, localization and signaling readouts, multiple orthogonal methods, widely replicated","pmids":["18497260"],"is_preprint":false},{"year":2008,"finding":"RSK1/2, activated by the Ras/MAPK pathway, directly phosphorylate raptor on conserved RXRXXpS/T motifs in an evolutionarily conserved region; raptor phosphorylation-deficient mutants show reduced mTOR kinase activity, linking MAPK pathway to mTORC1 activation.","method":"In vitro kinase assay, RNAi, quantitative mass spectrometry, site-directed mutagenesis, oncogenic Ras/MEK constructs","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation with MS-mapped sites, mutagenesis, RNAi confirmation, single lab but multiple orthogonal methods","pmids":["18722121"],"is_preprint":false},{"year":2008,"finding":"mTOR–raptor complex phosphorylates SGK1 at S422; raptor shRNA impairs mTOR-driven SGK1 activation (but not Akt), and mTOR/raptor/SGK1 complexes are detected in cells, implicating SGK1 as a direct mTORC1 substrate that mediates cytoplasmic p27 mislocalization.","method":"In vitro kinase assay, Co-immunoprecipitation, shRNA knockdown, phospho-specific immunoblot","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with S422A mutant confirmation, raptor shRNA epistasis, Co-IP, single lab","pmids":["18570873"],"is_preprint":false},{"year":2008,"finding":"Raptor is required for Akt-induced NF-κB activation downstream of mTOR; mTOR–raptor complex interacts with and stimulates IKK; rapamycin suppresses IKK activity possibly via raptor–mTOR dissociation.","method":"RNAi knockdown, Co-immunoprecipitation, IKK kinase assay, pharmacological inhibition","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of mTOR-raptor-IKK, RNAi with IKK activity readout, single lab","pmids":["18519641"],"is_preprint":false},{"year":2008,"finding":"FKBP12 deficiency in mouse brain increases basal mTOR phosphorylation and mTOR–Raptor interactions along with enhanced S6K phosphorylation, demonstrating that FKBP12 normally restrains mTOR–Raptor complex assembly.","method":"Brain-specific Fkbp12 conditional knockout mice, Co-immunoprecipitation, immunoblot","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with Co-IP, single lab","pmids":["19081378"],"is_preprint":false},{"year":2009,"finding":"Raptor binds the SAIN domain of IRS-1 and this interaction is required for mTOR-mediated phosphorylation of IRS-1 at Ser-636/639; IRS-1 lacking the SAIN domain does not interact with raptor, is not phosphorylated at these sites, and has enhanced PI3K association.","method":"Co-immunoprecipitation, deletion mutant constructs, RNAi, phospho-specific immunoblot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with deletion constructs, RNAi epistasis, single lab","pmids":["19561084"],"is_preprint":false},{"year":2009,"finding":"Raptor Ser863 is phosphorylated in response to insulin via the canonical PI3K/TSC/Rheb/mTORC1 pathway in a rapamycin-sensitive manner; Ser863 phosphorylation is a hierarchical master switch required for phosphorylation at Ser859 and Ser855; multisite phosphorylation-deficient raptor shows reduced in vitro mTORC1 kinase activity toward 4EBP1.","method":"Tandem mass spectrometry, phospho-specific antibody generation, site-directed mutagenesis, in vitro kinase assay, Rheb overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MS site mapping plus mutagenesis plus in vitro kinase activity, single lab but multiple orthogonal methods","pmids":["19864431"],"is_preprint":false},{"year":2009,"finding":"Hsp90 co-immunoprecipitates with raptor; geldanamycin disrupts Hsp90–raptor association (without affecting raptor–mTOR binding) and suppresses mTOR-mediated phosphorylation of S6K and 4E-BP1, indicating Hsp90 facilitates mTOR/raptor complex activity through raptor binding.","method":"Co-immunoprecipitation, pharmacological inhibition, immunoblot","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with pharmacological disruption, replicated in T cell context (PMID:19586661), single mechanistic readout","pmids":["16428328","19586661"],"is_preprint":false},{"year":2010,"finding":"ERK1/2 interact with raptor and directly phosphorylate it on Ser8, Ser696, and Ser863 in response to Ras/MAPK activation; phosphorylation-deficient raptor alleles reduce mTORC1 activity and 4E-BP1 phosphorylation.","method":"Co-immunoprecipitation, in vitro kinase assay, mass spectrometry, phospho-specific antibodies, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with MS site mapping and mutagenesis, functional consequence demonstrated, single lab","pmids":["21071439"],"is_preprint":false},{"year":2010,"finding":"CDC2/CDK1 (cdc2) phosphorylates raptor on Ser696 and Thr706 during mitosis; Cyclin B co-immunoprecipitates with raptor in mitotic cells, and these mitotic phosphorylation events regulate mTORC1 during cell division.","method":"Tandem mass spectrometry, phospho-specific antibodies, site-directed mutagenesis, Co-immunoprecipitation, cell synchronization","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MS site mapping, mutagenesis, kinase identity established by Co-IP, single lab; consistent with Ramírez-Valle 2010 findings","pmids":["20169205"],"is_preprint":false},{"year":2010,"finding":"Mitotic phosphorylation of raptor (by CDK1 and GSK3 pathways) facilitates G2/M cell cycle transit; phosphorylation-deficient raptor mutants cause G2/M delay while raptor depletion causes G1 accumulation; mitotic raptor promotes IRES-dependent mRNA translation.","method":"Phosphopeptide mapping, site-directed mutagenesis, cell cycle analysis, dominant-negative/constitutive kinase constructs","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-mutant functional analysis, cell cycle readout, single lab","pmids":["20439490"],"is_preprint":false},{"year":2011,"finding":"ULK1 phosphorylates raptor at multiple sites in vivo and in vitro (prominently Ser855 and Ser859, with moderate Ser792); ULK1-mediated raptor phosphorylation reduces the ability of raptor to bind substrate 4E-BP1 without disrupting mTORC1 complex integrity, providing a negative feedback mechanism.","method":"In vitro kinase assay, phospho-specific antibodies, Co-immunoprecipitation, shRNA knockdown, overexpression","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation plus substrate-docking assay plus shRNA epistasis, single lab but multiple orthogonal methods","pmids":["21460630"],"is_preprint":false},{"year":2011,"finding":"Raptor and Rheb negatively regulate skeletal myogenic differentiation through suppression of IRS1; raptor or Rheb knockdown enhances C2C12 differentiation accompanied by increased Akt activation and elevated IRS1 levels, and IRS1 knockdown abolishes this enhancement.","method":"RNAi knockdown, overexpression, C2C12 differentiation assay, immunoblot epistasis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi epistasis with rescue, genetic pathway placement, single lab","pmids":["21852229"],"is_preprint":false},{"year":2012,"finding":"ICK (intestinal cell kinase) phosphorylates raptor at Thr908 both in vitro and in vivo; Raptor T908A mutant markedly impairs mTORC1 activation by insulin or Rheb overexpression without disrupting mTORC1 complex integrity.","method":"In vitro kinase assay, mass spectrometry, phospho-specific antibody, site-directed mutagenesis, Co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with MS site mapping and mutagenesis-based functional validation, single lab","pmids":["22356909"],"is_preprint":false},{"year":2013,"finding":"FLIM-FRET in live cells confirmed direct physical interaction between mTOR and raptor in the cytoplasm and nucleus; amino acid withdrawal and re-addition (but not rapamycin) alter mTOR intracellular distribution.","method":"FRET-FLIM live-cell imaging, GFP/DsRed fusion proteins","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — live-cell FRET-FLIM is rigorous but single lab, no functional mutagenesis companion","pmids":["23311891"],"is_preprint":false},{"year":2015,"finding":"GSK3 phosphorylates raptor at Ser859; GSK3 inhibition or shRNA silencing reduces mTOR–raptor interaction and attenuates amino-acid-regulated mTORC1 signaling, increased autophagic flux, and reduced proliferation.","method":"Pharmacological inhibition, shRNA, phospho-specific antibody, Co-immunoprecipitation, site-directed mutagenesis (S859A)","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mutagenesis plus RNAi, single lab","pmids":["26348909"],"is_preprint":false},{"year":2015,"finding":"Glucose starvation in budding yeast triggers Snf1/AMPK-dependent phosphorylation of Kog1/Raptor at Ser491/494, driving TORC1 disassembly and condensation of Kog1 into a single body near the vacuole; these bodies increase the TORC1 activation threshold (hysteresis) during prolonged starvation.","method":"Yeast genetics, live-cell fluorescence microscopy, phospho-mutant constructs, TORC1 activity assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast ortholog (Kog1), genetic epistasis with phospho-mutants, live imaging, mechanistic readout of complex disassembly","pmids":["26439012"],"is_preprint":false},{"year":2015,"finding":"NLK phosphorylates raptor on Ser863 in response to osmotic/oxidative stress; this phosphorylation disrupts raptor's interaction with Rag GTPases, inhibits mTORC1 lysosomal localization, and suppresses mTORC1 activation; Raptor S863A knock-in cells are defective in stress-induced mTORC1 inhibition.","method":"In vitro kinase assay, Co-immunoprecipitation, phospho-specific antibody, Nlk knockout and Raptor knock-in cells, immunofluorescence","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, Raptor knock-in cells, Co-IP showing Rag disruption, localization readout, single lab but multiple orthogonal methods","pmids":["26588989"],"is_preprint":false},{"year":2016,"finding":"Free (mTORC1-independent) Raptor negatively regulates hepatic Akt activity and lipogenesis by stabilizing the Akt phosphatase PHLPP2, reducing its β-TrCP-mediated degradation; this reveals a scaffolding function of Raptor independent of mTOR kinase.","method":"Hepatocyte-specific Raptor knockout mice, overexpression constructs, Co-immunoprecipitation, immunoblot, liver lipid measurements","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model plus Co-IP plus PHLPP2 degradation assay, single lab","pmids":["26743335"],"is_preprint":false},{"year":2017,"finding":"The mTOR–Raptor–S6K1 axis regulates Runx2 expression through S6K1-mediated phosphorylation of estrogen receptor α, which binds DLX5 and augments Runx2 enhancer activity; heterozygous Raptor mutation in osteoblasts aggravates bone defects in Runx2+/− mice.","method":"Conditional knockout mice, immunoblot, chromatin immunoprecipitation, genetic epistasis (Raptor×Runx2 double mutant)","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mice plus ChIP mechanistic detail, single lab","pmids":["28686577"],"is_preprint":false},{"year":2017,"finding":"USP9X deubiquitylase physically associates with Raptor in embryonic brains, opposes proteasomal degradation of Raptor, and thereby maintains Raptor protein levels and mTORC1 signaling in neural progenitors; loss of Usp9x phenocopies Raptor-null neurospheres in reducing mTORC1 activity.","method":"Co-immunoprecipitation from embryonic brain, USP9X loss- and gain-of-function in cultured cells and Nestin-Cre Usp9x mice, proteasome inhibition assay, EdU proliferation assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in vivo, multiple loss-of-function models, proteasome assay, single lab","pmids":["28341829"],"is_preprint":false},{"year":2019,"finding":"PKA phosphorylates Raptor at Ser791 in response to Gαs-coupled GPCR activation, leading to decreased mTORC1 activity; Raptor S791A mutant partially rescues mTORC1 activity after PKA activation, and this pathway operates in multiple cell lines and mouse tissues.","method":"In vitro kinase assay, phospho-specific antibody, Raptor S791A site-directed mutagenesis, pharmacological GPCR agonists, immunoblot in mouse tissues","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, mutagenesis with functional rescue, in vivo confirmation, single lab but multiple orthogonal methods","pmids":["31112131"],"is_preprint":false},{"year":2019,"finding":"SHOC2 (a RAS activator) competes with mTOR for Raptor binding; SHOC2–Raptor interaction inhibits mTORC1 and induces autophagy, while Raptor binding to SHOC2 blocks RAS-MAPK signaling; FBXW7-mediated ubiquitination of SHOC2 terminates this cross-talk.","method":"Co-immunoprecipitation, competitive binding assay, ubiquitination assay, autophagy flux assay, cell proliferation assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP competition, multiple pathway readouts, single lab","pmids":["30865892"],"is_preprint":false},{"year":2019,"finding":"TBK1 phosphorylates Raptor at Ser877 in vitro and promotes Ser877 phosphorylation in cells in response to pathogen-associated molecules; phosphorylation at Ser877 inversely correlates with mTORC1 activity, and Raptor S877A mutant increases mTORC1 activity.","method":"In vitro kinase assay coupled with mass spectrometry, phospho-specific antibody, Raptor S877A site-directed mutagenesis, immunoblot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay with MS mapping and mutagenesis, but single lab with limited in vivo validation","pmids":["31530866"],"is_preprint":false},{"year":2020,"finding":"Leucine regulates autophagy via its metabolite acetyl-CoA: AcCoA promotes EP300-dependent acetylation of raptor, which activates mTORC1 and suppresses autophagy; leucine deprivation decreases raptor acetylation and causes mTORC1 inhibition predominantly through this mechanism.","method":"Pharmacological manipulation of AcCoA, EP300 inhibitor, Co-immunoprecipitation, raptor acetylation assay, autophagy flux assay in multiple cell lines and neurons","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — EP300-raptor acetylation mapped, multiple cell types including neurons, autophagy functional readout, single lab but multiple orthogonal methods","pmids":["32561715"],"is_preprint":false},{"year":2020,"finding":"Hepatic peroxisomal β-oxidation suppresses lipophagy via RPTOR acetylation and mTOR activation; ACOX1 deficiency decreases cytosolic acetyl-CoA, reduces RPTOR acetylation, inhibits mTORC1, and induces lipophagy.","method":"Liver-specific Acox1 knockout mice, acetylation assay, mTORC1 activity measurement, lipophagy quantification","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout model with acetylation readout, consistent with PMID:32561715, single lab","pmids":["32687428"],"is_preprint":false},{"year":2020,"finding":"AMPK-mediated phosphorylation of both RAPTOR (Ser722/Ser792) and TSC2 is required for full mTORC1 inhibition by metformin in primary hepatocytes and intact liver; Raptor knock-in mice (S722A/S792A) show incomplete mTORC1 inhibition and an attenuated transcriptional response to metformin.","method":"Raptor Ser722A/Ser792A knock-in mice, primary hepatocyte cultures, immunoblot, RNA-seq","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knock-in genetic model, primary cells, multiple readouts, extends PMID:18439900","pmids":["32912901"],"is_preprint":false},{"year":2021,"finding":"VHL interacts with RAPTOR and promotes RAPTOR degradation through ubiquitination, thereby suppressing mTORC1 signaling; loss of VHL in ccRCC increases RAPTOR levels and mTORC1 hyperactivation, consistent with a conserved mechanism also observed in C. elegans vhl-1 mutants.","method":"Co-immunoprecipitation, ubiquitination assay, VHL overexpression/silencing, C. elegans vhl-1 genetic analysis, immunoblot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with ubiquitination assay, in vivo C. elegans validation, single lab","pmids":["34290272"],"is_preprint":false},{"year":2023,"finding":"O-GlcNAcylation of Raptor at Thr700 by OGT (driven by glucose availability) facilitates Raptor–Rag GTPase interactions and promotes lysosomal translocation of mTOR, thereby activating mTORC1; AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor–Rag interactions.","method":"O-GlcNAc proteomics, site-directed mutagenesis (T700A), Co-immunoprecipitation, lysosomal fractionation, immunofluorescence, OGT inhibition","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical site mapping with mutagenesis, multiple orthogonal methods (Co-IP, fractionation, imaging), cross-talk with AMPK phosphorylation demonstrated, single lab","pmids":["37541260"],"is_preprint":false}],"current_model":"RPTOR (Raptor) is an essential scaffolding subunit of mTORC1 that recruits substrates (S6K1, 4E-BP1, SGK1, IRS-1) to mTOR via their TOS motifs and undergoes extensive regulatory phosphorylation by multiple kinases (AMPK, RSK1/2, ERK1/2, CDK1, GSK3, ULK1, NLK, PKA, TBK1, ICK, p38β), as well as acetylation by EP300 and O-GlcNAcylation at Thr700, each modulating mTORC1 activity in response to energy, growth factor, stress, and nutrient signals; its stability is additionally controlled by the DDB1-CUL4 ubiquitin ligase (ubiquitinating Raptor), UCH-L1 (deubiquitinating), USP9X (stabilizing), VHL (promoting degradation), and Hsp90 (chaperoning), while its interaction with Rag GTPases mediates amino-acid-dependent lysosomal recruitment of mTOR and its interaction with mTOR is disrupted by FKBP12-rapamycin, AMPK-driven 14-3-3 binding, NLK phosphorylation, and SHOC2 competition."},"narrative":{"mechanistic_narrative":"RPTOR (Raptor) is the defining scaffolding subunit of mTOR complex 1 (mTORC1), forming a stoichiometric complex with mTOR that couples nutrient and growth signals to control of cell size, translation, and proliferation [PMID:12150925, PMID:12150926]. Its central molecular function is substrate recruitment: Raptor binds the TOS motifs of S6K1 and 4E-BP1 and presents them to the mTOR kinase domain, such that TOS-motif mutations abolish Raptor binding and mTOR-catalyzed phosphorylation [PMID:12604610, PMID:12747827]; it likewise scaffolds direct phosphorylation of IRS-1 via the IRS-1 SAIN domain and of SGK1, defining the substrate repertoire of mTORC1 and a negative-feedback loop on PI3K/Akt signaling [PMID:16354680, PMID:19561084, PMID:18570873]. Complex assembly is stabilized by mLST8/GβL and is the target of rapamycin, which acts through FKBP12 to dissociate Raptor from mTOR without altering intrinsic kinase activity [PMID:12718876, PMID:15066126]. Raptor is the principal hub for upstream signal integration: amino acids and glucose promote Raptor–Rag GTPase interaction that drives lysosomal recruitment of mTORC1, gated positively by OGT-mediated O-GlcNAcylation at Thr700 and EP300-mediated acetylation, and negatively by AMPK phosphorylation (Ser722/Ser792) that recruits 14-3-3 and by NLK phosphorylation (Ser863) that disrupts Rag binding [PMID:18497260, PMID:37541260, PMID:32561715, PMID:18439900, PMID:26588989]. A dense array of kinases converges on Raptor to tune mTORC1 activity—RSK1/2, ERK1/2, CDK1, GSK3, ULK1, ICK, PKA, and TBK1—integrating MAPK, mitotic, autophagic, GPCR, and innate-immune inputs [PMID:18722121, PMID:21071439, PMID:20169205, PMID:21460630, PMID:22356909, PMID:31112131, PMID:31530866], while its abundance is governed by competing ubiquitination (DDB1-CUL4, VHL) and deubiquitination/stabilization (UCH-L1, USP9X) [PMID:23297343, PMID:34290272, PMID:28341829]. Genetic ablation of Raptor in mice is embryonic-lethal, establishing mTORC1/Raptor as essential for early development [PMID:17141160]. Beyond its mTOR-bound role, free Raptor scaffolds PHLPP2 stabilization to restrain hepatic Akt and lipogenesis, an mTOR-kinase-independent function [PMID:26743335].","teleology":[{"year":2002,"claim":"Established the existence and identity of Raptor as an mTOR-associated protein required for nutrient signaling and cell size, defining the founding subunit of what became mTORC1.","evidence":"Co-IP, mass spectrometry, RNAi, and cell-size assays in mammalian cells","pmids":["12150925","12150926"],"confidence":"High","gaps":["Did not resolve how Raptor mechanistically links mTOR to specific substrates","Stoichiometry and structural basis of the association unresolved"]},{"year":2003,"claim":"Defined the molecular basis of substrate recruitment, showing Raptor binds the TOS motif of S6K1 and 4E-BP1 to present them to mTOR, settling Raptor's role as a substrate-presenting scaffold.","evidence":"Co-IP, TOS-motif point mutants, in vitro kinase assays in mammalian cells","pmids":["12604610","12747827"],"confidence":"High","gaps":["Did not address how other substrates lacking canonical TOS motifs are recognized","Structural geometry of substrate delivery to the kinase domain unknown"]},{"year":2003,"claim":"Showed that mLST8/GβL stabilizes the Raptor–mTOR association and renders complex regulation by nutrients and rapamycin operative, integrating a third subunit into mTORC1.","evidence":"Co-IP, in vitro kinase assay, RNAi in mammalian cells","pmids":["12718876"],"confidence":"High","gaps":["Quantitative contribution of mLST8 versus Raptor to substrate phosphorylation not separated","Later shown dispensable for mTORC1 signaling in vivo (#10)"]},{"year":2004,"claim":"Distinguished Raptor-containing mTORC1 from Rictor-containing mTORC2, demonstrating Raptor specifies the rapamycin-sensitive, S6K1-directed branch of mTOR signaling.","evidence":"Reciprocal Co-IP, mass spectrometry, RNAi, immunofluorescence","pmids":["15268862"],"confidence":"High","gaps":["Did not define substrate-recognition rules separating the two complexes beyond TOS dependence"]},{"year":2004,"claim":"Resolved the mechanism of rapamycin action, showing FKBP12–rapamycin dissociates Raptor from mTOR rather than directly inhibiting catalysis, explaining substrate uncoupling.","evidence":"Co-IP and direct in vitro binding/kinase assays","pmids":["15066126"],"confidence":"High","gaps":["Did not explain rapamycin-resistant residual mTORC1 outputs","In vivo restraint of complex assembly by FKBP12 addressed only later (#17)"]},{"year":2006,"claim":"Identified IRS-1 and SGK1 as direct Raptor-scaffolded mTORC1 substrates, extending the substrate repertoire and revealing a feedback loop onto PI3K/Akt.","evidence":"Co-IP, RNAi, in vitro kinase and phospho-specific immunoblot in mammalian cells","pmids":["16354680","18570873"],"confidence":"High","gaps":["Did not map the IRS-1 docking surface (resolved in 2009, #18)","Physiological balance of feedback versus forward signaling not quantified"]},{"year":2006,"claim":"Demonstrated genetic essentiality, showing Raptor-null mice die in early embryogenesis while mLST8 is dispensable for mTORC1, separating the two subunits' in vivo roles.","evidence":"Conditional/constitutive knockout mice with signaling readouts","pmids":["17141160"],"confidence":"High","gaps":["Tissue-specific developmental requirements not dissected here"]},{"year":2007,"claim":"Provided the first structural framing of how Raptor/KOG1 positions its WD40 domain near the TOR kinase, supporting a physical substrate-delivery model.","evidence":"Single-particle electron microscopy of the yeast TOR1–KOG1 complex at 25 Å","pmids":["17679098"],"confidence":"Medium","gaps":["Low resolution and yeast ortholog; no mutagenesis validation","Substrate-bound state not captured"]},{"year":2008,"claim":"Identified Raptor as the convergence point for energy stress, showing AMPK phosphorylation of Ser722/Ser792 recruits 14-3-3 to inhibit mTORC1, linking AMPK to direct mTORC1 suppression.","evidence":"In vitro kinase, phospho-mutant rescue, 14-3-3 Co-IP, RNAi","pmids":["18439900"],"confidence":"High","gaps":["Mechanism by which 14-3-3 binding inhibits the complex not structurally defined","In vivo requirement confirmed only later (#39)"]},{"year":2008,"claim":"Established Raptor as the amino-acid sensing interface, showing GTP-loaded Rag GTPases bind Raptor to relocalize mTORC1 to lysosomes without directly stimulating kinase activity.","evidence":"Co-IP, dominant-active/negative Rag constructs, immunofluorescence, RNAi","pmids":["18497260"],"confidence":"High","gaps":["How relocalization activates kinase activity not resolved here","Modifications gating Raptor–Rag binding identified only later (#30, #41)"]},{"year":2008,"claim":"Connected the Ras/MAPK pathway to mTORC1 by showing RSK1/2 directly phosphorylate Raptor at conserved RXRXXS/T sites to promote kinase activity.","evidence":"In vitro kinase, MS site mapping, mutagenesis, RNAi, oncogenic Ras/MEK constructs","pmids":["18722121"],"confidence":"High","gaps":["Mechanism by which these phosphosites increase activity unknown","Overlap with ERK sites (#21) not fully deconvolved"]},{"year":2009,"claim":"Mapped insulin-driven Raptor phosphorylation hierarchy (Ser863 as master switch for Ser855/Ser859), defining how growth-factor signaling tunes mTORC1 kinase output.","evidence":"MS site mapping, phospho-antibodies, mutagenesis, in vitro kinase, Rheb overexpression","pmids":["19864431"],"confidence":"High","gaps":["Did not identify all kinases for each site (later: ERK, ULK1, GSK3, NLK)","Structural consequence of multisite phosphorylation unresolved"]},{"year":2010,"claim":"Identified ERK1/2 and CDK1 as additional direct Raptor kinases, integrating MAPK and mitotic signals into mTORC1 control of translation and cell-cycle progression.","evidence":"Co-IP, in vitro kinase, MS site mapping, phospho-mutant cell-cycle analysis","pmids":["21071439","20169205","20439490"],"confidence":"High","gaps":["Functional integration of overlapping ERK/RSK/CDK1 sites on Ser696/Ser863 not unified","Mitotic IRES-translation mechanism only partially defined"]},{"year":2011,"claim":"Revealed an autophagy feedback arm, showing ULK1 phosphorylates Raptor to reduce its 4E-BP1 binding without disrupting complex integrity.","evidence":"In vitro kinase, substrate-docking Co-IP, shRNA epistasis","pmids":["21460630"],"confidence":"High","gaps":["Whether ULK1 phosphorylation impairs all substrates or selectively 4E-BP1 unclear"]},{"year":2012,"claim":"Added ICK as a Raptor kinase whose Thr908 phosphorylation is required for insulin/Rheb-driven mTORC1 activation, broadening the activating-kinase set.","evidence":"In vitro kinase, MS mapping, T908A mutagenesis, Co-IP","pmids":["22356909"],"confidence":"High","gaps":["Mechanism by which Thr908 enables Rheb-driven activation unknown","Limited in vivo validation"]},{"year":2015,"claim":"Demonstrated multiple stress/nutrient kinases (GSK3, NLK) phosphorylate Ser859/Ser863 to control Raptor's mTOR and Rag interactions, mechanistically separating complex integrity from lysosomal recruitment.","evidence":"Co-IP, mutagenesis, shRNA/knockout, knock-in cells, immunofluorescence","pmids":["26348909","26588989"],"confidence":"High","gaps":["Crosstalk and hierarchy among kinases targeting the same Raptor residues unresolved"]},{"year":2015,"claim":"Showed a conserved starvation response in which Snf1/AMPK phosphorylation drives Kog1/Raptor condensation and TORC1 disassembly, establishing phase-separation-like hysteresis in TORC1 reactivation.","evidence":"Yeast genetics, live-cell imaging, phospho-mutants, TORC1 activity assays","pmids":["26439012"],"confidence":"High","gaps":["Whether mammalian Raptor undergoes analogous condensation untested here"]},{"year":2016,"claim":"Uncovered an mTOR-independent scaffolding role, showing free Raptor stabilizes PHLPP2 to restrain hepatic Akt and lipogenesis.","evidence":"Hepatocyte-specific Raptor knockout mice, Co-IP, PHLPP2 degradation assays","pmids":["26743335"],"confidence":"Medium","gaps":["Single lab; structural basis of Raptor–PHLPP2 interaction undefined","Generality beyond liver unknown"]},{"year":2019,"claim":"Extended the kinase network to GPCR/PKA, innate-immune TBK1, and RAS-pathway SHOC2 competition, defining additional physiological contexts that suppress mTORC1 through Raptor.","evidence":"In vitro kinase, phospho-mutant rescue, competitive Co-IP, autophagy/ubiquitination assays","pmids":["31112131","31530866","30865892"],"confidence":"Medium","gaps":["TBK1 (#36) and SHOC2 (#35) lack extensive in vivo validation","Integration of these inputs with the dominant nutrient pathway unclear"]},{"year":2020,"claim":"Defined acetyl-CoA-driven EP300 acetylation of Raptor as a metabolic switch coupling leucine and peroxisomal β-oxidation to mTORC1 activation and autophagy suppression.","evidence":"AcCoA/EP300 pharmacology, acetylation and autophagy assays, Acox1 knockout mice","pmids":["32561715","32687428"],"confidence":"High","gaps":["Acetylated residue(s) and structural effect on the complex not fully mapped"]},{"year":2020,"claim":"Confirmed the physiological requirement of Raptor Ser722/Ser792 phosphorylation, showing knock-in mice resist metformin-driven mTORC1 inhibition, validating AMPK→Raptor signaling in vivo.","evidence":"Raptor S722A/S792A knock-in mice, primary hepatocytes, RNA-seq","pmids":["32912901"],"confidence":"High","gaps":["Relative contribution of Raptor versus TSC2 phosphorylation not fully isolated"]},{"year":2021,"claim":"Identified VHL as a ubiquitin ligase that degrades Raptor to suppress mTORC1, adding tumor-suppressor control over Raptor abundance.","evidence":"Co-IP, ubiquitination assay, VHL gain/loss, C. elegans vhl-1 genetics","pmids":["34290272"],"confidence":"Medium","gaps":["Direct versus indirect ubiquitination by VHL not fully distinguished","Single lab"]},{"year":2023,"claim":"Showed glucose-driven OGT O-GlcNAcylation of Raptor Thr700 promotes Raptor–Rag binding and lysosomal mTOR recruitment, and that AMPK phosphorylation antagonizes this modification, unifying nutrient and energy inputs at the Rag interface.","evidence":"O-GlcNAc proteomics, T700A mutagenesis, Co-IP, lysosomal fractionation, imaging, OGT inhibition","pmids":["37541260"],"confidence":"High","gaps":["Structural basis of how Thr700 modification alters Rag binding unresolved","Crosstalk hierarchy with acetylation and phosphorylation not fully integrated"]},{"year":null,"claim":"How the dense, overlapping array of Raptor modifications (phosphorylation, acetylation, O-GlcNAcylation, ubiquitination) is hierarchically integrated into a single quantitative mTORC1 activity setpoint, and the high-resolution structural geometry of substrate delivery, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model reconciling competing modifications at shared residues (e.g., Ser863, Ser792)","No high-resolution structure of human Raptor presenting a substrate to the mTOR kinase domain","Whether mTOR-independent scaffolding roles generalize beyond liver"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,8,18,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,12,24,30,31]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[13,30,41]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[27]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[27]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,14,19,34]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[24,28,35,37,38]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,37,38,39]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[22,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,8]}],"complexes":["mTORC1"],"partners":["MTOR","MLST8","RPS6KB1","EIF4EBP1","IRS1","RRAGA","AKT1S1","SHOC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N122","full_name":"Regulatory-associated protein of mTOR","aliases":["p150 target of rapamycin (TOR)-scaffold protein"],"length_aa":1335,"mass_kda":149.0,"function":"Component of the mechanistic target of rapamycin complex 1 (mTORC1), an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth (PubMed:12150925, PubMed:12150926, PubMed:12747827, PubMed:24403073, PubMed:26588989, PubMed:32561715, PubMed:37541260). 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 several substrates, such as ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) (PubMed:12150925, PubMed:12150926, PubMed:12747827, PubMed:24403073, PubMed:26588989, PubMed:37541260). In the same time, it inhibits catabolic pathways by phosphorylating the autophagy initiation components ULK1 and ATG13, as well as transcription factor TFEB, a master regulators of lysosomal biogenesis and autophagy (PubMed:12150925, PubMed:12150926, PubMed:12747827, PubMed:24403073, PubMed:32561715, PubMed:37541260). The mTORC1 complex is inhibited in response to starvation and amino acid depletion (PubMed:12150925, PubMed:12150926, PubMed:12747827, PubMed:24403073, PubMed:37541260). Within the mTORC1 complex, RPTOR acts both as a molecular adapter, which (1) mediates recruitment of mTORC1 to lysosomal membranes via interaction with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD), and a (2) substrate-specific adapter, which promotes substrate specificity by binding to TOS motif-containing proteins and direct them towards the active site of the MTOR kinase domain for phosphorylation (PubMed:12747827, PubMed:24403073, PubMed:26588989, PubMed:37541260). mTORC1 complex regulates many cellular processes, such as odontoblast and osteoclast differentiation or neuronal transmission (By similarity). mTORC1 complex in excitatory neuronal transmission is required for the prosocial behavior induced by the psychoactive substance lysergic acid diethylamide (LSD) (By similarity)","subcellular_location":"Lysosome membrane; Cytoplasm; Cytoplasmic granule","url":"https://www.uniprot.org/uniprotkb/Q8N122/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPTOR","classification":"Common Essential","n_dependent_lines":1108,"n_total_lines":1208,"dependency_fraction":0.9172185430463576},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MTOR","stoichiometry":10.0},{"gene":"AKT1S1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RPTOR","total_profiled":1310},"omim":[{"mim_id":"620152","title":"HYPOMAGNESEMIA 7, RENAL, WITH OR WITHOUT DILATED CARDIOMYOPATHY; HOMG7","url":"https://www.omim.org/entry/620152"},{"mim_id":"616899","title":"TBC1 DOMAIN-CONTAINING KINASE; TBCK","url":"https://www.omim.org/entry/616899"},{"mim_id":"616203","title":"SOLUTE CARRIER FAMILY 38, MEMBER 9; SLC38A9","url":"https://www.omim.org/entry/616203"},{"mim_id":"615562","title":"SPERM-ASSOCIATED ANTIGEN 5; SPAG5","url":"https://www.omim.org/entry/615562"},{"mim_id":"614426","title":"TELO2-INTERACTING PROTEIN 2; TTI2","url":"https://www.omim.org/entry/614426"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Lysosomes","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPTOR"},"hgnc":{"alias_symbol":["KOG1","Mip1","KIAA1303","raptor"],"prev_symbol":[]},"alphafold":{"accession":"Q8N122","domains":[{"cath_id":"-","chopping":"58-373","consensus_level":"medium","plddt":89.8008,"start":58,"end":373},{"cath_id":"-","chopping":"435-503","consensus_level":"medium","plddt":91.6187,"start":435,"end":503},{"cath_id":"-","chopping":"518-615","consensus_level":"medium","plddt":96.3592,"start":518,"end":615},{"cath_id":"-","chopping":"633-691_780-794_802-844_954-964","consensus_level":"medium","plddt":84.4321,"start":633,"end":964}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N122","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N122-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N122-F1-predicted_aligned_error_v6.png","plddt_mean":79.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPTOR","jax_strain_url":"https://www.jax.org/strain/search?query=RPTOR"},"sequence":{"accession":"Q8N122","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N122.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N122/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N122"}},"corpus_meta":[{"pmid":"18439900","id":"PMC_18439900","title":"AMPK 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complex with mTOR; this association negatively regulates mTOR kinase activity under nutrient deprivation, while raptor is required for nutrient-stimulated signaling to S6K1, maintenance of cell size, and mTOR protein expression.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, RNAi knockdown, cell size measurements\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi phenotype, multiple orthogonal methods, replicated by independent lab in same issue (PMID:12150926)\",\n      \"pmids\": [\"12150925\", \"12150926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Raptor binds 4EBP1 and p70S6K and is required as a scaffold for mTOR-catalyzed phosphorylation of 4EBP1 in vitro; partial RNAi knockdown of raptor reduces mTOR-catalyzed 4EBP1 phosphorylation, and C. elegans raptor RNAi phenocopies Ce-TOR inactivation.\",\n      \"method\": \"In vitro kinase assay, Co-immunoprecipitation, RNAi in mammalian cells and C. elegans\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis support, RNAi in two organisms, independently replicated\",\n      \"pmids\": [\"12150926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Raptor binds the TOS (TOR signaling) motif of p70S6K and 4EBP1; a point mutation in the 4EBP1 TOS motif abolishes raptor binding and eliminates mTOR-catalyzed 4EBP1 phosphorylation in vitro and in vivo, demonstrating raptor as the substrate-recruiting scaffold.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, in vitro kinase assay, cell size measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis, replicated by independent lab (PMID:12747827)\",\n      \"pmids\": [\"12604610\", \"12747827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GbetaL (mLST8) binds the mTOR kinase domain and stabilizes the raptor–mTOR interaction; GbetaL stimulates mTOR kinase activity toward S6K1 and 4E-BP1, an effect reversed by stable raptor–mTOR association; nutrients and rapamycin regulate mTOR–raptor association only in complexes also containing GbetaL.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, RNAi, cell size measurement\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus Co-IP plus RNAi, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12718876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Rictor defines a second mTOR complex (mTORC2) that does not contain raptor and is rapamycin-insensitive; raptor-containing mTORC1 regulates S6K1 while rictor-containing mTORC2 modulates PKCα phosphorylation and the actin cytoskeleton.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, RNAi, immunofluorescence\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi with defined phenotypes, independently replicated\",\n      \"pmids\": [\"15268862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Rapamycin/FKBP12 complex inhibits mTOR function at least in part by dissociating raptor from mTOR both in vivo and directly in vitro; this dissociation uncouples mTOR from raptor-dependent substrates without altering intrinsic mTOR catalytic activity.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, in vitro kinase assay\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution showing rapamycin-induced dissociation, confirmed in vivo, single lab\",\n      \"pmids\": [\"15066126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The raptor–mTOR complex selectively phosphorylates rapamycin-sensitive forms of S6K1, while the rictor–mTOR complex phosphorylates rapamycin-resistant S6K1 mutants lacking the C-terminal domain; TOS motif-independent recognition is required for rictor-mTOR-mediated phosphorylation.\",\n      \"method\": \"In vitro kinase assay, Co-immunoprecipitation, mutant S6K1 constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with defined mutants, mechanistically discriminates the two complexes, single lab\",\n      \"pmids\": [\"15809305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Redox state regulates the raptor–mTOR complex: oxidizing agents increase S6K1 phosphorylation and make it nutrient-insensitive, while the reducing agent BAL stabilizes mTOR–raptor interaction (mimicking nutrient deprivation) and inhibits S6K1 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, immunoblot, pharmacological redox manipulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and signaling readouts, single lab, pharmacological tools only\",\n      \"pmids\": [\"16183647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Raptor-dependent mTOR directly phosphorylates IRS-1 at Ser636/639; raptor binds IRS-1 directly and serves as a scaffold for this phosphorylation, providing a mechanism for mTOR-mediated negative feedback on PI3K/Akt signaling.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, phospho-specific immunoblot, in vitro kinase assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding and in vitro phosphorylation demonstrated, RNAi confirmation, replicated in follow-up study (PMID:19561084)\",\n      \"pmids\": [\"16354680\", \"19561084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Raptor is ubiquitinated by the DDB1-CUL4 ubiquitin ligase complex; the deubiquitylase UCH-L1 disrupts this DDB1-CUL4–raptor complex, counteracts raptor ubiquitination, and leads to mTORC1 dissolution with secondary mTORC2 increase.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, Uchl1 transgenic and knockout mice\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vivo genetic models, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"23297343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mice lacking raptor die early in embryonic development, establishing that mTORC1/raptor function is essential for early development; mLST8 is required only for mTORC2 (rictor-mTOR) signaling to Akt and PKCα, not for raptor-mTOR signaling to S6K1.\",\n      \"method\": \"Conditional gene knockout mice, immunoprecipitation, immunoblot\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic ablation in mice, multiple signaling readouts, replicated across raptor/rictor/mLST8 models\",\n      \"pmids\": [\"17141160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Electron microscopy reconstruction revealed that yeast TOR1 N-terminal HEAT repeats form a curved tubular domain that associates with the C-terminal WD40 domain of KOG1/Raptor; the N terminus of KOG1 is proximal to the TOR kinase domain, supporting a substrate-delivery model.\",\n      \"method\": \"Single-particle electron microscopy, 3D reconstruction at 25 Å resolution\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural reconstruction of yeast ortholog, no mutagenesis validation, single lab\",\n      \"pmids\": [\"17679098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"AMPK directly phosphorylates raptor on Ser722 and Ser792 under energy stress; this phosphorylation induces 14-3-3 binding to raptor and is required for mTORC1 inhibition and cell-cycle arrest induced by energy stress.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibodies, Co-immunoprecipitation of 14-3-3, RNAi, phospho-mutant rescue experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation reconstituted, mutagenesis used, 14-3-3 binding consequence mapped, replicated by Van Nostrand et al. 2020 (PMID:32912901)\",\n      \"pmids\": [\"18439900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The Rag GTPases interact with mTORC1 in an amino-acid-sensitive manner through raptor; GTP-loaded Rag promotes mTORC1 lysosomal/intracellular relocalization to activate mTOR without directly stimulating mTOR kinase activity.\",\n      \"method\": \"Co-immunoprecipitation, dominant-active/dominant-negative Rag constructs, immunofluorescence localization, RNAi\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Rag–raptor interaction mapped, localization and signaling readouts, multiple orthogonal methods, widely replicated\",\n      \"pmids\": [\"18497260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RSK1/2, activated by the Ras/MAPK pathway, directly phosphorylate raptor on conserved RXRXXpS/T motifs in an evolutionarily conserved region; raptor phosphorylation-deficient mutants show reduced mTOR kinase activity, linking MAPK pathway to mTORC1 activation.\",\n      \"method\": \"In vitro kinase assay, RNAi, quantitative mass spectrometry, site-directed mutagenesis, oncogenic Ras/MEK constructs\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation with MS-mapped sites, mutagenesis, RNAi confirmation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18722121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"mTOR–raptor complex phosphorylates SGK1 at S422; raptor shRNA impairs mTOR-driven SGK1 activation (but not Akt), and mTOR/raptor/SGK1 complexes are detected in cells, implicating SGK1 as a direct mTORC1 substrate that mediates cytoplasmic p27 mislocalization.\",\n      \"method\": \"In vitro kinase assay, Co-immunoprecipitation, shRNA knockdown, phospho-specific immunoblot\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with S422A mutant confirmation, raptor shRNA epistasis, Co-IP, single lab\",\n      \"pmids\": [\"18570873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Raptor is required for Akt-induced NF-κB activation downstream of mTOR; mTOR–raptor complex interacts with and stimulates IKK; rapamycin suppresses IKK activity possibly via raptor–mTOR dissociation.\",\n      \"method\": \"RNAi knockdown, Co-immunoprecipitation, IKK kinase assay, pharmacological inhibition\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of mTOR-raptor-IKK, RNAi with IKK activity readout, single lab\",\n      \"pmids\": [\"18519641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FKBP12 deficiency in mouse brain increases basal mTOR phosphorylation and mTOR–Raptor interactions along with enhanced S6K phosphorylation, demonstrating that FKBP12 normally restrains mTOR–Raptor complex assembly.\",\n      \"method\": \"Brain-specific Fkbp12 conditional knockout mice, Co-immunoprecipitation, immunoblot\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with Co-IP, single lab\",\n      \"pmids\": [\"19081378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Raptor binds the SAIN domain of IRS-1 and this interaction is required for mTOR-mediated phosphorylation of IRS-1 at Ser-636/639; IRS-1 lacking the SAIN domain does not interact with raptor, is not phosphorylated at these sites, and has enhanced PI3K association.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutant constructs, RNAi, phospho-specific immunoblot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with deletion constructs, RNAi epistasis, single lab\",\n      \"pmids\": [\"19561084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Raptor Ser863 is phosphorylated in response to insulin via the canonical PI3K/TSC/Rheb/mTORC1 pathway in a rapamycin-sensitive manner; Ser863 phosphorylation is a hierarchical master switch required for phosphorylation at Ser859 and Ser855; multisite phosphorylation-deficient raptor shows reduced in vitro mTORC1 kinase activity toward 4EBP1.\",\n      \"method\": \"Tandem mass spectrometry, phospho-specific antibody generation, site-directed mutagenesis, in vitro kinase assay, Rheb overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS site mapping plus mutagenesis plus in vitro kinase activity, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19864431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Hsp90 co-immunoprecipitates with raptor; geldanamycin disrupts Hsp90–raptor association (without affecting raptor–mTOR binding) and suppresses mTOR-mediated phosphorylation of S6K and 4E-BP1, indicating Hsp90 facilitates mTOR/raptor complex activity through raptor binding.\",\n      \"method\": \"Co-immunoprecipitation, pharmacological inhibition, immunoblot\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with pharmacological disruption, replicated in T cell context (PMID:19586661), single mechanistic readout\",\n      \"pmids\": [\"16428328\", \"19586661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ERK1/2 interact with raptor and directly phosphorylate it on Ser8, Ser696, and Ser863 in response to Ras/MAPK activation; phosphorylation-deficient raptor alleles reduce mTORC1 activity and 4E-BP1 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, mass spectrometry, phospho-specific antibodies, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with MS site mapping and mutagenesis, functional consequence demonstrated, single lab\",\n      \"pmids\": [\"21071439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CDC2/CDK1 (cdc2) phosphorylates raptor on Ser696 and Thr706 during mitosis; Cyclin B co-immunoprecipitates with raptor in mitotic cells, and these mitotic phosphorylation events regulate mTORC1 during cell division.\",\n      \"method\": \"Tandem mass spectrometry, phospho-specific antibodies, site-directed mutagenesis, Co-immunoprecipitation, cell synchronization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS site mapping, mutagenesis, kinase identity established by Co-IP, single lab; consistent with Ramírez-Valle 2010 findings\",\n      \"pmids\": [\"20169205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mitotic phosphorylation of raptor (by CDK1 and GSK3 pathways) facilitates G2/M cell cycle transit; phosphorylation-deficient raptor mutants cause G2/M delay while raptor depletion causes G1 accumulation; mitotic raptor promotes IRES-dependent mRNA translation.\",\n      \"method\": \"Phosphopeptide mapping, site-directed mutagenesis, cell cycle analysis, dominant-negative/constitutive kinase constructs\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-mutant functional analysis, cell cycle readout, single lab\",\n      \"pmids\": [\"20439490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ULK1 phosphorylates raptor at multiple sites in vivo and in vitro (prominently Ser855 and Ser859, with moderate Ser792); ULK1-mediated raptor phosphorylation reduces the ability of raptor to bind substrate 4E-BP1 without disrupting mTORC1 complex integrity, providing a negative feedback mechanism.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibodies, Co-immunoprecipitation, shRNA knockdown, overexpression\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation plus substrate-docking assay plus shRNA epistasis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21460630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Raptor and Rheb negatively regulate skeletal myogenic differentiation through suppression of IRS1; raptor or Rheb knockdown enhances C2C12 differentiation accompanied by increased Akt activation and elevated IRS1 levels, and IRS1 knockdown abolishes this enhancement.\",\n      \"method\": \"RNAi knockdown, overexpression, C2C12 differentiation assay, immunoblot epistasis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi epistasis with rescue, genetic pathway placement, single lab\",\n      \"pmids\": [\"21852229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ICK (intestinal cell kinase) phosphorylates raptor at Thr908 both in vitro and in vivo; Raptor T908A mutant markedly impairs mTORC1 activation by insulin or Rheb overexpression without disrupting mTORC1 complex integrity.\",\n      \"method\": \"In vitro kinase assay, mass spectrometry, phospho-specific antibody, site-directed mutagenesis, Co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with MS site mapping and mutagenesis-based functional validation, single lab\",\n      \"pmids\": [\"22356909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FLIM-FRET in live cells confirmed direct physical interaction between mTOR and raptor in the cytoplasm and nucleus; amino acid withdrawal and re-addition (but not rapamycin) alter mTOR intracellular distribution.\",\n      \"method\": \"FRET-FLIM live-cell imaging, GFP/DsRed fusion proteins\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — live-cell FRET-FLIM is rigorous but single lab, no functional mutagenesis companion\",\n      \"pmids\": [\"23311891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GSK3 phosphorylates raptor at Ser859; GSK3 inhibition or shRNA silencing reduces mTOR–raptor interaction and attenuates amino-acid-regulated mTORC1 signaling, increased autophagic flux, and reduced proliferation.\",\n      \"method\": \"Pharmacological inhibition, shRNA, phospho-specific antibody, Co-immunoprecipitation, site-directed mutagenesis (S859A)\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mutagenesis plus RNAi, single lab\",\n      \"pmids\": [\"26348909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Glucose starvation in budding yeast triggers Snf1/AMPK-dependent phosphorylation of Kog1/Raptor at Ser491/494, driving TORC1 disassembly and condensation of Kog1 into a single body near the vacuole; these bodies increase the TORC1 activation threshold (hysteresis) during prolonged starvation.\",\n      \"method\": \"Yeast genetics, live-cell fluorescence microscopy, phospho-mutant constructs, TORC1 activity assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast ortholog (Kog1), genetic epistasis with phospho-mutants, live imaging, mechanistic readout of complex disassembly\",\n      \"pmids\": [\"26439012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NLK phosphorylates raptor on Ser863 in response to osmotic/oxidative stress; this phosphorylation disrupts raptor's interaction with Rag GTPases, inhibits mTORC1 lysosomal localization, and suppresses mTORC1 activation; Raptor S863A knock-in cells are defective in stress-induced mTORC1 inhibition.\",\n      \"method\": \"In vitro kinase assay, Co-immunoprecipitation, phospho-specific antibody, Nlk knockout and Raptor knock-in cells, immunofluorescence\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, Raptor knock-in cells, Co-IP showing Rag disruption, localization readout, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26588989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Free (mTORC1-independent) Raptor negatively regulates hepatic Akt activity and lipogenesis by stabilizing the Akt phosphatase PHLPP2, reducing its β-TrCP-mediated degradation; this reveals a scaffolding function of Raptor independent of mTOR kinase.\",\n      \"method\": \"Hepatocyte-specific Raptor knockout mice, overexpression constructs, Co-immunoprecipitation, immunoblot, liver lipid measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model plus Co-IP plus PHLPP2 degradation assay, single lab\",\n      \"pmids\": [\"26743335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The mTOR–Raptor–S6K1 axis regulates Runx2 expression through S6K1-mediated phosphorylation of estrogen receptor α, which binds DLX5 and augments Runx2 enhancer activity; heterozygous Raptor mutation in osteoblasts aggravates bone defects in Runx2+/− mice.\",\n      \"method\": \"Conditional knockout mice, immunoblot, chromatin immunoprecipitation, genetic epistasis (Raptor×Runx2 double mutant)\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mice plus ChIP mechanistic detail, single lab\",\n      \"pmids\": [\"28686577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP9X deubiquitylase physically associates with Raptor in embryonic brains, opposes proteasomal degradation of Raptor, and thereby maintains Raptor protein levels and mTORC1 signaling in neural progenitors; loss of Usp9x phenocopies Raptor-null neurospheres in reducing mTORC1 activity.\",\n      \"method\": \"Co-immunoprecipitation from embryonic brain, USP9X loss- and gain-of-function in cultured cells and Nestin-Cre Usp9x mice, proteasome inhibition assay, EdU proliferation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in vivo, multiple loss-of-function models, proteasome assay, single lab\",\n      \"pmids\": [\"28341829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PKA phosphorylates Raptor at Ser791 in response to Gαs-coupled GPCR activation, leading to decreased mTORC1 activity; Raptor S791A mutant partially rescues mTORC1 activity after PKA activation, and this pathway operates in multiple cell lines and mouse tissues.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody, Raptor S791A site-directed mutagenesis, pharmacological GPCR agonists, immunoblot in mouse tissues\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, mutagenesis with functional rescue, in vivo confirmation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31112131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SHOC2 (a RAS activator) competes with mTOR for Raptor binding; SHOC2–Raptor interaction inhibits mTORC1 and induces autophagy, while Raptor binding to SHOC2 blocks RAS-MAPK signaling; FBXW7-mediated ubiquitination of SHOC2 terminates this cross-talk.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assay, ubiquitination assay, autophagy flux assay, cell proliferation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP competition, multiple pathway readouts, single lab\",\n      \"pmids\": [\"30865892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TBK1 phosphorylates Raptor at Ser877 in vitro and promotes Ser877 phosphorylation in cells in response to pathogen-associated molecules; phosphorylation at Ser877 inversely correlates with mTORC1 activity, and Raptor S877A mutant increases mTORC1 activity.\",\n      \"method\": \"In vitro kinase assay coupled with mass spectrometry, phospho-specific antibody, Raptor S877A site-directed mutagenesis, immunoblot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay with MS mapping and mutagenesis, but single lab with limited in vivo validation\",\n      \"pmids\": [\"31530866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Leucine regulates autophagy via its metabolite acetyl-CoA: AcCoA promotes EP300-dependent acetylation of raptor, which activates mTORC1 and suppresses autophagy; leucine deprivation decreases raptor acetylation and causes mTORC1 inhibition predominantly through this mechanism.\",\n      \"method\": \"Pharmacological manipulation of AcCoA, EP300 inhibitor, Co-immunoprecipitation, raptor acetylation assay, autophagy flux assay in multiple cell lines and neurons\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EP300-raptor acetylation mapped, multiple cell types including neurons, autophagy functional readout, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32561715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hepatic peroxisomal β-oxidation suppresses lipophagy via RPTOR acetylation and mTOR activation; ACOX1 deficiency decreases cytosolic acetyl-CoA, reduces RPTOR acetylation, inhibits mTORC1, and induces lipophagy.\",\n      \"method\": \"Liver-specific Acox1 knockout mice, acetylation assay, mTORC1 activity measurement, lipophagy quantification\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout model with acetylation readout, consistent with PMID:32561715, single lab\",\n      \"pmids\": [\"32687428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AMPK-mediated phosphorylation of both RAPTOR (Ser722/Ser792) and TSC2 is required for full mTORC1 inhibition by metformin in primary hepatocytes and intact liver; Raptor knock-in mice (S722A/S792A) show incomplete mTORC1 inhibition and an attenuated transcriptional response to metformin.\",\n      \"method\": \"Raptor Ser722A/Ser792A knock-in mice, primary hepatocyte cultures, immunoblot, RNA-seq\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knock-in genetic model, primary cells, multiple readouts, extends PMID:18439900\",\n      \"pmids\": [\"32912901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VHL interacts with RAPTOR and promotes RAPTOR degradation through ubiquitination, thereby suppressing mTORC1 signaling; loss of VHL in ccRCC increases RAPTOR levels and mTORC1 hyperactivation, consistent with a conserved mechanism also observed in C. elegans vhl-1 mutants.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, VHL overexpression/silencing, C. elegans vhl-1 genetic analysis, immunoblot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ubiquitination assay, in vivo C. elegans validation, single lab\",\n      \"pmids\": [\"34290272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"O-GlcNAcylation of Raptor at Thr700 by OGT (driven by glucose availability) facilitates Raptor–Rag GTPase interactions and promotes lysosomal translocation of mTOR, thereby activating mTORC1; AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor–Rag interactions.\",\n      \"method\": \"O-GlcNAc proteomics, site-directed mutagenesis (T700A), Co-immunoprecipitation, lysosomal fractionation, immunofluorescence, OGT inhibition\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical site mapping with mutagenesis, multiple orthogonal methods (Co-IP, fractionation, imaging), cross-talk with AMPK phosphorylation demonstrated, single lab\",\n      \"pmids\": [\"37541260\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPTOR (Raptor) is an essential scaffolding subunit of mTORC1 that recruits substrates (S6K1, 4E-BP1, SGK1, IRS-1) to mTOR via their TOS motifs and undergoes extensive regulatory phosphorylation by multiple kinases (AMPK, RSK1/2, ERK1/2, CDK1, GSK3, ULK1, NLK, PKA, TBK1, ICK, p38β), as well as acetylation by EP300 and O-GlcNAcylation at Thr700, each modulating mTORC1 activity in response to energy, growth factor, stress, and nutrient signals; its stability is additionally controlled by the DDB1-CUL4 ubiquitin ligase (ubiquitinating Raptor), UCH-L1 (deubiquitinating), USP9X (stabilizing), VHL (promoting degradation), and Hsp90 (chaperoning), while its interaction with Rag GTPases mediates amino-acid-dependent lysosomal recruitment of mTOR and its interaction with mTOR is disrupted by FKBP12-rapamycin, AMPK-driven 14-3-3 binding, NLK phosphorylation, and SHOC2 competition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPTOR (Raptor) is the defining scaffolding subunit of mTOR complex 1 (mTORC1), forming a stoichiometric complex with mTOR that couples nutrient and growth signals to control of cell size, translation, and proliferation [#0, #1]. Its central molecular function is substrate recruitment: Raptor binds the TOS motifs of S6K1 and 4E-BP1 and presents them to the mTOR kinase domain, such that TOS-motif mutations abolish Raptor binding and mTOR-catalyzed phosphorylation [#2]; it likewise scaffolds direct phosphorylation of IRS-1 via the IRS-1 SAIN domain and of SGK1, defining the substrate repertoire of mTORC1 and a negative-feedback loop on PI3K/Akt signaling [#8, #18, #15]. Complex assembly is stabilized by mLST8/GβL and is the target of rapamycin, which acts through FKBP12 to dissociate Raptor from mTOR without altering intrinsic kinase activity [#3, #5]. Raptor is the principal hub for upstream signal integration: amino acids and glucose promote Raptor–Rag GTPase interaction that drives lysosomal recruitment of mTORC1, gated positively by OGT-mediated O-GlcNAcylation at Thr700 and EP300-mediated acetylation, and negatively by AMPK phosphorylation (Ser722/Ser792) that recruits 14-3-3 and by NLK phosphorylation (Ser863) that disrupts Rag binding [#13, #41, #37, #12, #30]. A dense array of kinases converges on Raptor to tune mTORC1 activity—RSK1/2, ERK1/2, CDK1, GSK3, ULK1, ICK, PKA, and TBK1—integrating MAPK, mitotic, autophagic, GPCR, and innate-immune inputs [#14, #21, #22, #24, #26, #34, #36], while its abundance is governed by competing ubiquitination (DDB1-CUL4, VHL) and deubiquitination/stabilization (UCH-L1, USP9X) [#9, #40, #33]. Genetic ablation of Raptor in mice is embryonic-lethal, establishing mTORC1/Raptor as essential for early development [#10]. Beyond its mTOR-bound role, free Raptor scaffolds PHLPP2 stabilization to restrain hepatic Akt and lipogenesis, an mTOR-kinase-independent function [#31].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the existence and identity of Raptor as an mTOR-associated protein required for nutrient signaling and cell size, defining the founding subunit of what became mTORC1.\",\n      \"evidence\": \"Co-IP, mass spectrometry, RNAi, and cell-size assays in mammalian cells\",\n      \"pmids\": [\"12150925\", \"12150926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how Raptor mechanistically links mTOR to specific substrates\", \"Stoichiometry and structural basis of the association unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the molecular basis of substrate recruitment, showing Raptor binds the TOS motif of S6K1 and 4E-BP1 to present them to mTOR, settling Raptor's role as a substrate-presenting scaffold.\",\n      \"evidence\": \"Co-IP, TOS-motif point mutants, in vitro kinase assays in mammalian cells\",\n      \"pmids\": [\"12604610\", \"12747827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how other substrates lacking canonical TOS motifs are recognized\", \"Structural geometry of substrate delivery to the kinase domain unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed that mLST8/GβL stabilizes the Raptor–mTOR association and renders complex regulation by nutrients and rapamycin operative, integrating a third subunit into mTORC1.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, RNAi in mammalian cells\",\n      \"pmids\": [\"12718876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of mLST8 versus Raptor to substrate phosphorylation not separated\", \"Later shown dispensable for mTORC1 signaling in vivo (#10)\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Distinguished Raptor-containing mTORC1 from Rictor-containing mTORC2, demonstrating Raptor specifies the rapamycin-sensitive, S6K1-directed branch of mTOR signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, mass spectrometry, RNAi, immunofluorescence\",\n      \"pmids\": [\"15268862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define substrate-recognition rules separating the two complexes beyond TOS dependence\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the mechanism of rapamycin action, showing FKBP12–rapamycin dissociates Raptor from mTOR rather than directly inhibiting catalysis, explaining substrate uncoupling.\",\n      \"evidence\": \"Co-IP and direct in vitro binding/kinase assays\",\n      \"pmids\": [\"15066126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain rapamycin-resistant residual mTORC1 outputs\", \"In vivo restraint of complex assembly by FKBP12 addressed only later (#17)\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified IRS-1 and SGK1 as direct Raptor-scaffolded mTORC1 substrates, extending the substrate repertoire and revealing a feedback loop onto PI3K/Akt.\",\n      \"evidence\": \"Co-IP, RNAi, in vitro kinase and phospho-specific immunoblot in mammalian cells\",\n      \"pmids\": [\"16354680\", \"18570873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the IRS-1 docking surface (resolved in 2009, #18)\", \"Physiological balance of feedback versus forward signaling not quantified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated genetic essentiality, showing Raptor-null mice die in early embryogenesis while mLST8 is dispensable for mTORC1, separating the two subunits' in vivo roles.\",\n      \"evidence\": \"Conditional/constitutive knockout mice with signaling readouts\",\n      \"pmids\": [\"17141160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific developmental requirements not dissected here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Provided the first structural framing of how Raptor/KOG1 positions its WD40 domain near the TOR kinase, supporting a physical substrate-delivery model.\",\n      \"evidence\": \"Single-particle electron microscopy of the yeast TOR1–KOG1 complex at 25 Å\",\n      \"pmids\": [\"17679098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Low resolution and yeast ortholog; no mutagenesis validation\", \"Substrate-bound state not captured\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified Raptor as the convergence point for energy stress, showing AMPK phosphorylation of Ser722/Ser792 recruits 14-3-3 to inhibit mTORC1, linking AMPK to direct mTORC1 suppression.\",\n      \"evidence\": \"In vitro kinase, phospho-mutant rescue, 14-3-3 Co-IP, RNAi\",\n      \"pmids\": [\"18439900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which 14-3-3 binding inhibits the complex not structurally defined\", \"In vivo requirement confirmed only later (#39)\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established Raptor as the amino-acid sensing interface, showing GTP-loaded Rag GTPases bind Raptor to relocalize mTORC1 to lysosomes without directly stimulating kinase activity.\",\n      \"evidence\": \"Co-IP, dominant-active/negative Rag constructs, immunofluorescence, RNAi\",\n      \"pmids\": [\"18497260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How relocalization activates kinase activity not resolved here\", \"Modifications gating Raptor–Rag binding identified only later (#30, #41)\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected the Ras/MAPK pathway to mTORC1 by showing RSK1/2 directly phosphorylate Raptor at conserved RXRXXS/T sites to promote kinase activity.\",\n      \"evidence\": \"In vitro kinase, MS site mapping, mutagenesis, RNAi, oncogenic Ras/MEK constructs\",\n      \"pmids\": [\"18722121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which these phosphosites increase activity unknown\", \"Overlap with ERK sites (#21) not fully deconvolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped insulin-driven Raptor phosphorylation hierarchy (Ser863 as master switch for Ser855/Ser859), defining how growth-factor signaling tunes mTORC1 kinase output.\",\n      \"evidence\": \"MS site mapping, phospho-antibodies, mutagenesis, in vitro kinase, Rheb overexpression\",\n      \"pmids\": [\"19864431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify all kinases for each site (later: ERK, ULK1, GSK3, NLK)\", \"Structural consequence of multisite phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified ERK1/2 and CDK1 as additional direct Raptor kinases, integrating MAPK and mitotic signals into mTORC1 control of translation and cell-cycle progression.\",\n      \"evidence\": \"Co-IP, in vitro kinase, MS site mapping, phospho-mutant cell-cycle analysis\",\n      \"pmids\": [\"21071439\", \"20169205\", \"20439490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional integration of overlapping ERK/RSK/CDK1 sites on Ser696/Ser863 not unified\", \"Mitotic IRES-translation mechanism only partially defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed an autophagy feedback arm, showing ULK1 phosphorylates Raptor to reduce its 4E-BP1 binding without disrupting complex integrity.\",\n      \"evidence\": \"In vitro kinase, substrate-docking Co-IP, shRNA epistasis\",\n      \"pmids\": [\"21460630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ULK1 phosphorylation impairs all substrates or selectively 4E-BP1 unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Added ICK as a Raptor kinase whose Thr908 phosphorylation is required for insulin/Rheb-driven mTORC1 activation, broadening the activating-kinase set.\",\n      \"evidence\": \"In vitro kinase, MS mapping, T908A mutagenesis, Co-IP\",\n      \"pmids\": [\"22356909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Thr908 enables Rheb-driven activation unknown\", \"Limited in vivo validation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated multiple stress/nutrient kinases (GSK3, NLK) phosphorylate Ser859/Ser863 to control Raptor's mTOR and Rag interactions, mechanistically separating complex integrity from lysosomal recruitment.\",\n      \"evidence\": \"Co-IP, mutagenesis, shRNA/knockout, knock-in cells, immunofluorescence\",\n      \"pmids\": [\"26348909\", \"26588989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk and hierarchy among kinases targeting the same Raptor residues unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed a conserved starvation response in which Snf1/AMPK phosphorylation drives Kog1/Raptor condensation and TORC1 disassembly, establishing phase-separation-like hysteresis in TORC1 reactivation.\",\n      \"evidence\": \"Yeast genetics, live-cell imaging, phospho-mutants, TORC1 activity assays\",\n      \"pmids\": [\"26439012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian Raptor undergoes analogous condensation untested here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered an mTOR-independent scaffolding role, showing free Raptor stabilizes PHLPP2 to restrain hepatic Akt and lipogenesis.\",\n      \"evidence\": \"Hepatocyte-specific Raptor knockout mice, Co-IP, PHLPP2 degradation assays\",\n      \"pmids\": [\"26743335\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; structural basis of Raptor–PHLPP2 interaction undefined\", \"Generality beyond liver unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the kinase network to GPCR/PKA, innate-immune TBK1, and RAS-pathway SHOC2 competition, defining additional physiological contexts that suppress mTORC1 through Raptor.\",\n      \"evidence\": \"In vitro kinase, phospho-mutant rescue, competitive Co-IP, autophagy/ubiquitination assays\",\n      \"pmids\": [\"31112131\", \"31530866\", \"30865892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TBK1 (#36) and SHOC2 (#35) lack extensive in vivo validation\", \"Integration of these inputs with the dominant nutrient pathway unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined acetyl-CoA-driven EP300 acetylation of Raptor as a metabolic switch coupling leucine and peroxisomal β-oxidation to mTORC1 activation and autophagy suppression.\",\n      \"evidence\": \"AcCoA/EP300 pharmacology, acetylation and autophagy assays, Acox1 knockout mice\",\n      \"pmids\": [\"32561715\", \"32687428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetylated residue(s) and structural effect on the complex not fully mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed the physiological requirement of Raptor Ser722/Ser792 phosphorylation, showing knock-in mice resist metformin-driven mTORC1 inhibition, validating AMPK→Raptor signaling in vivo.\",\n      \"evidence\": \"Raptor S722A/S792A knock-in mice, primary hepatocytes, RNA-seq\",\n      \"pmids\": [\"32912901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of Raptor versus TSC2 phosphorylation not fully isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified VHL as a ubiquitin ligase that degrades Raptor to suppress mTORC1, adding tumor-suppressor control over Raptor abundance.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, VHL gain/loss, C. elegans vhl-1 genetics\",\n      \"pmids\": [\"34290272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect ubiquitination by VHL not fully distinguished\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed glucose-driven OGT O-GlcNAcylation of Raptor Thr700 promotes Raptor–Rag binding and lysosomal mTOR recruitment, and that AMPK phosphorylation antagonizes this modification, unifying nutrient and energy inputs at the Rag interface.\",\n      \"evidence\": \"O-GlcNAc proteomics, T700A mutagenesis, Co-IP, lysosomal fractionation, imaging, OGT inhibition\",\n      \"pmids\": [\"37541260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how Thr700 modification alters Rag binding unresolved\", \"Crosstalk hierarchy with acetylation and phosphorylation not fully integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the dense, overlapping array of Raptor modifications (phosphorylation, acetylation, O-GlcNAcylation, ubiquitination) is hierarchically integrated into a single quantitative mTORC1 activity setpoint, and the high-resolution structural geometry of substrate delivery, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model reconciling competing modifications at shared residues (e.g., Ser863, Ser792)\", \"No high-resolution structure of human Raptor presenting a substrate to the mTOR kinase domain\", \"Whether mTOR-independent scaffolding roles generalize beyond liver\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 8, 18, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 12, 24, 30, 31]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [13, 30, 41]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 14, 19, 34]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [24, 28, 35, 37, 38]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 37, 38, 39]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [22, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 8]}\n    ],\n    \"complexes\": [\"mTORC1\"],\n    \"partners\": [\"MTOR\", \"MLST8\", \"RPS6KB1\", \"EIF4EBP1\", \"IRS1\", \"RRAGA\", \"AKT1S1\", \"SHOC2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}