{"gene":"RICTOR","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2005,"finding":"The rictor-mTOR complex directly phosphorylates Akt/PKB on Ser473 in vitro, and rictor and mTOR are necessary for Ser473 phosphorylation in Drosophila and human cells; the rictor-mTOR complex also facilitates Thr308 phosphorylation by PDK1.","method":"In vitro kinase assay (rictor-mTOR complex phosphorylating Akt Ser473), RNAi knockdown of rictor/mTOR in human and Drosophila cells measuring Akt phosphorylation","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro kinase reconstitution plus genetic knockdown in two organisms, widely replicated","pmids":["15718470"],"is_preprint":false},{"year":2005,"finding":"The rictor-mTOR complex (mTORC2) phosphorylates the hydrophobic motif (Thr389) of rapamycin-resistant S6K1 mutants in vitro, whereas the raptor-mTOR complex (mTORC1) phosphorylates rapamycin-sensitive forms; substrate selection by rictor-mTOR is independent of the TOR signaling motif and depends on removal of the C-terminal domain of S6K1.","method":"In vitro kinase assays with purified raptor-mTOR and rictor-mTOR complexes and S6K1 mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with domain-deletion mutants defining substrate determinants, single lab but multiple orthogonal experiments","pmids":["15809305"],"is_preprint":false},{"year":2005,"finding":"In 3T3-L1 adipocytes, mTOR complexed to RICTOR is the Ser473 kinase for Akt; vesicles immunoprecipitated with anti-mTOR or anti-RICTOR antibodies showed PIP3-stimulated Ser473 activity sensitive to wortmannin but not staurosporine, and RICTOR siRNA knockdown suppressed insulin-activated Ser473 phosphorylation.","method":"Subcellular fractionation, immunoprecipitation kinase assay, siRNA knockdown in 3T3-L1 adipocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — cell-free kinase assay plus RNAi in a classical insulin-responsive cell type, replicating the Sabatini lab finding","pmids":["16221682"],"is_preprint":false},{"year":2006,"finding":"SIN1/MIP1 is an essential mTORC2 subunit; genetic ablation of sin1 abolished Akt Ser473 phosphorylation and disrupted rictor-mTOR interaction while leaving Thr308 phosphorylation intact. Loss of Ser473 phosphorylation selectively impaired FoxO1/3a phosphorylation but not TSC2, GSK3, S6K, or 4E-BP1, demonstrating substrate selectivity of mTORC2 downstream signaling.","method":"sin1 genetic knockout, co-immunoprecipitation to assess rictor-mTOR complex integrity, phospho-specific immunoblotting for Akt and Akt substrates","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus genetic ablation with multiple downstream readouts, independently replicated","pmids":["16962653"],"is_preprint":false},{"year":2006,"finding":"During human cytomegalovirus (HCMV) infection, the rictor-containing mTOR complex is activated (elevated Akt Ser473 phosphorylation in a rapamycin-insensitive, caffeine-sensitive manner), and rictor is more significant than raptor for viral infection; depletion shows that in HCMV-infected cells both raptor and rictor complexes acquire altered substrate specificities and rapamycin sensitivities.","method":"shRNA depletion of rictor and raptor, phospho-immunoblotting, viral growth assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean shRNA knockdown with multiple substrates, single lab","pmids":["16959881"],"is_preprint":false},{"year":2007,"finding":"In Drosophila rictor-null mutants, Akt-Ser505 phosphorylation is decreased, FOXO-dependent apoptosis is augmented, and Akt-induced tissue hyperplasia is reduced, while S6K phosphorylation and S6K-induced cell overgrowth are unaffected, demonstrating that rictor/TORC2 specifically regulates the Akt-FOXO signaling module distinct from raptor/TORC1-S6K signaling.","method":"Drosophila rictor-null genetic mutants, phospho-specific immunoblotting, cell size/apoptosis measurements","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic loss-of-function in Drosophila with clear separation of two TOR complex functions","pmids":["17462592"],"is_preprint":false},{"year":2007,"finding":"Overexpression of rictor in glioma cell lines leads to increased mTORC2 assembly and activity, increased PKCα activity, and increased anchorage-independent growth, S-phase distribution, motility, and integrin β1/β3 expression; siRNA knockdown of rictor inhibited these phenotypes and reduced PKCα activity.","method":"Rictor overexpression and siRNA knockdown, mTORC2 kinase assays, soft agar growth, cell cycle analysis, PKCα activity assay, xenograft studies","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase assay plus multiple cellular phenotype readouts, single lab","pmids":["18089801"],"is_preprint":false},{"year":2007,"finding":"Rictor negatively regulates mTORC1 activity: shRNA-mediated downregulation of rictor increased S6K1 and 4E-BP1 phosphorylation and basal protein synthesis in TGFβ-treated renal cells, while raptor shRNA inhibited these effects, placing mTORC2/rictor as a negative regulator of mTORC1 to control basal protein synthesis.","method":"shRNA knockdown of raptor or rictor, phospho-immunoblotting of S6K and 4E-BP1, [35S]-methionine protein synthesis assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean RNAi with defined readout, single lab, single study","pmids":["18068336"],"is_preprint":false},{"year":2008,"finding":"Rictor interacts directly with integrin-linked kinase (ILK); yeast two-hybrid assays showed a direct interaction between the NH2- and COOH-terminal domains of rictor and the ILK kinase domain. ILK and rictor colocalize in membrane ruffles and leading edges of cancer cells, and rictor regulates ILK-associated Akt Ser473 phosphorylation.","method":"Proteomic screen, co-immunoprecipitation, yeast two-hybrid, colocalization imaging, siRNA knockdown","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction confirmed by yeast two-hybrid plus reciprocal co-IP, colocalization, and functional rescue, single lab","pmids":["18339839"],"is_preprint":false},{"year":2008,"finding":"Rictor forms a complex with Myo1c (a molecular motor) in adipocytes that is biochemically distinct from mTORC2 and can be immunoprecipitated independently of mTOR. Loss of either rictor or Myo1c inhibits paxillin Tyr118 phosphorylation and Myo1c-induced membrane ruffling, effects that are rapamycin- and wortmannin-insensitive, indicating a mTORC2-independent role of rictor in cortical actin remodeling.","method":"Co-immunoprecipitation, RNAi knockdown, phospho-paxillin immunoblotting, membrane ruffling assay, rapamycin/wortmannin treatment","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical complex distinct from mTORC2 demonstrated by co-IP plus functional phenotypes, single lab","pmids":["18426911"],"is_preprint":false},{"year":2008,"finding":"Hsp70 physically associates with rictor and is required for mTORC2 formation and activity; in cells with antisense RNA targeting Hsp70, mTORC2 assembly and mTORC2 kinase activity were impaired, while mTORC1 was unaffected.","method":"Yeast two-hybrid screen, co-immunoprecipitation, colocalization, mTORC2 kinase assay in Hsp70-depleted cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP plus functional mTORC2 kinase assay, single lab","pmids":["18505677"],"is_preprint":false},{"year":2009,"finding":"S6K1 (p70 ribosomal S6 kinase 1) directly phosphorylates rictor on Thr1135 in vitro and in vivo in a rapamycin-sensitive manner; cells expressing rictor T1135A have increased mTORC2-dependent Akt phosphorylation and increased phosphorylation of FoxO1/3a and GSK3, demonstrating that S6K1-mediated phosphorylation of rictor on Thr1135 inhibits mTORC2 activity as a feedback mechanism from mTORC1.","method":"In vitro S6K1 kinase assay with rictor, phospho-site mapping, rapamycin treatment in cells, T1135A phospho-dead mutant expression, phospho-immunoblotting","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay demonstrating direct phosphorylation plus cellular phospho-dead mutant functional studies, independently replicated (Treins et al. same year)","pmids":["19995915"],"is_preprint":false},{"year":2009,"finding":"S6K1 directly phosphorylates rictor on Thr1135 (a conserved vertebrate site) via a rapamycin-sensitive cascade; Thr1135 phosphorylation mediates 14-3-3 binding to rictor/mTORC2 but does not cause major changes in mTORC2 kinase activity.","method":"In vitro S6K1 kinase assay, phosphorylation site mapping, 14-3-3 binding assay, mTORC2 kinase assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — independent replication of Julien et al. direct S6K1-rictor phosphorylation with additional 14-3-3 binding finding","pmids":["19935711"],"is_preprint":false},{"year":2009,"finding":"In C. elegans, rictor/TORC2 controls fat storage, body size, growth, feeding, reproduction, and lifespan; these phenotypes are genetically dependent on akt-1, akt-2, and sgk-1, with fat metabolism and growth principally mediated by sgk-1 in the intestine, placing rictor upstream of AKT and SGK in a tissue-specific manner.","method":"Forward genetic screen, rictor loss-of-function mutants, epistasis analysis with akt-1, akt-2, sgk-1 double mutants, tissue-specific rescue experiments","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple double-mutant combinations in vivo defining pathway hierarchy, tissue rescue experiments","pmids":["19240135"],"is_preprint":false},{"year":2009,"finding":"In C. elegans, loss of CeRictor phenocopies loss of sgk-1 (not akt), and a gain-of-function sgk-1 mutation suppresses CeRictor mutant phenotypes (developmental delay, decreased body size, increased lipid storage), establishing SGK1 as the primary mediator of TORC2 in regulating growth and metabolism, distinct from AKT.","method":"Loss-of-function mutant analysis, epistasis with sgk-1 and akt double mutants, gain-of-function sgk-1 suppressor analysis","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with gain-of-function suppressor identifying SGK1 as primary TORC2 effector, independent replication of Soukas et al.","pmids":["19260765"],"is_preprint":false},{"year":2010,"finding":"FoxO1 transcription factor induces rictor gene expression, increasing mTORC2 assembly and activity, which subsequently activates Akt; in Tsc2-deficient cells, FoxO1-induced rictor elevation increases mTORC2 at the expense of mTORC1, creating a feedback loop.","method":"Overexpression/knockdown of FoxO1, rictor expression measurements, mTORC2 kinase assays, genetic epistasis with Tsc2-/- cells","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with mechanistic follow-up in multiple genetic backgrounds, single lab","pmids":["20412774"],"is_preprint":false},{"year":2010,"finding":"Rictor interacts with PKCζ, and EGF induces translocation and colocalization of rictor with PKCζ independently of the mTORC2 complex; rictor knockdown inhibited EGF-induced PKCζ phosphorylation and translocation, phosphorylation of cofilin, and cellular chemotaxis, and ablated pulmonary metastasis in a xenograft model.","method":"Co-immunoprecipitation, colocalization imaging, siRNA knockdown, chemotaxis assay, xenograft metastasis model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus in vivo xenograft, interaction shown outside mTORC2 context, single lab","pmids":["20978191"],"is_preprint":false},{"year":2010,"finding":"Rictor suppresses RhoGDI2 protein levels by a mechanism independent of Sin1 and raptor (hence independent of mTORC2 and mTORC1), and this rictor-dependent suppression of RhoGDI2 promotes Rac and Cdc42 activity and cell migration.","method":"Proteomics, rictor/sin1/raptor knockdown, Rac/Cdc42 activity assays, RhoGDI2 expression analysis, migration assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-guided mechanistic study with genetic separation from mTORC1/2, single lab","pmids":["22777355"],"is_preprint":false},{"year":2010,"finding":"Rictor contains a novel ubiquitin E3 ligase activity by forming a complex with Cullin-1 (but not other Cullins); SGK1 is identified as a substrate of this Rictor/Cullin-1 E3 ligase. Phosphorylation of rictor at Thr1135 by AGC kinases (Akt, S6K, SGK1) disrupts Rictor-Cullin-1 interaction, impairing SGK1 ubiquitination and leading to SGK1 accumulation.","method":"Co-immunoprecipitation of Cullin proteins, ubiquitination assays, rictor-/- MEFs, T1135E phosphomimetic mutant, SGK1 stability assays","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional ubiquitination assay and phosphomimetic mutant demonstrating mechanism, single lab","pmids":["21204013"],"is_preprint":false},{"year":2012,"finding":"Rictor associates with FBXW7 to form an E3 ligase complex (distinct from mTORC2) that mediates ubiquitination and degradation of c-Myc and cyclin E; rictor knockdown decreased ubiquitination and increased c-Myc and cyclin E levels, while FBXW7 knockout blocked rictor's effects on these substrates.","method":"Co-immunoprecipitation, rictor overexpression/knockdown, FBXW7 knockout, ubiquitination assays, c-Myc and cyclin E protein stability","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying complex plus genetic rescue with FBXW7 KO, single lab","pmids":["22285861"],"is_preprint":false},{"year":2013,"finding":"IKKα and IKKβ physically interact with rictor (in vitro binding mapped to rictor amino acids 999–1397); chemical or genetic inhibition of IKK reduced Akt Ser473 and PKCα Ser657 phosphorylation and decreased mTORC2 kinase activity; inactive IKK competed with mTOR for rictor binding, reducing mTORC2 levels and activity.","method":"Co-immunoprecipitation, in vitro binding assay with rictor fragments, siRNA knockdown, kinase-dead IKK expression, mTORC2 kinase assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding domain mapping plus cellular functional assays, single lab","pmids":["23872070"],"is_preprint":false},{"year":2013,"finding":"Rictor/Sin1 complexes are required for type I interferon-induced STAT pathway activation; knockdown of rictor or Sin1 resulted in defective STAT activation, reduced STAT-DNA binding, and decreased IFN-inducible gene expression, establishing a role for mTORC2 in IFN signaling.","method":"Stable and transient rictor/Sin1 knockdown, STAT phosphorylation assays, STAT-DNA binding (EMSA), IFN-inducible gene expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable KD with multiple downstream readouts linking mTORC2 to IFN-STAT pathway, single lab","pmids":["24469448"],"is_preprint":false},{"year":2014,"finding":"Conditional deletion of rictor in CNS oligodendrocytes revealed that mTORC2/rictor ablation has a modest positive effect on oligodendrocyte differentiation and very little effect on myelination when mTORC1 is intact, whereas raptor (mTORC1) ablation causes significant dysmyelination; this establishes distinct roles of the two mTOR complexes in CNS myelination.","method":"Conditional Cre/loxP knockout of rictor or raptor in oligodendrocyte lineage, histology, electron microscopy, myelin protein immunoblotting","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific genetic knockout with histological and molecular readouts, single lab","pmids":["24671993"],"is_preprint":false},{"year":2015,"finding":"GSK3 phosphorylates rictor at Thr1695 (within a CDC4 phospho-degron motif), promoting interaction between rictor and the E3 ubiquitin ligase FBXW7 and subsequent rictor ubiquitination and proteasomal degradation; mutation of Thr1695 impaired FBXW7 binding and stabilized rictor. Akt activation enhanced rictor levels by suppressing GSK3-dependent rictor degradation.","method":"In vitro GSK3 kinase assay on rictor, co-IP of FBXW7 and rictor, proteasome inhibitor treatment, T1695A/E mutagenesis, FBXW7 overexpression/knockout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay identifying GSK3 as the writer on Thr1695, domain mutagenesis validating degron, and functional consequence on mTORC2 assembly, single lab multiple orthogonal methods","pmids":["25897075"],"is_preprint":false},{"year":2015,"finding":"Glucose or acetate promotes acetyl-CoA-dependent acetylation of rictor, which activates mTORC2 and creates an autoactivation loop maintaining mTORC2 activity even when upstream growth factor receptor components are inactive, rendering GBM cells resistant to EGFR/PI3K/AKT-targeted therapies.","method":"Cell line and mouse tumor models, acetylation assays of rictor, acetyl-CoA manipulation, pharmacological inhibition of upstream signaling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rictor acetylation demonstrated with functional consequence in cell and mouse models, single lab","pmids":["26170313"],"is_preprint":false},{"year":2015,"finding":"Thyroid hormone (TH) increases SIRT1-mTORC2 interaction and promotes RICTOR deacetylation, leading to decreased AKT and FOXO1 phosphorylation; this increases FOXO1 nuclear localization and target gene transcription, demonstrating that RICTOR deacetylation is a mechanism linking TH signaling to mTORC2-AKT-FOXO1 axis.","method":"SIRT1-mTORC2 co-IP, RICTOR deacetylation assays, AKT and FOXO1 phospho-immunoblotting, hepatic transcriptome profiling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus biochemical deacetylation linked to downstream signaling, single lab","pmids":["26453307"],"is_preprint":false},{"year":2015,"finding":"Rictor/mTORC2 signaling in oocytes is required for folliculogenesis and follicle survival; oocyte-specific rictor knockout mice exhibited premature ovarian failure, massive follicular death, reduced Akt Ser473 phosphorylation, reduced Foxo3a phosphorylation, and elevated pro-apoptotic proteins, establishing a rictor/mTORC2/Akt/Foxo3a pro-survival axis in folliculogenesis.","method":"Conditional oocyte-specific rictor knockout (Cre/loxP), phospho-immunoblotting, apoptosis markers, ovarian histology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined signaling pathway (Akt-Foxo3a) and cellular phenotype, single lab multiple methods","pmids":["25564616"],"is_preprint":false},{"year":2015,"finding":"Conditional deletion of rictor in Sertoli cells causes azoospermia and sterility; rictor regulates actin organization via both mTORC2-dependent (Rac1 GTPase) and mTORC2-independent (paxillin phosphorylation) mechanisms, and loss of rictor disrupts Sertoli cell polarity, BTB integrity, and spermatogenesis.","method":"Conditional Sertoli cell-specific rictor knockout, actin filament staining, Rac1 activity assay, paxillin phospho-immunoblotting, electron microscopy","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with mechanistic dissection of mTORC2-dependent and -independent actin pathways, single lab","pmids":["26360620"],"is_preprint":false},{"year":2015,"finding":"Rictor regulates actin cytoskeleton organization via RhoA-GTPase; resveratrol-mediated downregulation of rictor in A431 cells reduced RhoA-GTPase activity and altered actin cytoskeleton, and exogenous overexpression of rictor restored RhoA activity and actin network, establishing a direct role of rictor in RhoA-mediated actin organization.","method":"Rictor overexpression/knockdown, RhoA-GTPase activity assay, actin cytoskeleton staining, senescence assay","journal":"Photochemistry and photobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression/knockdown approach with functional rescue, indirect pathway connection","pmids":["22272775"],"is_preprint":false},{"year":2015,"finding":"SMAD4 physically interacts with and inhibits RICTOR; SMAD4 deficiency activates mTORC2/AKT Ser473 signaling, and overexpression of SMAD4 or depletion of RICTOR suppresses AKT signaling and increases irinotecan sensitivity in SMAD4-deficient colon cancer cells.","method":"Co-immunoprecipitation of SMAD4 and RICTOR, SMAD4 overexpression and RICTOR depletion, phospho-AKT immunoblotting, cell viability and in vivo tumor assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying direct interaction plus functional genetic rescue in vitro and in vivo, single lab","pmids":["31932471"],"is_preprint":false},{"year":2015,"finding":"Tetraspanin 8 (Tspan8) forms a complex with rictor and integrin α3 in glioma cells; Tspan8-rictor association is required for mTORC2 activation; knockdown of Tspan8 prevented mTOR-rictor assembly and phosphorylation of AKT Ser473 and PKCα, and inhibited glioma cell migration.","method":"Co-immunoprecipitation, siRNA knockdown of Tspan8/rictor/integrin α3, mTORC2 assembly assay, AKT/PKCα phospho-immunoblotting, migration assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of trimeric complex plus functional consequence on mTORC2 assembly and kinase activity, single lab","pmids":["25761241"],"is_preprint":false},{"year":2015,"finding":"In Saccharomyces cerevisiae, TSC11/AVO3 (rictor ortholog) is genetically linked to cell integrity regulation; temperature-sensitive tsc11 mutants show cell wall defects, and dosage suppression identifies functional interactions with AVO1, AVO2, PKC1, and SLM1 as TORC2 components, with Tsc11p acting via a Pkc1p-independent mechanism through Avo1p and a Pkc1p-dependent mechanism through Avo2p/Slm1p.","method":"Temperature-sensitive allele analysis, osmotic stabilizer rescue, dosage suppression genetics, cell wall integrity assays","journal":"Current genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic genetic interaction mapping in yeast TORC2 pathway, well-controlled epistasis","pmids":["15809876"],"is_preprint":false},{"year":2017,"finding":"A small molecule (CID613034) that specifically blocks the rictor-mTOR protein-protein interaction inhibited mTORC2 kinase activity at submicromolar concentrations in vitro, selectively blocked phosphorylation of mTORC2 substrates (AKT Ser473, NDRG1 Thr346, PKCα Ser657) without affecting mTORC1 substrate S6K phosphorylation, and had anti-tumor effects in GBM xenografts.","method":"High-throughput yeast two-hybrid screen, in vitro mTORC2 kinase assay, phospho-selective immunoblotting in cells, xenograft tumor model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific PPI inhibitor with in vitro kinase validation and cellular/in vivo selectivity, single lab","pmids":["28453552"],"is_preprint":false},{"year":2017,"finding":"mTORC2/AKT signaling activates HSF1, which induces HuR expression; HuR directly binds the 3'UTR of the rictor transcript to enhance its translational efficiency, creating a feed-forward loop in which mTORC2 activity drives rictor expression in GBM.","method":"HuR-rictor 3'UTR binding assay, RNAi of AKT/HSF1/HuR, rictor protein/mRNA measurements, xenograft tumor growth","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-binding assay plus gain/loss-of-function with pathway dissection, single lab","pmids":["29059166"],"is_preprint":false},{"year":2018,"finding":"In vascular smooth muscle cells, TGFβ activates rictor in an integrin-linked kinase (ILK)-dependent manner, and β3-integrin expression modulates TGFβ-induced rictor phosphorylation (Thr1135); rictor activation is associated with an altered proliferative-migratory and metabolic phenotype resembling the aneurysm phenotype in Marfan syndrome aorta.","method":"Proteomics of MFS mouse aorta (data-independent acquisition MS), Western blot validation of rictor Thr1135 phosphorylation in vivo, ILK inhibition and β3-integrin manipulation in cultured aortic vascular smooth muscle cells","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo proteomic discovery validated by Western blot plus in vitro mechanistic experiments linking ILK and β3-integrin to rictor activation","pmids":["30004239"],"is_preprint":false},{"year":2020,"finding":"USP9X deubiquitinase removes Lys63-linked ubiquitin from RICTOR to promote its interaction with mTOR, thereby facilitating mTORC2 assembly and activity; growth factors regulate USP9X activity to stimulate mTORC2 assembly, establishing a ubiquitin-dependent mechanism for mTORC2 complex formation.","method":"Co-IP of USP9X and RICTOR, ubiquitin linkage-specific immunoblotting, USP9X knockdown in human cell lines and mice, mTORC2 kinase activity assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus linkage-specific ubiquitin analysis and functional mTORC2 kinase assay validated in both cell lines and mice","pmids":["33378666"],"is_preprint":false},{"year":2020,"finding":"Rictor interacts with ABLIM1 and regulates its serine phosphorylation (at Ser214 and Ser431); dominant-negative mutations at these sites inhibited ABLIM1-mediated actin polymerization and MKL1/SRF-dependent transcription (Arp3, c-Fos), linking rictor to actin dynamics through ABLIM1 phosphorylation in HCC cells.","method":"Co-immunoprecipitation, ABLIM1 knockout cell lines, phospho-site mutation (S214A, S431A), actin polymerization assay, MKL1 nuclear translocation imaging, SRF reporter assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with novel substrate identification plus functional validation with phospho-dead mutations, single lab","pmids":["33061800"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures of human mTORC2 in apo form and in complex with substrates Akt and SGK1 revealed: (1) Rictor-mTOR side chain interactions that sterically occlude mTORC1 substrates and confer rapamycin resistance; (2) mSin1 forms extensive contacts with Rictor via α-helices and an extended strand; (3) SGK1 (but not Akt) markedly alters mSin1 N-terminal conformation, inducing rotation of mSin1 Arg83 to interact with negatively charged Rictor residues; mutation of mSin1 Arg83 to Ala selectively disrupts mTORC2 phosphorylation of SGK1 but not Akt.","method":"Cryo-EM structure determination of human mTORC2 apo and substrate-bound complexes, functional phosphorylation assays with mSin1 R83A mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structures with mutagenesis functionally validating structural predictions for substrate specificity","pmids":["35926713"],"is_preprint":false},{"year":2022,"finding":"mTORC2 inactivation (via rictor deletion) in the inner ear is the major driver of sensorineural hearing loss induced by high-dose sirolimus; mTORC2 exerts its effects primarily through AKT phosphorylation, and ablation of P53 activity greatly attenuated hearing loss severity in mTORC2-deficient mice; selective activation of mTORC2 protects against acoustic trauma and cisplatin-induced ototoxicity.","method":"Pharmacological and genetic interventions in murine hearing models, rictor conditional knockout, p53 knockout epistasis, auditory brainstem response testing, AKT phosphorylation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological interventions with defined mechanistic pathway (mTORC2-AKT-p53) and functional readout, single lab","pmids":["35238644"],"is_preprint":false},{"year":2024,"finding":"Rictor/mTORC2 facilitates MARCH5-mediated K48-linked ubiquitination and degradation of BNIP3 at the K130 site, thereby reducing BNIP3-dependent mitophagy; rictor knockout increases BNIP3-mediated mitophagy in endothelial cells, ameliorates EndMT, and reduces allograft interstitial fibrosis.","method":"Rictor knockout in endothelial cells and in allogeneic kidney transplant mouse model, BNIP3 ubiquitination assays (K48 linkage-specific), MARCH5 interaction studies, mitophagy assays, histology of renal fibrosis","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assays with defined lysine site and in vivo genetic rescue, single lab","pmids":["38769658"],"is_preprint":false}],"current_model":"RICTOR is the defining scaffold subunit of mTOR complex 2 (mTORC2), where it directly positions mTOR to phosphorylate AGC kinases (Akt Ser473, PKCα Ser657, SGK1) and sterically excludes mTORC1 substrates as revealed by cryo-EM structures; mTORC2 assembly and activity are regulated by USP9X-mediated Lys63 deubiquitination of RICTOR (promoting mTOR binding), GSK3-phosphorylation of RICTOR at Thr1695 followed by FBXW7-mediated proteasomal degradation, glucose/acetate-driven acetylation of RICTOR that creates a nutrient-sensitive autoactivation loop, and a negative feedback from mTORC1-S6K1, which phosphorylates RICTOR at Thr1135 to promote 14-3-3 binding; independently of mTORC2, RICTOR also forms complexes with Myo1c, ILK, FBXW7/Cullin-1, and PKCζ to regulate cortical actin remodeling, c-Myc/cyclin E degradation, and chemotaxis; genetically, RICTOR/TORC2 acts upstream of both AKT and SGK1, with SGK1 being the primary effector for metabolic and growth phenotypes in C. elegans, and the Akt-FOXO axis being the primary effector for survival in mammals."},"narrative":{"mechanistic_narrative":"RICTOR is the defining scaffold subunit of mTOR complex 2 (mTORC2), where it positions mTOR to phosphorylate the hydrophobic motif of AGC kinases—most notably Akt at Ser473, which in turn licenses Thr308 phosphorylation by PDK1 [PMID:15718470, PMID:16221682], as well as PKCα Ser657 and SGK1 [PMID:18089801, PMID:28453552]. mTORC2 substrate selection is intrinsic to the complex architecture: cryo-EM structures show Rictor–mTOR side-chain contacts that sterically occlude mTORC1 substrates and confer rapamycin resistance, while mSin1 makes extensive contacts with Rictor and undergoes a conformational switch (rotation of Arg83) that selectively gates SGK1 versus Akt phosphorylation [PMID:35926713]. Sin1 is itself an obligate mTORC2 subunit required for Rictor–mTOR integrity and for the selective downstream phosphorylation of FoxO transcription factors [PMID:16962653]. Genetic dissection across organisms places Rictor/TORC2 upstream of both Akt and SGK, with SGK1 the primary effector for growth and metabolic phenotypes in C. elegans and the Akt–FoxO axis the principal pro-survival output in mammalian tissues such as the ovary [PMID:19240135, PMID:19260765, PMID:25564616]. mTORC2 assembly and Rictor abundance are tightly regulated: USP9X removes Lys63-linked ubiquitin from Rictor to promote mTOR binding [PMID:33378666], GSK3 phosphorylates Rictor at Thr1695 within a phosphodegron to trigger FBXW7-mediated proteasomal degradation [PMID:25897075], glucose/acetate-driven acetylation creates a nutrient-sensitive autoactivation loop [PMID:26170313], and mTORC1–S6K1 imposes negative feedback by phosphorylating Rictor at Thr1135 to recruit 14-3-3 [PMID:19995915, PMID:19935711]. Independently of mTORC2, Rictor assembles distinct complexes—with Myo1c, ILK, PKCζ, and Cullin-1/FBXW7—to control cortical actin remodeling, chemotaxis, and the ubiquitin-dependent turnover of SGK1, c-Myc, and cyclin E [PMID:18426911, PMID:18339839, PMID:20978191, PMID:21204013, PMID:22285861].","teleology":[{"year":2005,"claim":"Established that the Rictor–mTOR complex is the long-sought Ser473 kinase for Akt, defining mTORC2 as a direct effector kinase rather than merely a scaffold.","evidence":"In vitro kinase reconstitution and RNAi of rictor/mTOR in human and Drosophila cells, plus an immunoprecipitation kinase assay in insulin-responsive adipocytes","pmids":["15718470","16221682"],"confidence":"High","gaps":["Did not resolve how PIP3/insulin signals are transduced to activate the complex","Structural basis of substrate recognition unknown at this stage"]},{"year":2005,"claim":"Defined the substrate determinants that distinguish mTORC2 from mTORC1, showing rictor-mTOR selects rapamycin-resistant substrates independent of the TOR signaling motif.","evidence":"In vitro kinase assays with purified raptor-mTOR and rictor-mTOR complexes and S6K1 domain-deletion mutants","pmids":["15809305"],"confidence":"High","gaps":["Did not identify the structural feature on Rictor responsible for discrimination","In-cell physiological relevance of S6K1 as an mTORC2 substrate not established"]},{"year":2006,"claim":"Identified Sin1 as an obligate mTORC2 subunit required for complex integrity and Akt Ser473 phosphorylation, and demonstrated selectivity of mTORC2's downstream signaling toward FoxO.","evidence":"sin1 genetic knockout, reciprocal co-IP for complex integrity, and phospho-specific immunoblotting of multiple Akt substrates","pmids":["16962653"],"confidence":"High","gaps":["How Sin1 stabilizes the Rictor–mTOR interface not structurally defined","Did not explain why only a subset of Akt substrates depend on Ser473"]},{"year":2007,"claim":"In vivo genetic loss-of-function separated TORC2/rictor (Akt-FOXO) from TORC1/raptor (S6K) functions, fixing the pathway architecture in a whole organism.","evidence":"Drosophila rictor-null mutants with phospho-immunoblotting and cell size/apoptosis readouts","pmids":["17462592"],"confidence":"High","gaps":["Tissue-specific contributions not dissected","Did not address mTORC2-independent rictor functions"]},{"year":2009,"claim":"Resolved the pathway hierarchy in C. elegans, showing rictor/TORC2 acts upstream of AKT and SGK with SGK-1 as the primary effector for growth and fat metabolism—revealing effector usage is tissue- and species-dependent.","evidence":"Forward genetics, epistasis with akt-1/akt-2/sgk-1 double mutants, gain-of-function sgk-1 suppressors, and tissue-specific rescue","pmids":["19240135","19260765"],"confidence":"High","gaps":["Whether SGK1 dominance generalizes to mammalian tissues left open","Molecular basis of effector choice not determined"]},{"year":2009,"claim":"Uncovered an mTORC1→mTORC2 feedback loop in which S6K1 directly phosphorylates Rictor at Thr1135 to recruit 14-3-3, integrating the two complexes.","evidence":"In vitro S6K1 kinase assays, phospho-site mapping, T1135A mutant analysis, and 14-3-3 binding assays in two independent labs","pmids":["19995915","19935711"],"confidence":"High","gaps":["The two reports differed on whether Thr1135 alters mTORC2 kinase activity","Physiological consequences of 14-3-3 sequestration incompletely defined"]},{"year":2008,"claim":"Demonstrated mTORC2-independent functions of Rictor in cytoskeletal regulation by identifying distinct complexes with Myo1c and ILK that control actin remodeling and paxillin/ILK-associated phosphorylation.","evidence":"Co-IP showing complexes distinct from mTOR, yeast two-hybrid mapping of direct ILK binding, colocalization, and rapamycin/wortmannin-insensitive functional assays","pmids":["18426911","18339839"],"confidence":"Medium","gaps":["Single-lab findings for each complex","Kinase responsible for paxillin Tyr118 in the Myo1c complex not identified"]},{"year":2010,"claim":"Revealed Rictor moonlighting as an E3 ligase component, forming Cullin-1– and FBXW7-based complexes that ubiquitinate SGK1, c-Myc, and cyclin E independently of mTORC2.","evidence":"Co-IP of Cullin/FBXW7, ubiquitination assays, rictor-/- MEFs, phosphomimetic mutants, and FBXW7 knockout rescue","pmids":["21204013","22285861"],"confidence":"Medium","gaps":["Single-lab demonstrations of ligase activity","Whether Rictor confers substrate specificity or acts as an adaptor unclear"]},{"year":2015,"claim":"Defined a layered regulation of Rictor stability and activity through GSK3/FBXW7-mediated degradation, nutrient-driven acetylation, and SIRT1/thyroid-hormone deacetylation.","evidence":"In vitro GSK3 kinase assay with degron mutagenesis, acetyl-CoA manipulation in tumor models, and SIRT1-mTORC2 co-IP with deacetylation assays","pmids":["25897075","26170313","26453307"],"confidence":"High","gaps":["Cross-talk between phospho-degron and acetylation switches not integrated","Acetylation site(s) and the writer/eraser enzymes only partly defined"]},{"year":2015,"claim":"Mammalian conditional knockouts established a tissue-specific rictor/mTORC2/Akt-Foxo pro-survival axis (oogenesis, spermatogenesis) and distinguished mTORC2 from mTORC1 roles in CNS myelination.","evidence":"Cell-type-specific Cre/loxP rictor (and comparative raptor) knockouts with phospho-immunoblotting, histology, and electron microscopy","pmids":["25564616","26360620","24671993"],"confidence":"High","gaps":["Effector divergence (Akt vs SGK) across these tissues not systematically compared","Contribution of mTORC2-independent rictor actin functions in these phenotypes only partially separated"]},{"year":2020,"claim":"Identified USP9X-mediated Lys63 deubiquitination of Rictor as a growth-factor-regulated switch controlling mTORC2 assembly, adding a ubiquitin-dependent layer to complex formation.","evidence":"Reciprocal co-IP, linkage-specific ubiquitin immunoblotting, USP9X knockdown in cells and mice, and mTORC2 kinase assays","pmids":["33378666"],"confidence":"High","gaps":["E3 ligase that deposits the K63 chains not identified","How growth factors regulate USP9X activity unresolved"]},{"year":2022,"claim":"Cryo-EM structures provided the structural basis for mTORC2 substrate selectivity and rapamycin resistance, showing how Rictor occludes mTORC1 substrates and how Sin1 conformational changes gate SGK1 versus Akt.","evidence":"Cryo-EM of apo and substrate-bound human mTORC2 with mSin1 R83A mutagenesis validating substrate-specific predictions","pmids":["35926713"],"confidence":"High","gaps":["Structures of regulated states (phosphorylated/acetylated Rictor) not resolved","Dynamics of substrate loading and product release not captured"]},{"year":2024,"claim":"Extended Rictor/mTORC2 function to organelle quality control, showing it facilitates MARCH5-mediated K48 ubiquitination and degradation of BNIP3 to restrain mitophagy.","evidence":"Rictor knockout in endothelial cells and a transplant model, K48-linkage-specific BNIP3 ubiquitination assays, and MARCH5 interaction studies","pmids":["38769658"],"confidence":"Medium","gaps":["Single-lab finding","Whether this requires mTORC2 kinase activity or a separate Rictor complex not fully resolved"]},{"year":null,"claim":"How the distinct regulatory inputs on Rictor (K63 deubiquitination, GSK3 phosphodegron, acetylation, S6K1 feedback) are integrated to set mTORC2 output in a given cell, and what determines Akt- versus SGK1-effector dominance across mammalian tissues, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated quantitative model of competing Rictor modifications","Mammalian rules governing AGC-kinase effector choice undefined","Relationship between mTORC2-dependent and mTORC2-independent Rictor complexes in vivo unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,37]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,32]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[18,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,12,23,35]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,9]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[9,27,28,36]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,32]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[18,19,23,35]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,26]}],"complexes":["mTORC2","Rictor-Cullin-1 E3 ligase","Rictor-FBXW7 E3 ligase","Rictor-Myo1c complex"],"partners":["MTOR","MAPKAP1 (SIN1)","ILK","MYO1C","FBXW7","CUL1","USP9X","PRKCZ"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6R327","full_name":"Rapamycin-insensitive companion of mTOR","aliases":["AVO3 homolog","hAVO3"],"length_aa":1708,"mass_kda":192.2,"function":"Component of the mechanistic target of rapamycin complex 2 (mTORC2), which transduces signals from growth factors to pathways involved in proliferation, cytoskeletal organization, lipogenesis and anabolic output (PubMed:15268862, PubMed:15718470, PubMed:19720745, PubMed:19995915, PubMed:21343617, PubMed:33158864, PubMed:35904232, PubMed:35926713). In response to growth factors, mTORC2 phosphorylates and activates AGC protein kinase family members, including AKT (AKT1, AKT2 and AKT3), PKC (PRKCA, PRKCB and PRKCE) and SGK1 (PubMed:19720745, PubMed:19935711, PubMed:19995915). In contrast to mTORC1, mTORC2 is nutrient-insensitive (PubMed:15467718, PubMed:21343617). Within the mTORC2 complex, RICTOR probably acts as a molecular adapter (PubMed:21343617, PubMed:33158864, PubMed:35926713). RICTOR is responsible for the FKBP12-rapamycin-insensitivity of mTORC2 (PubMed:33158864). mTORC2 plays a critical role in AKT1 activation by mediating phosphorylation of different sites depending on the context, such as 'Thr-450', 'Ser-473', 'Ser-477' or 'Thr-479', facilitating the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDPK1/PDK1 which is a prerequisite for full activation (PubMed:15718470, PubMed:19720745, PubMed:19935711, PubMed:35926713). mTORC2 catalyzes the phosphorylation of SGK1 at 'Ser-422' and of PRKCA on 'Ser-657' (By similarity). The mTORC2 complex also phosphorylates various proteins involved in insulin signaling, such as FBXW8 and IGF2BP1 (By similarity). mTORC2 acts upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors (PubMed:15467718). mTORC2 promotes the serum-induced formation of stress-fibers or F-actin (PubMed:15467718)","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q6R327/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RICTOR","classification":"Not Classified","n_dependent_lines":524,"n_total_lines":1208,"dependency_fraction":0.4337748344370861},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000164327","cell_line_id":"CID001693","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"membrane","grade":2},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"MTOR","stoichiometry":10.0},{"gene":"MAPKAP1","stoichiometry":10.0},{"gene":"AHSA1","stoichiometry":0.2},{"gene":"CSNK2A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001693","total_profiled":1310},"omim":[{"mim_id":"616899","title":"TBC1 DOMAIN-CONTAINING KINASE; TBCK","url":"https://www.omim.org/entry/616899"},{"mim_id":"614426","title":"TELO2-INTERACTING PROTEIN 2; TTI2","url":"https://www.omim.org/entry/614426"},{"mim_id":"614425","title":"TELO2-INTERACTING PROTEIN 1; TTI1","url":"https://www.omim.org/entry/614425"},{"mim_id":"611728","title":"PROLINE-RICH PROTEIN 5-LIKE; PRR5L","url":"https://www.omim.org/entry/611728"},{"mim_id":"611140","title":"TELOMERE MAINTENANCE 2; TELO2","url":"https://www.omim.org/entry/611140"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RICTOR"},"hgnc":{"alias_symbol":["MGC39830","AVO3","PIA","KIAA1999"],"prev_symbol":[]},"alphafold":{"accession":"Q6R327","domains":[{"cath_id":"-","chopping":"885-1004","consensus_level":"high","plddt":89.7322,"start":885,"end":1004},{"cath_id":"-","chopping":"1517-1528_1602-1701","consensus_level":"medium","plddt":81.5779,"start":1517,"end":1701},{"cath_id":"1.25.40","chopping":"492-506_522-725","consensus_level":"medium","plddt":82.4658,"start":492,"end":725}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6R327","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6R327-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6R327-F1-predicted_aligned_error_v6.png","plddt_mean":65.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RICTOR","jax_strain_url":"https://www.jax.org/strain/search?query=RICTOR"},"sequence":{"accession":"Q6R327","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6R327.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6R327/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6R327"}},"corpus_meta":[{"pmid":"15718470","id":"PMC_15718470","title":"Phosphorylation 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Ser473 in vitro, and rictor and mTOR are necessary for Ser473 phosphorylation in Drosophila and human cells; the rictor-mTOR complex also facilitates Thr308 phosphorylation by PDK1.\",\n      \"method\": \"In vitro kinase assay (rictor-mTOR complex phosphorylating Akt Ser473), RNAi knockdown of rictor/mTOR in human and Drosophila cells measuring Akt phosphorylation\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro kinase reconstitution plus genetic knockdown in two organisms, widely replicated\",\n      \"pmids\": [\"15718470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The rictor-mTOR complex (mTORC2) phosphorylates the hydrophobic motif (Thr389) of rapamycin-resistant S6K1 mutants in vitro, whereas the raptor-mTOR complex (mTORC1) phosphorylates rapamycin-sensitive forms; substrate selection by rictor-mTOR is independent of the TOR signaling motif and depends on removal of the C-terminal domain of S6K1.\",\n      \"method\": \"In vitro kinase assays with purified raptor-mTOR and rictor-mTOR complexes and S6K1 mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with domain-deletion mutants defining substrate determinants, single lab but multiple orthogonal experiments\",\n      \"pmids\": [\"15809305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In 3T3-L1 adipocytes, mTOR complexed to RICTOR is the Ser473 kinase for Akt; vesicles immunoprecipitated with anti-mTOR or anti-RICTOR antibodies showed PIP3-stimulated Ser473 activity sensitive to wortmannin but not staurosporine, and RICTOR siRNA knockdown suppressed insulin-activated Ser473 phosphorylation.\",\n      \"method\": \"Subcellular fractionation, immunoprecipitation kinase assay, siRNA knockdown in 3T3-L1 adipocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — cell-free kinase assay plus RNAi in a classical insulin-responsive cell type, replicating the Sabatini lab finding\",\n      \"pmids\": [\"16221682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SIN1/MIP1 is an essential mTORC2 subunit; genetic ablation of sin1 abolished Akt Ser473 phosphorylation and disrupted rictor-mTOR interaction while leaving Thr308 phosphorylation intact. Loss of Ser473 phosphorylation selectively impaired FoxO1/3a phosphorylation but not TSC2, GSK3, S6K, or 4E-BP1, demonstrating substrate selectivity of mTORC2 downstream signaling.\",\n      \"method\": \"sin1 genetic knockout, co-immunoprecipitation to assess rictor-mTOR complex integrity, phospho-specific immunoblotting for Akt and Akt substrates\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus genetic ablation with multiple downstream readouts, independently replicated\",\n      \"pmids\": [\"16962653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"During human cytomegalovirus (HCMV) infection, the rictor-containing mTOR complex is activated (elevated Akt Ser473 phosphorylation in a rapamycin-insensitive, caffeine-sensitive manner), and rictor is more significant than raptor for viral infection; depletion shows that in HCMV-infected cells both raptor and rictor complexes acquire altered substrate specificities and rapamycin sensitivities.\",\n      \"method\": \"shRNA depletion of rictor and raptor, phospho-immunoblotting, viral growth assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean shRNA knockdown with multiple substrates, single lab\",\n      \"pmids\": [\"16959881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Drosophila rictor-null mutants, Akt-Ser505 phosphorylation is decreased, FOXO-dependent apoptosis is augmented, and Akt-induced tissue hyperplasia is reduced, while S6K phosphorylation and S6K-induced cell overgrowth are unaffected, demonstrating that rictor/TORC2 specifically regulates the Akt-FOXO signaling module distinct from raptor/TORC1-S6K signaling.\",\n      \"method\": \"Drosophila rictor-null genetic mutants, phospho-specific immunoblotting, cell size/apoptosis measurements\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic loss-of-function in Drosophila with clear separation of two TOR complex functions\",\n      \"pmids\": [\"17462592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Overexpression of rictor in glioma cell lines leads to increased mTORC2 assembly and activity, increased PKCα activity, and increased anchorage-independent growth, S-phase distribution, motility, and integrin β1/β3 expression; siRNA knockdown of rictor inhibited these phenotypes and reduced PKCα activity.\",\n      \"method\": \"Rictor overexpression and siRNA knockdown, mTORC2 kinase assays, soft agar growth, cell cycle analysis, PKCα activity assay, xenograft studies\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase assay plus multiple cellular phenotype readouts, single lab\",\n      \"pmids\": [\"18089801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Rictor negatively regulates mTORC1 activity: shRNA-mediated downregulation of rictor increased S6K1 and 4E-BP1 phosphorylation and basal protein synthesis in TGFβ-treated renal cells, while raptor shRNA inhibited these effects, placing mTORC2/rictor as a negative regulator of mTORC1 to control basal protein synthesis.\",\n      \"method\": \"shRNA knockdown of raptor or rictor, phospho-immunoblotting of S6K and 4E-BP1, [35S]-methionine protein synthesis assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean RNAi with defined readout, single lab, single study\",\n      \"pmids\": [\"18068336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Rictor interacts directly with integrin-linked kinase (ILK); yeast two-hybrid assays showed a direct interaction between the NH2- and COOH-terminal domains of rictor and the ILK kinase domain. ILK and rictor colocalize in membrane ruffles and leading edges of cancer cells, and rictor regulates ILK-associated Akt Ser473 phosphorylation.\",\n      \"method\": \"Proteomic screen, co-immunoprecipitation, yeast two-hybrid, colocalization imaging, siRNA knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction confirmed by yeast two-hybrid plus reciprocal co-IP, colocalization, and functional rescue, single lab\",\n      \"pmids\": [\"18339839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Rictor forms a complex with Myo1c (a molecular motor) in adipocytes that is biochemically distinct from mTORC2 and can be immunoprecipitated independently of mTOR. Loss of either rictor or Myo1c inhibits paxillin Tyr118 phosphorylation and Myo1c-induced membrane ruffling, effects that are rapamycin- and wortmannin-insensitive, indicating a mTORC2-independent role of rictor in cortical actin remodeling.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, phospho-paxillin immunoblotting, membrane ruffling assay, rapamycin/wortmannin treatment\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical complex distinct from mTORC2 demonstrated by co-IP plus functional phenotypes, single lab\",\n      \"pmids\": [\"18426911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Hsp70 physically associates with rictor and is required for mTORC2 formation and activity; in cells with antisense RNA targeting Hsp70, mTORC2 assembly and mTORC2 kinase activity were impaired, while mTORC1 was unaffected.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, colocalization, mTORC2 kinase assay in Hsp70-depleted cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP plus functional mTORC2 kinase assay, single lab\",\n      \"pmids\": [\"18505677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"S6K1 (p70 ribosomal S6 kinase 1) directly phosphorylates rictor on Thr1135 in vitro and in vivo in a rapamycin-sensitive manner; cells expressing rictor T1135A have increased mTORC2-dependent Akt phosphorylation and increased phosphorylation of FoxO1/3a and GSK3, demonstrating that S6K1-mediated phosphorylation of rictor on Thr1135 inhibits mTORC2 activity as a feedback mechanism from mTORC1.\",\n      \"method\": \"In vitro S6K1 kinase assay with rictor, phospho-site mapping, rapamycin treatment in cells, T1135A phospho-dead mutant expression, phospho-immunoblotting\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay demonstrating direct phosphorylation plus cellular phospho-dead mutant functional studies, independently replicated (Treins et al. same year)\",\n      \"pmids\": [\"19995915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"S6K1 directly phosphorylates rictor on Thr1135 (a conserved vertebrate site) via a rapamycin-sensitive cascade; Thr1135 phosphorylation mediates 14-3-3 binding to rictor/mTORC2 but does not cause major changes in mTORC2 kinase activity.\",\n      \"method\": \"In vitro S6K1 kinase assay, phosphorylation site mapping, 14-3-3 binding assay, mTORC2 kinase assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — independent replication of Julien et al. direct S6K1-rictor phosphorylation with additional 14-3-3 binding finding\",\n      \"pmids\": [\"19935711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In C. elegans, rictor/TORC2 controls fat storage, body size, growth, feeding, reproduction, and lifespan; these phenotypes are genetically dependent on akt-1, akt-2, and sgk-1, with fat metabolism and growth principally mediated by sgk-1 in the intestine, placing rictor upstream of AKT and SGK in a tissue-specific manner.\",\n      \"method\": \"Forward genetic screen, rictor loss-of-function mutants, epistasis analysis with akt-1, akt-2, sgk-1 double mutants, tissue-specific rescue experiments\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple double-mutant combinations in vivo defining pathway hierarchy, tissue rescue experiments\",\n      \"pmids\": [\"19240135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In C. elegans, loss of CeRictor phenocopies loss of sgk-1 (not akt), and a gain-of-function sgk-1 mutation suppresses CeRictor mutant phenotypes (developmental delay, decreased body size, increased lipid storage), establishing SGK1 as the primary mediator of TORC2 in regulating growth and metabolism, distinct from AKT.\",\n      \"method\": \"Loss-of-function mutant analysis, epistasis with sgk-1 and akt double mutants, gain-of-function sgk-1 suppressor analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with gain-of-function suppressor identifying SGK1 as primary TORC2 effector, independent replication of Soukas et al.\",\n      \"pmids\": [\"19260765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FoxO1 transcription factor induces rictor gene expression, increasing mTORC2 assembly and activity, which subsequently activates Akt; in Tsc2-deficient cells, FoxO1-induced rictor elevation increases mTORC2 at the expense of mTORC1, creating a feedback loop.\",\n      \"method\": \"Overexpression/knockdown of FoxO1, rictor expression measurements, mTORC2 kinase assays, genetic epistasis with Tsc2-/- cells\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with mechanistic follow-up in multiple genetic backgrounds, single lab\",\n      \"pmids\": [\"20412774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rictor interacts with PKCζ, and EGF induces translocation and colocalization of rictor with PKCζ independently of the mTORC2 complex; rictor knockdown inhibited EGF-induced PKCζ phosphorylation and translocation, phosphorylation of cofilin, and cellular chemotaxis, and ablated pulmonary metastasis in a xenograft model.\",\n      \"method\": \"Co-immunoprecipitation, colocalization imaging, siRNA knockdown, chemotaxis assay, xenograft metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus in vivo xenograft, interaction shown outside mTORC2 context, single lab\",\n      \"pmids\": [\"20978191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rictor suppresses RhoGDI2 protein levels by a mechanism independent of Sin1 and raptor (hence independent of mTORC2 and mTORC1), and this rictor-dependent suppression of RhoGDI2 promotes Rac and Cdc42 activity and cell migration.\",\n      \"method\": \"Proteomics, rictor/sin1/raptor knockdown, Rac/Cdc42 activity assays, RhoGDI2 expression analysis, migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-guided mechanistic study with genetic separation from mTORC1/2, single lab\",\n      \"pmids\": [\"22777355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rictor contains a novel ubiquitin E3 ligase activity by forming a complex with Cullin-1 (but not other Cullins); SGK1 is identified as a substrate of this Rictor/Cullin-1 E3 ligase. Phosphorylation of rictor at Thr1135 by AGC kinases (Akt, S6K, SGK1) disrupts Rictor-Cullin-1 interaction, impairing SGK1 ubiquitination and leading to SGK1 accumulation.\",\n      \"method\": \"Co-immunoprecipitation of Cullin proteins, ubiquitination assays, rictor-/- MEFs, T1135E phosphomimetic mutant, SGK1 stability assays\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional ubiquitination assay and phosphomimetic mutant demonstrating mechanism, single lab\",\n      \"pmids\": [\"21204013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rictor associates with FBXW7 to form an E3 ligase complex (distinct from mTORC2) that mediates ubiquitination and degradation of c-Myc and cyclin E; rictor knockdown decreased ubiquitination and increased c-Myc and cyclin E levels, while FBXW7 knockout blocked rictor's effects on these substrates.\",\n      \"method\": \"Co-immunoprecipitation, rictor overexpression/knockdown, FBXW7 knockout, ubiquitination assays, c-Myc and cyclin E protein stability\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying complex plus genetic rescue with FBXW7 KO, single lab\",\n      \"pmids\": [\"22285861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IKKα and IKKβ physically interact with rictor (in vitro binding mapped to rictor amino acids 999–1397); chemical or genetic inhibition of IKK reduced Akt Ser473 and PKCα Ser657 phosphorylation and decreased mTORC2 kinase activity; inactive IKK competed with mTOR for rictor binding, reducing mTORC2 levels and activity.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay with rictor fragments, siRNA knockdown, kinase-dead IKK expression, mTORC2 kinase assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding domain mapping plus cellular functional assays, single lab\",\n      \"pmids\": [\"23872070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rictor/Sin1 complexes are required for type I interferon-induced STAT pathway activation; knockdown of rictor or Sin1 resulted in defective STAT activation, reduced STAT-DNA binding, and decreased IFN-inducible gene expression, establishing a role for mTORC2 in IFN signaling.\",\n      \"method\": \"Stable and transient rictor/Sin1 knockdown, STAT phosphorylation assays, STAT-DNA binding (EMSA), IFN-inducible gene expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable KD with multiple downstream readouts linking mTORC2 to IFN-STAT pathway, single lab\",\n      \"pmids\": [\"24469448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Conditional deletion of rictor in CNS oligodendrocytes revealed that mTORC2/rictor ablation has a modest positive effect on oligodendrocyte differentiation and very little effect on myelination when mTORC1 is intact, whereas raptor (mTORC1) ablation causes significant dysmyelination; this establishes distinct roles of the two mTOR complexes in CNS myelination.\",\n      \"method\": \"Conditional Cre/loxP knockout of rictor or raptor in oligodendrocyte lineage, histology, electron microscopy, myelin protein immunoblotting\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific genetic knockout with histological and molecular readouts, single lab\",\n      \"pmids\": [\"24671993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GSK3 phosphorylates rictor at Thr1695 (within a CDC4 phospho-degron motif), promoting interaction between rictor and the E3 ubiquitin ligase FBXW7 and subsequent rictor ubiquitination and proteasomal degradation; mutation of Thr1695 impaired FBXW7 binding and stabilized rictor. Akt activation enhanced rictor levels by suppressing GSK3-dependent rictor degradation.\",\n      \"method\": \"In vitro GSK3 kinase assay on rictor, co-IP of FBXW7 and rictor, proteasome inhibitor treatment, T1695A/E mutagenesis, FBXW7 overexpression/knockout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay identifying GSK3 as the writer on Thr1695, domain mutagenesis validating degron, and functional consequence on mTORC2 assembly, single lab multiple orthogonal methods\",\n      \"pmids\": [\"25897075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Glucose or acetate promotes acetyl-CoA-dependent acetylation of rictor, which activates mTORC2 and creates an autoactivation loop maintaining mTORC2 activity even when upstream growth factor receptor components are inactive, rendering GBM cells resistant to EGFR/PI3K/AKT-targeted therapies.\",\n      \"method\": \"Cell line and mouse tumor models, acetylation assays of rictor, acetyl-CoA manipulation, pharmacological inhibition of upstream signaling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rictor acetylation demonstrated with functional consequence in cell and mouse models, single lab\",\n      \"pmids\": [\"26170313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Thyroid hormone (TH) increases SIRT1-mTORC2 interaction and promotes RICTOR deacetylation, leading to decreased AKT and FOXO1 phosphorylation; this increases FOXO1 nuclear localization and target gene transcription, demonstrating that RICTOR deacetylation is a mechanism linking TH signaling to mTORC2-AKT-FOXO1 axis.\",\n      \"method\": \"SIRT1-mTORC2 co-IP, RICTOR deacetylation assays, AKT and FOXO1 phospho-immunoblotting, hepatic transcriptome profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus biochemical deacetylation linked to downstream signaling, single lab\",\n      \"pmids\": [\"26453307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rictor/mTORC2 signaling in oocytes is required for folliculogenesis and follicle survival; oocyte-specific rictor knockout mice exhibited premature ovarian failure, massive follicular death, reduced Akt Ser473 phosphorylation, reduced Foxo3a phosphorylation, and elevated pro-apoptotic proteins, establishing a rictor/mTORC2/Akt/Foxo3a pro-survival axis in folliculogenesis.\",\n      \"method\": \"Conditional oocyte-specific rictor knockout (Cre/loxP), phospho-immunoblotting, apoptosis markers, ovarian histology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined signaling pathway (Akt-Foxo3a) and cellular phenotype, single lab multiple methods\",\n      \"pmids\": [\"25564616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Conditional deletion of rictor in Sertoli cells causes azoospermia and sterility; rictor regulates actin organization via both mTORC2-dependent (Rac1 GTPase) and mTORC2-independent (paxillin phosphorylation) mechanisms, and loss of rictor disrupts Sertoli cell polarity, BTB integrity, and spermatogenesis.\",\n      \"method\": \"Conditional Sertoli cell-specific rictor knockout, actin filament staining, Rac1 activity assay, paxillin phospho-immunoblotting, electron microscopy\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with mechanistic dissection of mTORC2-dependent and -independent actin pathways, single lab\",\n      \"pmids\": [\"26360620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rictor regulates actin cytoskeleton organization via RhoA-GTPase; resveratrol-mediated downregulation of rictor in A431 cells reduced RhoA-GTPase activity and altered actin cytoskeleton, and exogenous overexpression of rictor restored RhoA activity and actin network, establishing a direct role of rictor in RhoA-mediated actin organization.\",\n      \"method\": \"Rictor overexpression/knockdown, RhoA-GTPase activity assay, actin cytoskeleton staining, senescence assay\",\n      \"journal\": \"Photochemistry and photobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression/knockdown approach with functional rescue, indirect pathway connection\",\n      \"pmids\": [\"22272775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SMAD4 physically interacts with and inhibits RICTOR; SMAD4 deficiency activates mTORC2/AKT Ser473 signaling, and overexpression of SMAD4 or depletion of RICTOR suppresses AKT signaling and increases irinotecan sensitivity in SMAD4-deficient colon cancer cells.\",\n      \"method\": \"Co-immunoprecipitation of SMAD4 and RICTOR, SMAD4 overexpression and RICTOR depletion, phospho-AKT immunoblotting, cell viability and in vivo tumor assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying direct interaction plus functional genetic rescue in vitro and in vivo, single lab\",\n      \"pmids\": [\"31932471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tetraspanin 8 (Tspan8) forms a complex with rictor and integrin α3 in glioma cells; Tspan8-rictor association is required for mTORC2 activation; knockdown of Tspan8 prevented mTOR-rictor assembly and phosphorylation of AKT Ser473 and PKCα, and inhibited glioma cell migration.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of Tspan8/rictor/integrin α3, mTORC2 assembly assay, AKT/PKCα phospho-immunoblotting, migration assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of trimeric complex plus functional consequence on mTORC2 assembly and kinase activity, single lab\",\n      \"pmids\": [\"25761241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In Saccharomyces cerevisiae, TSC11/AVO3 (rictor ortholog) is genetically linked to cell integrity regulation; temperature-sensitive tsc11 mutants show cell wall defects, and dosage suppression identifies functional interactions with AVO1, AVO2, PKC1, and SLM1 as TORC2 components, with Tsc11p acting via a Pkc1p-independent mechanism through Avo1p and a Pkc1p-dependent mechanism through Avo2p/Slm1p.\",\n      \"method\": \"Temperature-sensitive allele analysis, osmotic stabilizer rescue, dosage suppression genetics, cell wall integrity assays\",\n      \"journal\": \"Current genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic genetic interaction mapping in yeast TORC2 pathway, well-controlled epistasis\",\n      \"pmids\": [\"15809876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A small molecule (CID613034) that specifically blocks the rictor-mTOR protein-protein interaction inhibited mTORC2 kinase activity at submicromolar concentrations in vitro, selectively blocked phosphorylation of mTORC2 substrates (AKT Ser473, NDRG1 Thr346, PKCα Ser657) without affecting mTORC1 substrate S6K phosphorylation, and had anti-tumor effects in GBM xenografts.\",\n      \"method\": \"High-throughput yeast two-hybrid screen, in vitro mTORC2 kinase assay, phospho-selective immunoblotting in cells, xenograft tumor model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific PPI inhibitor with in vitro kinase validation and cellular/in vivo selectivity, single lab\",\n      \"pmids\": [\"28453552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"mTORC2/AKT signaling activates HSF1, which induces HuR expression; HuR directly binds the 3'UTR of the rictor transcript to enhance its translational efficiency, creating a feed-forward loop in which mTORC2 activity drives rictor expression in GBM.\",\n      \"method\": \"HuR-rictor 3'UTR binding assay, RNAi of AKT/HSF1/HuR, rictor protein/mRNA measurements, xenograft tumor growth\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-binding assay plus gain/loss-of-function with pathway dissection, single lab\",\n      \"pmids\": [\"29059166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In vascular smooth muscle cells, TGFβ activates rictor in an integrin-linked kinase (ILK)-dependent manner, and β3-integrin expression modulates TGFβ-induced rictor phosphorylation (Thr1135); rictor activation is associated with an altered proliferative-migratory and metabolic phenotype resembling the aneurysm phenotype in Marfan syndrome aorta.\",\n      \"method\": \"Proteomics of MFS mouse aorta (data-independent acquisition MS), Western blot validation of rictor Thr1135 phosphorylation in vivo, ILK inhibition and β3-integrin manipulation in cultured aortic vascular smooth muscle cells\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo proteomic discovery validated by Western blot plus in vitro mechanistic experiments linking ILK and β3-integrin to rictor activation\",\n      \"pmids\": [\"30004239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP9X deubiquitinase removes Lys63-linked ubiquitin from RICTOR to promote its interaction with mTOR, thereby facilitating mTORC2 assembly and activity; growth factors regulate USP9X activity to stimulate mTORC2 assembly, establishing a ubiquitin-dependent mechanism for mTORC2 complex formation.\",\n      \"method\": \"Co-IP of USP9X and RICTOR, ubiquitin linkage-specific immunoblotting, USP9X knockdown in human cell lines and mice, mTORC2 kinase activity assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus linkage-specific ubiquitin analysis and functional mTORC2 kinase assay validated in both cell lines and mice\",\n      \"pmids\": [\"33378666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rictor interacts with ABLIM1 and regulates its serine phosphorylation (at Ser214 and Ser431); dominant-negative mutations at these sites inhibited ABLIM1-mediated actin polymerization and MKL1/SRF-dependent transcription (Arp3, c-Fos), linking rictor to actin dynamics through ABLIM1 phosphorylation in HCC cells.\",\n      \"method\": \"Co-immunoprecipitation, ABLIM1 knockout cell lines, phospho-site mutation (S214A, S431A), actin polymerization assay, MKL1 nuclear translocation imaging, SRF reporter assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with novel substrate identification plus functional validation with phospho-dead mutations, single lab\",\n      \"pmids\": [\"33061800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures of human mTORC2 in apo form and in complex with substrates Akt and SGK1 revealed: (1) Rictor-mTOR side chain interactions that sterically occlude mTORC1 substrates and confer rapamycin resistance; (2) mSin1 forms extensive contacts with Rictor via α-helices and an extended strand; (3) SGK1 (but not Akt) markedly alters mSin1 N-terminal conformation, inducing rotation of mSin1 Arg83 to interact with negatively charged Rictor residues; mutation of mSin1 Arg83 to Ala selectively disrupts mTORC2 phosphorylation of SGK1 but not Akt.\",\n      \"method\": \"Cryo-EM structure determination of human mTORC2 apo and substrate-bound complexes, functional phosphorylation assays with mSin1 R83A mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structures with mutagenesis functionally validating structural predictions for substrate specificity\",\n      \"pmids\": [\"35926713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"mTORC2 inactivation (via rictor deletion) in the inner ear is the major driver of sensorineural hearing loss induced by high-dose sirolimus; mTORC2 exerts its effects primarily through AKT phosphorylation, and ablation of P53 activity greatly attenuated hearing loss severity in mTORC2-deficient mice; selective activation of mTORC2 protects against acoustic trauma and cisplatin-induced ototoxicity.\",\n      \"method\": \"Pharmacological and genetic interventions in murine hearing models, rictor conditional knockout, p53 knockout epistasis, auditory brainstem response testing, AKT phosphorylation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological interventions with defined mechanistic pathway (mTORC2-AKT-p53) and functional readout, single lab\",\n      \"pmids\": [\"35238644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Rictor/mTORC2 facilitates MARCH5-mediated K48-linked ubiquitination and degradation of BNIP3 at the K130 site, thereby reducing BNIP3-dependent mitophagy; rictor knockout increases BNIP3-mediated mitophagy in endothelial cells, ameliorates EndMT, and reduces allograft interstitial fibrosis.\",\n      \"method\": \"Rictor knockout in endothelial cells and in allogeneic kidney transplant mouse model, BNIP3 ubiquitination assays (K48 linkage-specific), MARCH5 interaction studies, mitophagy assays, histology of renal fibrosis\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assays with defined lysine site and in vivo genetic rescue, single lab\",\n      \"pmids\": [\"38769658\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RICTOR is the defining scaffold subunit of mTOR complex 2 (mTORC2), where it directly positions mTOR to phosphorylate AGC kinases (Akt Ser473, PKCα Ser657, SGK1) and sterically excludes mTORC1 substrates as revealed by cryo-EM structures; mTORC2 assembly and activity are regulated by USP9X-mediated Lys63 deubiquitination of RICTOR (promoting mTOR binding), GSK3-phosphorylation of RICTOR at Thr1695 followed by FBXW7-mediated proteasomal degradation, glucose/acetate-driven acetylation of RICTOR that creates a nutrient-sensitive autoactivation loop, and a negative feedback from mTORC1-S6K1, which phosphorylates RICTOR at Thr1135 to promote 14-3-3 binding; independently of mTORC2, RICTOR also forms complexes with Myo1c, ILK, FBXW7/Cullin-1, and PKCζ to regulate cortical actin remodeling, c-Myc/cyclin E degradation, and chemotaxis; genetically, RICTOR/TORC2 acts upstream of both AKT and SGK1, with SGK1 being the primary effector for metabolic and growth phenotypes in C. elegans, and the Akt-FOXO axis being the primary effector for survival in mammals.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RICTOR is the defining scaffold subunit of mTOR complex 2 (mTORC2), where it positions mTOR to phosphorylate the hydrophobic motif of AGC kinases—most notably Akt at Ser473, which in turn licenses Thr308 phosphorylation by PDK1 [#0, #2], as well as PKCα Ser657 and SGK1 [#6, #32]. mTORC2 substrate selection is intrinsic to the complex architecture: cryo-EM structures show Rictor–mTOR side-chain contacts that sterically occlude mTORC1 substrates and confer rapamycin resistance, while mSin1 makes extensive contacts with Rictor and undergoes a conformational switch (rotation of Arg83) that selectively gates SGK1 versus Akt phosphorylation [#37]. Sin1 is itself an obligate mTORC2 subunit required for Rictor–mTOR integrity and for the selective downstream phosphorylation of FoxO transcription factors [#3]. Genetic dissection across organisms places Rictor/TORC2 upstream of both Akt and SGK, with SGK1 the primary effector for growth and metabolic phenotypes in C. elegans and the Akt–FoxO axis the principal pro-survival output in mammalian tissues such as the ovary [#13, #14, #26]. mTORC2 assembly and Rictor abundance are tightly regulated: USP9X removes Lys63-linked ubiquitin from Rictor to promote mTOR binding [#35], GSK3 phosphorylates Rictor at Thr1695 within a phosphodegron to trigger FBXW7-mediated proteasomal degradation [#23], glucose/acetate-driven acetylation creates a nutrient-sensitive autoactivation loop [#24], and mTORC1–S6K1 imposes negative feedback by phosphorylating Rictor at Thr1135 to recruit 14-3-3 [#11, #12]. Independently of mTORC2, Rictor assembles distinct complexes—with Myo1c, ILK, PKCζ, and Cullin-1/FBXW7—to control cortical actin remodeling, chemotaxis, and the ubiquitin-dependent turnover of SGK1, c-Myc, and cyclin E [#9, #8, #16, #18, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that the Rictor–mTOR complex is the long-sought Ser473 kinase for Akt, defining mTORC2 as a direct effector kinase rather than merely a scaffold.\",\n      \"evidence\": \"In vitro kinase reconstitution and RNAi of rictor/mTOR in human and Drosophila cells, plus an immunoprecipitation kinase assay in insulin-responsive adipocytes\",\n      \"pmids\": [\"15718470\", \"16221682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how PIP3/insulin signals are transduced to activate the complex\", \"Structural basis of substrate recognition unknown at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the substrate determinants that distinguish mTORC2 from mTORC1, showing rictor-mTOR selects rapamycin-resistant substrates independent of the TOR signaling motif.\",\n      \"evidence\": \"In vitro kinase assays with purified raptor-mTOR and rictor-mTOR complexes and S6K1 domain-deletion mutants\",\n      \"pmids\": [\"15809305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the structural feature on Rictor responsible for discrimination\", \"In-cell physiological relevance of S6K1 as an mTORC2 substrate not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified Sin1 as an obligate mTORC2 subunit required for complex integrity and Akt Ser473 phosphorylation, and demonstrated selectivity of mTORC2's downstream signaling toward FoxO.\",\n      \"evidence\": \"sin1 genetic knockout, reciprocal co-IP for complex integrity, and phospho-specific immunoblotting of multiple Akt substrates\",\n      \"pmids\": [\"16962653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Sin1 stabilizes the Rictor–mTOR interface not structurally defined\", \"Did not explain why only a subset of Akt substrates depend on Ser473\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"In vivo genetic loss-of-function separated TORC2/rictor (Akt-FOXO) from TORC1/raptor (S6K) functions, fixing the pathway architecture in a whole organism.\",\n      \"evidence\": \"Drosophila rictor-null mutants with phospho-immunoblotting and cell size/apoptosis readouts\",\n      \"pmids\": [\"17462592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions not dissected\", \"Did not address mTORC2-independent rictor functions\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the pathway hierarchy in C. elegans, showing rictor/TORC2 acts upstream of AKT and SGK with SGK-1 as the primary effector for growth and fat metabolism—revealing effector usage is tissue- and species-dependent.\",\n      \"evidence\": \"Forward genetics, epistasis with akt-1/akt-2/sgk-1 double mutants, gain-of-function sgk-1 suppressors, and tissue-specific rescue\",\n      \"pmids\": [\"19240135\", \"19260765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SGK1 dominance generalizes to mammalian tissues left open\", \"Molecular basis of effector choice not determined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Uncovered an mTORC1→mTORC2 feedback loop in which S6K1 directly phosphorylates Rictor at Thr1135 to recruit 14-3-3, integrating the two complexes.\",\n      \"evidence\": \"In vitro S6K1 kinase assays, phospho-site mapping, T1135A mutant analysis, and 14-3-3 binding assays in two independent labs\",\n      \"pmids\": [\"19995915\", \"19935711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The two reports differed on whether Thr1135 alters mTORC2 kinase activity\", \"Physiological consequences of 14-3-3 sequestration incompletely defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated mTORC2-independent functions of Rictor in cytoskeletal regulation by identifying distinct complexes with Myo1c and ILK that control actin remodeling and paxillin/ILK-associated phosphorylation.\",\n      \"evidence\": \"Co-IP showing complexes distinct from mTOR, yeast two-hybrid mapping of direct ILK binding, colocalization, and rapamycin/wortmannin-insensitive functional assays\",\n      \"pmids\": [\"18426911\", \"18339839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings for each complex\", \"Kinase responsible for paxillin Tyr118 in the Myo1c complex not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed Rictor moonlighting as an E3 ligase component, forming Cullin-1– and FBXW7-based complexes that ubiquitinate SGK1, c-Myc, and cyclin E independently of mTORC2.\",\n      \"evidence\": \"Co-IP of Cullin/FBXW7, ubiquitination assays, rictor-/- MEFs, phosphomimetic mutants, and FBXW7 knockout rescue\",\n      \"pmids\": [\"21204013\", \"22285861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab demonstrations of ligase activity\", \"Whether Rictor confers substrate specificity or acts as an adaptor unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a layered regulation of Rictor stability and activity through GSK3/FBXW7-mediated degradation, nutrient-driven acetylation, and SIRT1/thyroid-hormone deacetylation.\",\n      \"evidence\": \"In vitro GSK3 kinase assay with degron mutagenesis, acetyl-CoA manipulation in tumor models, and SIRT1-mTORC2 co-IP with deacetylation assays\",\n      \"pmids\": [\"25897075\", \"26170313\", \"26453307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cross-talk between phospho-degron and acetylation switches not integrated\", \"Acetylation site(s) and the writer/eraser enzymes only partly defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mammalian conditional knockouts established a tissue-specific rictor/mTORC2/Akt-Foxo pro-survival axis (oogenesis, spermatogenesis) and distinguished mTORC2 from mTORC1 roles in CNS myelination.\",\n      \"evidence\": \"Cell-type-specific Cre/loxP rictor (and comparative raptor) knockouts with phospho-immunoblotting, histology, and electron microscopy\",\n      \"pmids\": [\"25564616\", \"26360620\", \"24671993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effector divergence (Akt vs SGK) across these tissues not systematically compared\", \"Contribution of mTORC2-independent rictor actin functions in these phenotypes only partially separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified USP9X-mediated Lys63 deubiquitination of Rictor as a growth-factor-regulated switch controlling mTORC2 assembly, adding a ubiquitin-dependent layer to complex formation.\",\n      \"evidence\": \"Reciprocal co-IP, linkage-specific ubiquitin immunoblotting, USP9X knockdown in cells and mice, and mTORC2 kinase assays\",\n      \"pmids\": [\"33378666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase that deposits the K63 chains not identified\", \"How growth factors regulate USP9X activity unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Cryo-EM structures provided the structural basis for mTORC2 substrate selectivity and rapamycin resistance, showing how Rictor occludes mTORC1 substrates and how Sin1 conformational changes gate SGK1 versus Akt.\",\n      \"evidence\": \"Cryo-EM of apo and substrate-bound human mTORC2 with mSin1 R83A mutagenesis validating substrate-specific predictions\",\n      \"pmids\": [\"35926713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of regulated states (phosphorylated/acetylated Rictor) not resolved\", \"Dynamics of substrate loading and product release not captured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended Rictor/mTORC2 function to organelle quality control, showing it facilitates MARCH5-mediated K48 ubiquitination and degradation of BNIP3 to restrain mitophagy.\",\n      \"evidence\": \"Rictor knockout in endothelial cells and a transplant model, K48-linkage-specific BNIP3 ubiquitination assays, and MARCH5 interaction studies\",\n      \"pmids\": [\"38769658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Whether this requires mTORC2 kinase activity or a separate Rictor complex not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct regulatory inputs on Rictor (K63 deubiquitination, GSK3 phosphodegron, acetylation, S6K1 feedback) are integrated to set mTORC2 output in a given cell, and what determines Akt- versus SGK1-effector dominance across mammalian tissues, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated quantitative model of competing Rictor modifications\", \"Mammalian rules governing AGC-kinase effector choice undefined\", \"Relationship between mTORC2-dependent and mTORC2-independent Rictor complexes in vivo unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 37]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 32]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [18, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 12, 23, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [9, 27, 28, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 32]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [18, 19, 23, 35]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 26]}\n    ],\n    \"complexes\": [\n      \"mTORC2\",\n      \"Rictor-Cullin-1 E3 ligase\",\n      \"Rictor-FBXW7 E3 ligase\",\n      \"Rictor-Myo1c complex\"\n    ],\n    \"partners\": [\n      \"MTOR\",\n      \"MAPKAP1 (Sin1)\",\n      \"ILK\",\n      \"MYO1C\",\n      \"FBXW7\",\n      \"CUL1\",\n      \"USP9X\",\n      \"PRKCZ\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}