{"gene":"DEPTOR","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2009,"finding":"DEPTOR directly interacts with mTOR and functions as an endogenous inhibitor of both mTORC1 and mTORC2 kinase activities. Loss of DEPTOR activates S6K1, Akt, and SGK1, while DEPTOR overexpression suppresses S6K1 but, by relieving mTORC1-to-PI3K feedback inhibition, activates Akt.","method":"Co-immunoprecipitation, RNAi knockdown, overexpression with downstream signaling readouts (S6K1, Akt, SGK1 phosphorylation)","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, loss-of-function and gain-of-function with multiple orthogonal downstream readouts; foundational paper replicated extensively by independent labs","pmids":["19446321"],"is_preprint":false},{"year":2011,"finding":"DEPTOR is a physiological substrate of SCF(βTrCP) E3 ubiquitin ligase. Upon growth factor stimulation, RSK1 and S6K1 phosphorylate DEPTOR, enabling recognition by βTrCP via its degron sequence, leading to ubiquitination and proteasomal degradation. DEPTOR half-life is shortened by βTrCP and extended by a dominant-negative βTrCP mutant or RSK1/S6K1 inhibition.","method":"In vitro ubiquitination assay, co-immunoprecipitation, dominant-negative mutant expression, degron site mutagenesis, half-life measurement","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of ubiquitination, mutagenesis of degron, replicated independently by two concurrent papers (PMID:22017875, 22017877)","pmids":["22017876"],"is_preprint":false},{"year":2011,"finding":"mTOR and casein kinase I (CKI) cooperate to phosphorylate DEPTOR, generating a phosphodegron recognized by βTrCP, driving SCF(βTrCP)-dependent proteasomal degradation. This creates a positive feedback loop in which mTOR promotes its own activation by destroying its inhibitor DEPTOR.","method":"Phosphorylation assays, co-immunoprecipitation, βTrCP depletion, degron mutation, mTOR inhibitor treatment with signaling readouts","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation assay, mutagenesis, replicated by two concurrent independent labs (PMID:22017876, 22017877)","pmids":["22017875"],"is_preprint":false},{"year":2011,"finding":"DEPTOR is phosphorylated on three serines in a conserved degron by CK1α (after a priming phosphorylation by mTORC1 or mTORC2) in response to mitogens, facilitating binding and ubiquitylation by βTrCP and consequent proteasomal degradation. Blocking this pathway via βTrCP knockdown or a stable DEPTOR mutant unable to bind βTrCP results in mTOR inhibition.","method":"Phosphorylation-site mapping, mutagenesis, βTrCP knockdown, stable mutant expression, CK1α involvement established by kinase assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis, in vitro kinase assays, replicated by two concurrent independent labs (PMID:22017875, 22017876)","pmids":["22017877"],"is_preprint":false},{"year":2010,"finding":"Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR. The inhibitory effect of RSV on leucine-stimulated mTORC1 activation was greatly reduced when DEPTOR was suppressed by RNAi, establishing DEPTOR-dependence of this mechanism.","method":"Co-immunoprecipitation, RNAi knockdown, pharmacological treatment with downstream signaling readouts","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP showing enhanced mTOR/DEPTOR association plus RNAi epistasis, single lab, two orthogonal methods","pmids":["20851890"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM and biochemical analysis revealed that both structured regions of DEPTOR — the PDZ domain and the DEP domain tandem (DEPt) — engage mTOR. The PDZ domain binds with a mildly activating effect and acts as an anchor for DEPt, which allosterically suppresses mTOR activation. DEPTOR is itself phosphorylated by mTOR in a substrate-like mode, rationalizing inhibition of non-stimulated mTOR at higher DEPTOR concentrations.","method":"Cryo-EM structure determination, biochemical binding assays, domain mutagenesis, kinase assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structural determination combined with biochemical and mutagenesis validation in a single rigorous study; independently corroborated by concurrent structural paper PMID:34519269","pmids":["34519268"],"is_preprint":false},{"year":2021,"finding":"Reconstitution of mTORC1 with DEPTOR showed DEPTOR is a partial inhibitor of mTORC1. DEPTOR's PDZ domain interacts with the mTOR FAT region and the unstructured linker preceding the PDZ binds the mTOR FRB domain. The linker and PDZ form the minimal inhibitory unit; the N-terminal tandem DEP domains also contribute. mTORC1 activated by RHEB or oncogenic mutation is more potently inhibited by DEPTOR. mTORC1 prevents DEPTOR inhibition by phosphorylating DEPTOR (mutual antagonism).","method":"In vitro reconstitution, structural analysis, domain mutagenesis, kinase assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with structural analyses and mutagenesis, two concurrent independent structural papers (PMID:34519268)","pmids":["34519269"],"is_preprint":false},{"year":2021,"finding":"Crystal structure (1.5 Å) of DEPTOR's N-terminal tandem DEP domains shows a dumbbell-shaped structure with an 18-amino-acid DDEX motif at the end of DEP2 that interacts with DEP1 to stabilize the structure. Biochemical studies showed the tandem DEP domains directly interact with phosphatidic acid via two distinct positively charged patches, providing a structural basis for DEPTOR dissociation from mTORC1 upon phosphatidic acid stimulation.","method":"X-ray crystallography (1.5 Å resolution), biochemical binding assays with phosphatidic acid","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure combined with biochemical validation of lipid binding","pmids":["33865870"],"is_preprint":false},{"year":2018,"finding":"OTUB1 directly interacts with DEPTOR via its N-terminal domain and deubiquitinates DEPTOR to stabilize it, in a Cys-91-independent but Asp-88-dependent (non-canonical) manner. The OTUB1-DEPTOR interaction is enhanced by amino acid treatment. OTUB1 suppresses amino acid-induced mTORC1 activation in a DEPTOR-dependent manner, thereby controlling autophagy, cell proliferation, and cell size.","method":"Deubiquitination assay, co-immunoprecipitation, domain mutagenesis (Cys-91, Asp-88), siRNA knockdown with signaling readouts","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro deubiquitination assay plus reciprocal Co-IP and mutagenesis, single lab","pmids":["29382726"],"is_preprint":false},{"year":2016,"finding":"p38γ and p38δ phosphorylate DEPTOR, leading to its degradation and subsequent mTOR activation, thereby promoting cardiac hypertrophy. Hearts from mice lacking p38γ/δ have high DEPTOR levels and low mTOR pathway activity. shRNA-mediated knockdown of Deptor reverted the small-heart phenotype of p38γ/δ knockout mice.","method":"In vivo mouse knockout model, shRNA knockdown, cardiomyocyte-specific overexpression, phosphorylation assays, genetic epistasis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double knockout rescue, in vivo KO with defined cardiac phenotype, multiple orthogonal methods across independent experiments","pmids":["26795633"],"is_preprint":false},{"year":2023,"finding":"UBE2C couples with APC/C(CDH1) E3 ligase to promote ubiquitylation and degradation of DEPTOR, leading to mTORC signaling activation and promotion of cell cycle progression. KrasG12D-induced UBE2C expression drives DEPTOR degradation; Deptor deletion fully rescued the tumor inhibitory effect of Ube2c deletion in a KrasG12D lung tumor model, establishing DEPTOR as the key downstream effector.","method":"Ubiquitination assay, co-immunoprecipitation, genetic mouse models (Ube2c deletion, Deptor deletion, KrasG12D), epistasis rescue experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with Deptor deletion rescuing Ube2c KO phenotype, combined with biochemical ubiquitination assays; multiple orthogonal methods","pmids":["36548081"],"is_preprint":false},{"year":2016,"finding":"DEPTOR functions as a nuclear protein in multiple myeloma cells, capable of binding DNA and regulating transcription. Nuclear DEPTOR sustains expression of genes involved in the ER network, and DEPTOR depletion induces ER stress and synergizes with proteasome inhibitor bortezomib.","method":"Subcellular fractionation, chromatin immunoprecipitation, siRNA knockdown, ER stress marker analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation plus ChIP demonstrating nuclear localization and DNA binding, single lab, two orthogonal methods","pmids":["27655709"],"is_preprint":false},{"year":2015,"finding":"The ESCRT pathway mediates CXCR4-promoted lysosomal degradation of DEPTOR. CXCR4 stimulates DEPTOR degradation via Gαi and PI3K signaling and via the ESCRT machinery; depletion of ESCRTs by siRNA leads to increased DEPTOR levels and attenuated CXCR4-promoted Akt activation, consistent with decreased mTORC2 activity.","method":"siRNA knockdown of ESCRT components, pharmacological inhibition of Gαi and PI3K, western blot for DEPTOR levels and Akt phosphorylation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis with pharmacological confirmation, single lab, two orthogonal approaches","pmids":["25605718"],"is_preprint":false},{"year":2013,"finding":"TGF-β-stimulated Smad3 acts as a key node to suppress DEPTOR abundance, thereby releasing mTORC1/2 inhibition and driving mesangial cell hypertrophy. Sustained (not acute) mTOR activation is required for DEPTOR suppression. Knockdown of Smad3 prevented TGF-β-induced DEPTOR suppression; overexpression of Smad3 decreased DEPTOR; knockdown of DEPTOR reversed Smad7-mediated inhibition of TGF-β-induced hypertrophy.","method":"siRNA knockdown, overexpression, mTOR inhibitor (PP242), western blot for DEPTOR levels and mTORC1/2 activity, protein synthesis and cell size assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via siRNA plus pharmacological inhibition, single lab, multiple orthogonal manipulations","pmids":["23362262"],"is_preprint":false},{"year":2012,"finding":"GNMT (glycine N-methyltransferase) interacts with DEPTOR/DEPDC6; FRET assay demonstrated that the C-terminal half of GNMT interacts with the PDZ domain of DEPDC6/DEPTOR.","method":"Yeast two-hybrid screening, fluorescence resonance energy transfer (FRET) assay, knockdown and overexpression with signaling readouts","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET plus yeast two-hybrid with domain mapping, single lab","pmids":["22160218"],"is_preprint":false},{"year":2013,"finding":"Baf60c induces expression of DEPTOR via the Baf60c-Six4 transcriptional complex, and DEPTOR then mediates activation of Akt (by relieving mTORC1 negative feedback to PI3K) and glycolytic metabolism in a cell-autonomous manner in skeletal muscle.","method":"Transgenic muscle-specific overexpression, ChIP for Baf60c-Six4 binding to Deptor promoter, siRNA knockdown epistasis, metabolic phenotyping in vivo","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model plus ChIP and cell-autonomous epistasis with multiple orthogonal readouts","pmids":["23563706"],"is_preprint":false},{"year":2021,"finding":"Tyrosine 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. SYK (spleen tyrosine kinase) was identified as the kinase responsible for DEPTOR Tyr289 phosphorylation in an ephrin receptor-dependent manner, as established by proximity biotinylation assays and functional validation.","method":"Site-directed mutagenesis (Y289), proximity biotinylation (BioID), co-immunoprecipitation, pharmacological inhibition, mTOR signaling readouts","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of phosphorylation site combined with proximity biotinylation identification of kinase, single lab","pmids":["34634301"],"is_preprint":false},{"year":2022,"finding":"ERK1 phosphorylates DEPTOR at serine 235 (S235), regulating DEPTOR stability. An S235 phosphomimetic DEPTOR mutant was resistant to proteasomal degradation. S235 phosphorylation enables USP-7 deubiquitinase association with DEPTOR; inhibition of USP-7 results in DEPTOR polyubiquitination and degradation. ERK1-mediated S235 phosphorylation of DEPTOR maintains Akt activity in multiple myeloma cells.","method":"In vitro kinase assay (ERK1), mutagenesis (S235A and S235D), co-immunoprecipitation for USP-7, proteasome inhibitor rescue, ERK1 knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis confirming S235 regulation, single lab","pmids":["35216969"],"is_preprint":false},{"year":2016,"finding":"NOTCH1 directly binds to and activates the human DEPTOR promoter in T-ALL cells, transcriptionally upregulating DEPTOR expression. DEPTOR depletion inhibited Akt activation, abolished cellular proliferation, attenuated glycolytic metabolism, and enhanced cell death in T-ALL cells.","method":"Chromatin immunoprecipitation, NOTCH1 overexpression/knockdown with DEPTOR promoter reporter, siRNA knockdown with proliferation/metabolism/apoptosis readouts, xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct NOTCH1 binding to DEPTOR promoter, combined with functional knockdown experiments, single lab","pmids":["27593934"],"is_preprint":false},{"year":2018,"finding":"DEPTOR directly interacts with c-Myc (via Wnt/β-catenin/c-Myc signaling), and c-Myc binds the DEPTOR promoter to transcriptionally regulate DEPTOR expression in colorectal cancer cells. Inhibition of Wnt/β-catenin or c-Myc knockdown decreased DEPTOR expression; c-Myc overexpression increased it.","method":"Chromatin immunoprecipitation (c-Myc binding to DEPTOR promoter), siRNA/shRNA knockdown, luciferase reporter, in vitro and in vivo tumor models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing direct c-Myc binding to DEPTOR promoter, combined with loss/gain-of-function and reporter assays, single lab","pmids":["29666061"],"is_preprint":false},{"year":2020,"finding":"p53 directly binds to the DEPTOR promoter and transactivates DEPTOR expression. Deletion of the p53-binding site on the DEPTOR promoter by CRISPR-Cas9 decreases DEPTOR expression and promotes cell proliferation via Akt signaling. Upon doxorubicin treatment, p53 induces DEPTOR expression leading to cancer cell resistance.","method":"Chromatin immunoprecipitation, CRISPR-Cas9 deletion of p53-binding site, luciferase reporter, western blot for downstream signaling","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus CRISPR-Cas9 functional deletion of binding site, single lab, two orthogonal methods","pmids":["33184290"],"is_preprint":false},{"year":2015,"finding":"Androgen receptor (AR) functions as a negative transcriptional regulator of DEPTOR. DHT treatment repressed DEPTOR mRNA in LNCaP cells in a time-dependent manner, reversed by the AR antagonist bicalutamide. ChIP assay demonstrated AR binds to an AR-responsive element-like region within the 4th intron of the DEPTOR gene, accompanied by reduced acetylated histone H3.","method":"RT-PCR, ChIP assay, pharmacological (DHT, bicalutamide), siRNA knockdown with mTORC1 readouts","journal":"The Journal of toxicological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing direct AR binding to DEPTOR gene, combined with pharmacological manipulation, single lab","pmids":["26558456"],"is_preprint":false},{"year":2016,"finding":"p65/NF-κB directly binds the DEPTOR promoter at a -145/-127 region and represses DEPTOR transcription in response to LPS stimulation. Progressive deletions and mutations of the promoter, plus ChIP assays, confirmed this NF-κB binding site is essential for DEPTOR promoter activity.","method":"Chromatin immunoprecipitation, promoter deletion/mutation analysis, luciferase reporter, NF-κB inhibitor (PDTC) and IκBα overexpression","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus promoter mutagenesis with reporter assay, single lab","pmids":["27179948"],"is_preprint":false},{"year":2018,"finding":"TNFAIP3 (A20) interacts with and stabilizes DEPTOR via its zinc-finger domains; the TNFAIP3-DEPTOR complex rapidly promotes autophagy after LPS treatment to prevent NLRP3 inflammasome formation in monocytes. This interaction was established by GST pull-down, yeast two-hybrid, confocal microscopy, and co-immunoprecipitation.","method":"GST pull-down, yeast two-hybrid, co-immunoprecipitation, confocal microscopy, siRNA knockdown with autophagy and inflammasome readouts","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding assays (GST pull-down, co-IP, Y2H) plus functional epistasis, single lab","pmids":["29940800"],"is_preprint":false},{"year":2021,"finding":"DEPTOR directly interacts with ErbB2 at the cell membrane, disrupting ErbB2 polyubiquitination and degradation by β-TrCP. DEPTOR knockdown destabilizes ErbB2, shortens its protein half-life, and inactivates ErbB2-PI3K-AKT-mTOR signaling. A constitutively active ErbB2 mutant fully rescued the reduction in cell proliferation and survival caused by DEPTOR knockdown.","method":"Co-immunoprecipitation, immunofluorescence, subcellular fractionation, ubiquitination assay, half-life measurement, constitutively active mutant rescue, siRNA knockdown","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with subcellular fractionation and ubiquitination assay, single lab, multiple orthogonal methods","pmids":["33995662"],"is_preprint":false},{"year":2021,"finding":"Nuclear ErbB2 directly binds to a consensus sequence in the DEPTOR promoter to repress its transcription. ErbB2 kinase activity is required for its nuclear translocation and transcriptional repression of DEPTOR. Repression of DEPTOR by nuclear ErbB2 inhibits autophagy induction by activating mTORC1.","method":"Chromatin immunoprecipitation, ErbB2 nuclear translocation experiments (kinase-dead mutant), DEPTOR promoter reporter, autophagy assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus kinase-dead mutant demonstrating kinase requirement, single lab","pmids":["33854045"],"is_preprint":false},{"year":2022,"finding":"DEPTOR binds transcriptional coactivator TAZ and inhibits its transactivation properties, thereby repressing RUNX2 transcriptional activity and elevating PPARγ gene transcription in BMSCs, promoting adipogenesis over osteogenesis. TAZ knockdown in BMSCs abolished the beneficial effects of Deptor ablation on bone-fat balance in mice.","method":"Co-immunoprecipitation, TAZ knockdown epistasis, in vivo mouse model of osteoporosis, western blot for RUNX2/PPARγ targets","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing DEPTOR-TAZ interaction plus TAZ epistasis rescue, single lab","pmids":["35609371"],"is_preprint":false},{"year":2020,"finding":"DEPTOR interplays with TRC8 E3 ubiquitin ligase in chondrocytes, promoting TRC8 auto-ubiquitination and TRC8 degradation by the ubiquitin-proteasome system. Loss of DEPTOR leads to TRC8 accumulation, excessive ER stress, chondrocyte apoptosis, and osteoarthritis progression, independent of mTOR signaling.","method":"Proteomics analysis, co-immunoprecipitation, ubiquitination assay, conditional DEPTOR knockout mice, intra-articular lentivirus injection, ER stress inhibitor rescue","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo conditional KO with ER stress inhibitor epistasis, single lab, multiple orthogonal approaches","pmids":["32916025"],"is_preprint":false},{"year":2018,"finding":"DEPTOR expression in CD4+ T regulatory cells stabilizes Foxp3 expression, shifts metabolism toward oxidative phosphorylation, increases Treg survival and suppressive function. In vivo, induced DEPTOR expression in CD4+ T regulatory cells (not effectors) mediates prolonged cardiac allograft survival in a fully MHC-mismatched transplant model.","method":"Conditional knock-in mouse model, in vitro T cell differentiation/metabolism assays, in vivo cardiac allograft transplant model, Foxp3 stability analysis","journal":"American journal of transplantation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knock-in model with defined immunological phenotype and metabolic readouts, single lab","pmids":["29969188"],"is_preprint":false},{"year":2017,"finding":"Liver-specific DEPTOR knockout mice showed sustained mTORC1 activation upon fasting and a reduction in circulating glucose and hepatic glycogen during fasting. Acute rapamycin treatment normalized glycemia, establishing that hepatic DEPTOR accelerates mTORC1 inhibition during the transition to fasting. Loss of DEPTOR also increased oxidative metabolism in hepatocytes, associated with increased cytochrome c expression.","method":"Conditional knockout mouse model (Albumin-cre), metabolic phenotyping, rapamycin rescue experiment, hepatocyte oxidative metabolism assays","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined metabolic phenotype and pharmacological rescue, single lab","pmids":["28462079"],"is_preprint":false},{"year":2014,"finding":"DEPTOR is a stemness factor that maintains pluripotency in embryonic stem cells by limiting mTOR activity. DEPTOR levels dramatically decrease with ESC differentiation, and knockdown of DEPTOR is sufficient to promote ESC differentiation, accompanied by a corresponding increase in mTORC1 activity.","method":"shRNA knockdown, western blot for DEPTOR and mTORC1 activity during differentiation, pluripotency marker analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined differentiation phenotype correlated with mTORC1 activation, single lab","pmids":["25258312"],"is_preprint":false},{"year":2021,"finding":"DEPTOR directly binds to the kinase domain of EGFR via its PDZ domain to inactivate EGFR signaling. DEPTOR depletion not only directly activates mTORC1/2 but also relieves EGFR inhibition, further activating mTOR signals and inducing EMT via ZEB1 and SLUG upregulation. In vivo, Deptor deletion accelerated KrasG12D;p53fl/fl-induced lung tumorigenesis via EGFR-mTOR signals.","method":"Co-immunoprecipitation (PDZ domain binding to EGFR kinase domain), domain mutagenesis, in vivo KrasG12D;p53fl/fl;Deptor-KO mouse model, signaling readouts","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus in vivo genetic model, single lab","pmids":["34320372"],"is_preprint":false},{"year":2019,"finding":"DEPTOR depletion in prostate cancer cells activates both mTORC1 and mTORC2, induces AKT-dependent EMT, and promotes β-catenin nuclear translocation. In a Deptor-KO mouse model, Deptor knockout accelerated Pten loss-induced prostate tumorigenesis via mTOR signaling activation. Abrogation of mTOR or AKT activation rescued the biological consequences of DEPTOR depletion.","method":"Conditional knockout mouse model (Deptor-KO x Pten-loss), siRNA knockdown, pharmacological inhibitors of mTOR and AKT as epistasis tools, migration/invasion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis in mouse tumor model plus pharmacological rescue, single lab","pmids":["31685947"],"is_preprint":false},{"year":2018,"finding":"RPS27L silencing shortens the protein half-life of β-TrCP (the DEPTOR E3 ligase receptor), leading to DEPTOR accumulation, mTORC1 inactivation, and autophagy induction. Simultaneous DEPTOR silencing partially rescued mTORC1 inactivation and autophagy caused by RPS27L loss, establishing DEPTOR as a causal mediator of this pathway.","method":"siRNA knockdown, half-life measurement of β-TrCP, DEPTOR and mTORC1 signaling readouts, double knockdown epistasis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiment (double knockdown rescue) plus mechanistic half-life measurements, single lab","pmids":["30425236"],"is_preprint":false},{"year":2012,"finding":"DEPTOR is a cell-autonomous pro-adipogenic factor. DEPTOR is induced by glucocorticoids during adipogenesis, and its overexpression promotes while its suppression blocks adipogenesis. DEPTOR activates the proadipogenic Akt/PKB-PPARγ axis by dampening mTORC1-mediated negative feedback inhibition of insulin signaling.","method":"Transgenic mouse overexpression model, siRNA knockdown, adipogenesis assays, signaling readouts for Akt/PPARγ, glucocorticoid treatment","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model combined with in vitro loss-of-function and mechanistic signaling studies, single lab","pmids":["22883231"],"is_preprint":false},{"year":2025,"finding":"Trophoblast-specific Deptor knockdown activates placental mTORC1 and mTORC2 signaling, increases trophoblast plasma membrane LAT1 and SNAT2 amino acid transporter expression and activity, and stimulates in vivo transplacental system A and L amino acid transport and fetal growth. In human FGR placentas, DEPTOR protein expression is higher and negatively correlated with birth weight and system A amino acid transporter activity.","method":"Lentiviral shRNA trophoblast-specific knockdown in mice, mTOR signaling readouts, transporter expression/activity assays, in vivo transplacental transport measurement","journal":"Function (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — trophoblast-specific in vivo KD with functional transport assays and signaling readouts, single lab, corroborated by concurrent independent paper (PMID:40042094)","pmids":["40133007"],"is_preprint":false}],"current_model":"DEPTOR is a constitutive inhibitory subunit of both mTORC1 and mTORC2 that binds mTOR through a bipartite interface involving its PDZ domain (contacting the FAT region) and DEP domain tandem (allosterically suppressing kinase activation); it is regulated by a phosphorylation-driven destruction cycle in which mTOR, CK1α, RSK1, S6K1, p38γ/δ, and ERK1 sequentially phosphorylate DEPTOR to generate a phosphodegron recognized by the SCF(βTrCP) E3 ligase for ubiquitination and proteasomal degradation, while OTUB1 and USP-7 (stabilized by S235 phosphorylation) antagonize this destruction; additional non-canonical interactions include binding to EGFR (via PDZ domain), ErbB2, TAZ, TRC8, and TNFAIP3, nuclear localization with transcriptional regulatory activity, and sensitivity to phosphatidic acid at its tandem DEP domains, collectively positioning DEPTOR as a multifunctional hub that coordinates mTOR activity with PI3K/Akt feedback, autophagy, adipogenesis, cardiac hypertrophy, immune function, placental nutrient transport, and stem cell pluripotency."},"narrative":{"mechanistic_narrative":"DEPTOR is an endogenous inhibitory subunit of both mTORC1 and mTORC2 that sets the cellular threshold for mTOR signaling and the PI3K/Akt feedback loop downstream of it [PMID:19446321]. It engages mTOR through a bipartite interface: a PDZ domain (with its preceding unstructured linker) binds the mTOR FAT and FRB regions and acts as an anchor, while the N-terminal tandem DEP domains allosterically suppress kinase activation, with mTORC1 reciprocally phosphorylating DEPTOR in a substrate-like mode to relieve inhibition [PMID:34519268, PMID:34519269, PMID:33865870]. Loss of DEPTOR activates S6K1, Akt, and SGK1, whereas its accumulation suppresses mTORC1 and, by relieving mTORC1-to-PI3K feedback, can paradoxically activate Akt [PMID:19446321]. DEPTOR abundance is governed by a phosphorylation-driven destruction cycle: priming by mTOR followed by CK1α, together with RSK1, S6K1, p38γ/δ and ERK1, generates a phosphodegron recognized by SCF(βTrCP) for ubiquitination and proteasomal degradation, creating a positive feedback loop in which active mTOR destroys its own inhibitor [PMID:22017876, PMID:22017875, PMID:22017877, PMID:26795633, PMID:35216969]; APC/C(CDH1) via UBE2C provides an additional degradative input, while OTUB1 and USP-7 (the latter recruited upon ERK1-mediated S235 phosphorylation) deubiquitinate and stabilize DEPTOR [PMID:36548081, PMID:29382726, PMID:35216969]. The tandem DEP domains also bind phosphatidic acid, providing a lipid-sensing route for DEPTOR dissociation from mTORC1 [PMID:33865870]. Through these activities DEPTOR controls autophagy, adipogenesis, cardiac and mesangial hypertrophy, hepatic fasting metabolism, embryonic stem cell pluripotency, regulatory T cell function, and placental amino acid transport and fetal growth [PMID:26795633, PMID:29940800, PMID:28462079, PMID:25258312, PMID:29969188, PMID:22883231, PMID:40133007]. Beyond its mTOR-centered role, DEPTOR also acts as a nuclear DNA-binding transcriptional regulator and engages non-canonical partners including EGFR and ErbB2 (via its PDZ domain), TAZ, and the E3 ligase TRC8 in mTOR-independent functions [PMID:27655709, PMID:34320372, PMID:33995662, PMID:35609371, PMID:32916025]. Its expression is set by a wide transcriptional network including NOTCH1, c-Myc, p53, androgen receptor, NF-κB, and the Baf60c-Six4 complex [PMID:27593934, PMID:29666061, PMID:33184290, PMID:26558456, PMID:27179948, PMID:23563706].","teleology":[{"year":2009,"claim":"Established the founding mechanistic identity of DEPTOR as an mTOR-binding protein that inhibits both mTOR complexes, defining its place in the mTOR/PI3K/Akt signaling axis.","evidence":"Reciprocal Co-IP with mTOR plus RNAi and overexpression read out on S6K1, Akt, and SGK1 phosphorylation","pmids":["19446321"],"confidence":"High","gaps":["Structural basis of inhibition not defined","Did not resolve how DEPTOR levels are regulated"]},{"year":2011,"claim":"Resolved how DEPTOR levels are controlled, showing growth factor signaling triggers SCF(βTrCP)-mediated degradation through a multi-kinase phosphodegron, creating a feedback loop coupling mTOR activity to destruction of its own inhibitor.","evidence":"In vitro ubiquitination and kinase assays, degron mutagenesis, βTrCP depletion and dominant-negative expression, half-life measurement (three concurrent independent papers; kinases RSK1, S6K1, mTOR priming, CK1α)","pmids":["22017876","22017875","22017877"],"confidence":"High","gaps":["Did not address deubiquitinating opposition to degradation","In vivo physiological relevance of the loop not yet tested"]},{"year":2010,"claim":"Linked a pharmacological mTOR inhibitor to DEPTOR, showing resveratrol acts in part by promoting the mTOR-DEPTOR interaction.","evidence":"Co-IP showing enhanced mTOR/DEPTOR association plus RNAi epistasis on leucine-stimulated mTORC1","pmids":["20851890"],"confidence":"Medium","gaps":["Molecular mechanism by which resveratrol enhances binding unknown","Single lab"]},{"year":2012,"claim":"Defined a physiological output of DEPTOR by showing it is a pro-adipogenic factor that activates the Akt-PPARγ axis through relief of mTORC1 feedback.","evidence":"Transgenic overexpression, siRNA knockdown, adipogenesis and signaling assays with glucocorticoid induction","pmids":["22883231"],"confidence":"Medium","gaps":["Direct transcriptional partners in adipocytes not defined here","Single lab"]},{"year":2013,"claim":"Connected upstream signaling to DEPTOR abundance in tissue hypertrophy, showing TGF-β/Smad3 and Baf60c-Six4 transcriptionally set DEPTOR levels to tune mTOR output and metabolism.","evidence":"siRNA/overexpression epistasis with mTOR inhibitor in mesangial cells; transgenic muscle model plus ChIP for the Baf60c-Six4 complex on the Deptor promoter","pmids":["23362262","23563706"],"confidence":"Medium","gaps":["How multiple transcriptional inputs are integrated unknown","Tissue-specific relevance of each input untested"]},{"year":2014,"claim":"Extended DEPTOR function to stem cell biology, showing it maintains pluripotency by restraining mTOR activity.","evidence":"shRNA knockdown with pluripotency markers and mTORC1 activity during ESC differentiation","pmids":["25258312"],"confidence":"Medium","gaps":["Mechanism linking mTOR restraint to pluripotency network not defined","Single lab"]},{"year":2016,"claim":"Identified non-degradative and non-cytoplasmic functions — a p38γ/δ degradation route driving cardiac hypertrophy, and a nuclear DNA-binding transcriptional role sustaining the ER gene network.","evidence":"In vivo p38γ/δ knockout with shRNA rescue of cardiac phenotype; subcellular fractionation and ChIP in myeloma cells","pmids":["26795633","27655709"],"confidence":"High","gaps":["Nuclear DEPTOR DNA-binding specificity and direct targets incompletely mapped","Relationship between nuclear and mTOR-bound pools unknown"]},{"year":2018,"claim":"Defined the stabilizing arm of DEPTOR turnover and additional protein partners, with OTUB1 and TNFAIP3 stabilizing DEPTOR to control mTORC1, autophagy, and inflammasome activity.","evidence":"In vitro deubiquitination, GST pull-down, Y2H, Co-IP, and confocal microscopy with functional autophagy/inflammasome readouts","pmids":["29382726","29940800"],"confidence":"Medium","gaps":["Non-canonical OTUB1 catalytic mechanism on DEPTOR not fully resolved","Single lab for each partner"]},{"year":2021,"claim":"Delivered the structural mechanism of inhibition: cryo-EM, reconstitution, and crystallography showed a bipartite PDZ-plus-tandem-DEP engagement of mTOR, substrate-like phosphorylation by mTOR, and phosphatidic acid binding by the DEP domains as a dissociation switch.","evidence":"Cryo-EM and in vitro reconstitution of mTORC1 with DEPTOR (two concurrent papers), 1.5 Å crystal structure of tandem DEP domains with lipid-binding assays","pmids":["34519268","34519269","33865870"],"confidence":"High","gaps":["Structure of DEPTOR bound within intact mTORC2 not resolved","Cellular conditions controlling phosphatidic-acid-driven dissociation untested in vivo"]},{"year":2021,"claim":"Expanded the regulatory and non-canonical interaction repertoire, identifying SYK/ephrin-driven Tyr289 phosphorylation that weakens mTOR binding, and PDZ-mediated control of EGFR and ErbB2 receptor signaling and stability.","evidence":"Site mutagenesis with BioID; Co-IP with domain mapping, subcellular fractionation, ubiquitination assays, and in vivo Kras;p53 lung tumor models","pmids":["34634301","34320372","33995662","33854045"],"confidence":"Medium","gaps":["Interplay between receptor-binding and mTOR-inhibitory pools unclear","Single lab for each interaction"]},{"year":2022,"claim":"Mapped the transcriptional network setting DEPTOR levels (NOTCH1, c-Myc, p53, androgen receptor, NF-κB) and defined ERK1-S235 phosphorylation that recruits USP-7 to stabilize DEPTOR, plus a TAZ-binding adipogenic mechanism.","evidence":"ChIP, promoter reporters, and CRISPR binding-site deletion across multiple cancer models; in vitro ERK1 kinase assay with phosphomimetic mutants and USP-7 Co-IP; Co-IP and epistasis for TAZ","pmids":["27593934","29666061","33184290","26558456","27179948","35216969","35609371"],"confidence":"Medium","gaps":["How competing transcriptional inputs are integrated in a given cell type unknown","Each regulatory link rests on a single lab"]},{"year":2023,"claim":"Established DEPTOR as the key downstream effector of additional degradation machinery in vivo, with APC/C(CDH1)/UBE2C-driven turnover required for Kras-induced tumorigenesis.","evidence":"Ubiquitination assays plus genetic mouse epistasis (Deptor deletion rescuing Ube2c-loss phenotype in KrasG12D lung tumors)","pmids":["36548081"],"confidence":"High","gaps":["Cell-cycle timing of APC/C-dependent DEPTOR turnover not resolved","Relationship to the βTrCP route during tumorigenesis unclear"]},{"year":2025,"claim":"Demonstrated an organismal physiological role at the maternal-fetal interface, with trophoblast DEPTOR restraining placental mTOR signaling, amino acid transport, and fetal growth, and elevated DEPTOR in human fetal growth restriction.","evidence":"Trophoblast-specific shRNA knockdown in mice with transporter activity and transplacental transport assays, plus human FGR placental correlation (corroborated by concurrent paper)","pmids":["40133007"],"confidence":"Medium","gaps":["Causal direction of elevated DEPTOR in human FGR not established","Upstream signals driving placental DEPTOR levels unknown"]},{"year":null,"claim":"How the distinct DEPTOR pools — mTOR-inhibitory, nuclear/transcriptional, and receptor-binding — are partitioned and coordinated within a single cell, and which functions are mTOR-dependent versus independent, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling cytoplasmic, nuclear, and membrane functions","Stoichiometry of DEPTOR within mTORC1 vs mTORC2 in vivo unknown","Physiological triggers selecting among degradation and stabilization routes unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[11]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[24,31]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,3,10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8,23,25,33]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[29,34,35]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[11,18,19,20]}],"complexes":["mTORC1","mTORC2"],"partners":["MTOR","BTRC","OTUB1","USP7","EGFR","ERBB2","WWTR1","RNF139"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TB45","full_name":"DEP domain-containing mTOR-interacting protein","aliases":["DEP domain-containing protein 6"],"length_aa":409,"mass_kda":46.3,"function":"Negative regulator of the mTORC1 and mTORC2 complexes: inhibits the protein kinase activity of MTOR, thereby inactivating both complexes (PubMed:19446321, PubMed:22017875, PubMed:22017876, PubMed:22017877, PubMed:25936805, PubMed:29382726, PubMed:34519268, PubMed:34519269). DEPTOR inhibits mTORC1 and mTORC2 to induce autophagy (PubMed:22017875, PubMed:22017876, PubMed:22017877). In contrast to AKT1S1/PRAS40, only partially inhibits mTORC1 activity (PubMed:34519268, PubMed:34519269)","subcellular_location":"Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q8TB45/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DEPTOR","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DEPTOR","total_profiled":1310},"omim":[{"mim_id":"618162","title":"SPONDYLOEPIMETAPHYSEAL DYSPLASIA, KRAKOW TYPE; SEMDK","url":"https://www.omim.org/entry/618162"},{"mim_id":"618054","title":"MEMBRANE INTEGRAL NOTCH2-ASSOCIATED RECEPTOR 1; MINAR1","url":"https://www.omim.org/entry/618054"},{"mim_id":"614776","title":"SIK FAMILY KINASE 3; SIK3","url":"https://www.omim.org/entry/614776"},{"mim_id":"612974","title":"DEP DOMAIN-CONTAINING PROTEIN 6; DEPDC6","url":"https://www.omim.org/entry/612974"},{"mim_id":"156400","title":"METAPHYSEAL CHONDRODYSPLASIA, JANSEN TYPE; MCDJ","url":"https://www.omim.org/entry/156400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":148.1},{"tissue":"tongue","ntpm":114.2}],"url":"https://www.proteinatlas.org/search/DEPTOR"},"hgnc":{"alias_symbol":["DEP.6","FLJ12428"],"prev_symbol":["DEPDC6"]},"alphafold":{"accession":"Q8TB45","domains":[{"cath_id":"1.10.10.10","chopping":"21-116","consensus_level":"high","plddt":93.5323,"start":21,"end":116},{"cath_id":"1.10.10.10","chopping":"127-216","consensus_level":"high","plddt":93.5617,"start":127,"end":216},{"cath_id":"2.30.42.10","chopping":"315-405","consensus_level":"high","plddt":89.9878,"start":315,"end":405}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TB45","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TB45-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TB45-F1-predicted_aligned_error_v6.png","plddt_mean":79.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DEPTOR","jax_strain_url":"https://www.jax.org/strain/search?query=DEPTOR"},"sequence":{"accession":"Q8TB45","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TB45.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TB45/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TB45"}},"corpus_meta":[{"pmid":"19446321","id":"PMC_19446321","title":"DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival.","date":"2009","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/19446321","citation_count":978,"is_preprint":false},{"pmid":"22017876","id":"PMC_22017876","title":"DEPTOR, an mTOR inhibitor, is a physiological substrate of SCF(βTrCP) E3 ubiquitin ligase and regulates survival and autophagy.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/22017876","citation_count":245,"is_preprint":false},{"pmid":"22017875","id":"PMC_22017875","title":"mTOR drives its own activation via SCF(βTrCP)-dependent degradation of the mTOR inhibitor DEPTOR.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/22017875","citation_count":216,"is_preprint":false},{"pmid":"22017877","id":"PMC_22017877","title":"mTOR generates an auto-amplification loop by triggering the βTrCP- and CK1α-dependent degradation of DEPTOR.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/22017877","citation_count":181,"is_preprint":false},{"pmid":"20851890","id":"PMC_20851890","title":"Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20851890","citation_count":150,"is_preprint":false},{"pmid":"22951983","id":"PMC_22951983","title":"Targeting Cullin-RING ligases by MLN4924 induces autophagy via modulating the HIF1-REDD1-TSC1-mTORC1-DEPTOR axis.","date":"2012","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/22951983","citation_count":128,"is_preprint":false},{"pmid":"23563706","id":"PMC_23563706","title":"Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation.","date":"2013","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23563706","citation_count":124,"is_preprint":false},{"pmid":"22883231","id":"PMC_22883231","title":"DEPTOR cell-autonomously promotes adipogenesis, and its expression is associated with obesity.","date":"2012","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/22883231","citation_count":97,"is_preprint":false},{"pmid":"28086984","id":"PMC_28086984","title":"Deptor: not only a mTOR inhibitor.","date":"2017","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/28086984","citation_count":81,"is_preprint":false},{"pmid":"29666061","id":"PMC_29666061","title":"Deptor Is a Novel Target of Wnt/β-Catenin/c-Myc and Contributes to Colorectal Cancer Cell Growth.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29666061","citation_count":69,"is_preprint":false},{"pmid":"29897294","id":"PMC_29897294","title":"DEPTOR at the Nexus of Cancer, Metabolism, and Immunity.","date":"2018","source":"Physiological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/29897294","citation_count":66,"is_preprint":false},{"pmid":"26795633","id":"PMC_26795633","title":"p38γ and δ promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26795633","citation_count":66,"is_preprint":false},{"pmid":"36548081","id":"PMC_36548081","title":"The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer cells.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/36548081","citation_count":64,"is_preprint":false},{"pmid":"22745582","id":"PMC_22745582","title":"Targeting the mTOR-DEPTOR pathway by CRL E3 ubiquitin ligases: therapeutic application.","date":"2012","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22745582","citation_count":57,"is_preprint":false},{"pmid":"29382726","id":"PMC_29382726","title":"OTUB1 protein suppresses mTOR complex 1 (mTORC1) activity by deubiquitinating the mTORC1 inhibitor DEPTOR.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29382726","citation_count":53,"is_preprint":false},{"pmid":"22160218","id":"PMC_22160218","title":"Functional characterization of glycine N-methyltransferase and its interactive protein DEPDC6/DEPTOR in hepatocellular carcinoma.","date":"2012","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/22160218","citation_count":53,"is_preprint":false},{"pmid":"22745583","id":"PMC_22745583","title":"An evolving role for DEPTOR in tumor development and progression.","date":"2012","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22745583","citation_count":53,"is_preprint":false},{"pmid":"29973283","id":"PMC_29973283","title":"DEPTOR regulates osteogenic differentiation via inhibiting MEG3-mediated activation of BMP4 signaling and is involved in osteoporosis.","date":"2018","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29973283","citation_count":50,"is_preprint":false},{"pmid":"21607293","id":"PMC_21607293","title":"Deptor knockdown enhances mTOR Activity and protein synthesis in myocytes and ameliorates disuse muscle atrophy.","date":"2011","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/21607293","citation_count":46,"is_preprint":false},{"pmid":"24458360","id":"PMC_24458360","title":"The Baf60c/Deptor pathway links skeletal muscle inflammation to glucose homeostasis in obesity.","date":"2014","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/24458360","citation_count":45,"is_preprint":false},{"pmid":"29940800","id":"PMC_29940800","title":"TNFAIP3-DEPTOR complex regulates inflammasome secretion through autophagy in ankylosing spondylitis monocytes.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/29940800","citation_count":45,"is_preprint":false},{"pmid":"25810016","id":"PMC_25810016","title":"Deptor enhances triple-negative breast cancer metastasis and chemoresistance through coupling to survivin expression.","date":"2015","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/25810016","citation_count":41,"is_preprint":false},{"pmid":"23881914","id":"PMC_23881914","title":"DEPTOR regulates vascular endothelial cell activation and proinflammatory and angiogenic responses.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23881914","citation_count":38,"is_preprint":false},{"pmid":"31685947","id":"PMC_31685947","title":"DEPTOR is an in vivo tumor suppressor that inhibits prostate tumorigenesis via the inactivation of mTORC1/2 signals.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31685947","citation_count":37,"is_preprint":false},{"pmid":"27593934","id":"PMC_27593934","title":"DEPTOR is a direct NOTCH1 target that promotes cell proliferation and survival in T-cell leukemia.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27593934","citation_count":36,"is_preprint":false},{"pmid":"26992219","id":"PMC_26992219","title":"DEPTOR promotes survival of cervical squamous cell carcinoma cells and its silencing induces apoptosis through downregulating PI3K/AKT and by up-regulating p38 MAP kinase.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26992219","citation_count":33,"is_preprint":false},{"pmid":"28462079","id":"PMC_28462079","title":"Loss of hepatic DEPTOR alters the metabolic transition to fasting.","date":"2017","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/28462079","citation_count":32,"is_preprint":false},{"pmid":"25258312","id":"PMC_25258312","title":"DEPTOR is a stemness factor that regulates pluripotency of embryonic stem cells.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25258312","citation_count":32,"is_preprint":false},{"pmid":"37469018","id":"PMC_37469018","title":"PUM1 Promotes Tumor Progression by Activating DEPTOR-Meditated Glycolysis in Gastric Cancer.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37469018","citation_count":31,"is_preprint":false},{"pmid":"30425236","id":"PMC_30425236","title":"Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30425236","citation_count":31,"is_preprint":false},{"pmid":"34519268","id":"PMC_34519268","title":"Regulation of human mTOR complexes by DEPTOR.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34519268","citation_count":30,"is_preprint":false},{"pmid":"26909318","id":"PMC_26909318","title":"Mediobasal hypothalamic overexpression of DEPTOR protects against high-fat diet-induced obesity.","date":"2015","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26909318","citation_count":30,"is_preprint":false},{"pmid":"23362262","id":"PMC_23362262","title":"Transforming growth factor β integrates Smad 3 to mechanistic target of rapamycin complexes to arrest deptor abundance for glomerular mesangial cell hypertrophy.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23362262","citation_count":30,"is_preprint":false},{"pmid":"25544749","id":"PMC_25544749","title":"DEPTOR has growth suppression activity against pancreatic cancer cells.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25544749","citation_count":29,"is_preprint":false},{"pmid":"35609371","id":"PMC_35609371","title":"DEPTOR exacerbates bone-fat imbalance in osteoporosis by transcriptionally modulating BMSC differentiation.","date":"2022","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/35609371","citation_count":27,"is_preprint":false},{"pmid":"25843797","id":"PMC_25843797","title":"DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25843797","citation_count":26,"is_preprint":false},{"pmid":"22965024","id":"PMC_22965024","title":"Protective autophagy induced by RBX1/ROC1 knockdown or CRL inactivation via modulating the DEPTOR-MTOR axis.","date":"2012","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/22965024","citation_count":26,"is_preprint":false},{"pmid":"32510855","id":"PMC_32510855","title":"miRNA-182/Deptor/mTOR axis regulates autophagy to reduce intestinal ischaemia/reperfusion injury.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32510855","citation_count":25,"is_preprint":false},{"pmid":"27224922","id":"PMC_27224922","title":"Inhibition of neddylation regulates dendritic cell functions via Deptor accumulation driven mTOR inactivation.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27224922","citation_count":25,"is_preprint":false},{"pmid":"23503641","id":"PMC_23503641","title":"Knockdown of DEPTOR induces apoptosis, increases chemosensitivity to doxorubicin and suppresses autophagy in RPMI-8226 human multiple myeloma cells in vitro.","date":"2013","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23503641","citation_count":25,"is_preprint":false},{"pmid":"29614494","id":"PMC_29614494","title":"DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29614494","citation_count":24,"is_preprint":false},{"pmid":"28932123","id":"PMC_28932123","title":"Downregulation of DEPTOR inhibits the proliferation, migration, and survival of osteosarcoma through PI3K/Akt/mTOR pathway.","date":"2017","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/28932123","citation_count":24,"is_preprint":false},{"pmid":"23613505","id":"PMC_23613505","title":"Knockdown of DEPTOR inhibits cell proliferation and increases chemosensitivity to melphalan in human multiple myeloma RPMI-8226 cells via inhibiting PI3K/AKT activity.","date":"2013","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/23613505","citation_count":24,"is_preprint":false},{"pmid":"26896556","id":"PMC_26896556","title":"Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma.","date":"2016","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/26896556","citation_count":24,"is_preprint":false},{"pmid":"25605718","id":"PMC_25605718","title":"The endosomal sorting complex required for transport pathway mediates chemokine receptor CXCR4-promoted lysosomal degradation of the mammalian target of rapamycin antagonist DEPTOR.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25605718","citation_count":24,"is_preprint":false},{"pmid":"29330362","id":"PMC_29330362","title":"Dynamic modelling of the mTOR signalling network reveals complex emergent behaviours conferred by DEPTOR.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29330362","citation_count":24,"is_preprint":false},{"pmid":"21992080","id":"PMC_21992080","title":"Placental DEPTOR as a stress sensor during pregnancy.","date":"2012","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/21992080","citation_count":23,"is_preprint":false},{"pmid":"31189691","id":"PMC_31189691","title":"Phosphoproteome Analysis Reveals Estrogen-ER Pathway as a Modulator of mTOR Activity Via DEPTOR.","date":"2019","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/31189691","citation_count":23,"is_preprint":false},{"pmid":"22454292","id":"PMC_22454292","title":"DEPTOR ubiquitination and destruction by SCF(β-TrCP).","date":"2012","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/22454292","citation_count":21,"is_preprint":false},{"pmid":"31176743","id":"PMC_31176743","title":"DEPTOR inhibits cell proliferation and confers sensitivity to dopamine agonist in pituitary adenoma.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/31176743","citation_count":21,"is_preprint":false},{"pmid":"24969890","id":"PMC_24969890","title":"DEPTOR expression negatively correlates with mTORC1 activity and tumor progression in colorectal cancer.","date":"2014","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/24969890","citation_count":21,"is_preprint":false},{"pmid":"28358054","id":"PMC_28358054","title":"Argininosuccinate Synthase 1-Deficiency Enhances the Cell Sensitivity to Arginine through Decreased DEPTOR Expression in Endometrial Cancer.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28358054","citation_count":21,"is_preprint":false},{"pmid":"27530328","id":"PMC_27530328","title":"Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27530328","citation_count":19,"is_preprint":false},{"pmid":"31710966","id":"PMC_31710966","title":"HIF-mediated Suppression of DEPTOR Confers Resistance to mTOR Kinase Inhibition in Renal Cancer.","date":"2019","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/31710966","citation_count":19,"is_preprint":false},{"pmid":"25119265","id":"PMC_25119265","title":"Elucidating the role of DEPTOR in Alzheimer's disease.","date":"2014","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25119265","citation_count":19,"is_preprint":false},{"pmid":"27655709","id":"PMC_27655709","title":"Deptor transcriptionally regulates endoplasmic reticulum homeostasis in multiple myeloma cells.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27655709","citation_count":19,"is_preprint":false},{"pmid":"21966552","id":"PMC_21966552","title":"Resveratrol inhibits mTOR signaling by targeting DEPTOR.","date":"2011","source":"Communicative & integrative biology","url":"https://pubmed.ncbi.nlm.nih.gov/21966552","citation_count":18,"is_preprint":false},{"pmid":"29670094","id":"PMC_29670094","title":"Loss of DEPTOR in renal tubules protects against cisplatin-induced acute kidney injury.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29670094","citation_count":17,"is_preprint":false},{"pmid":"25568666","id":"PMC_25568666","title":"DEPTOR is linked to a TORC1-p21 survival proliferation pathway in multiple myeloma cells.","date":"2014","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25568666","citation_count":17,"is_preprint":false},{"pmid":"34843935","id":"PMC_34843935","title":"Morin inhibits the transformation of fibroblasts towards myofibroblasts through regulating \"PPAR-γ-glutaminolysis-DEPTOR\" pathway in pulmonary fibrosis.","date":"2021","source":"The Journal of nutritional biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34843935","citation_count":17,"is_preprint":false},{"pmid":"33184290","id":"PMC_33184290","title":"DEPTOR is a direct p53 target that suppresses cell growth and chemosensitivity.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33184290","citation_count":16,"is_preprint":false},{"pmid":"34320372","id":"PMC_34320372","title":"DEPTOR inhibits lung tumorigenesis by inactivating the EGFR-mTOR signals.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34320372","citation_count":16,"is_preprint":false},{"pmid":"34224844","id":"PMC_34224844","title":"High glucose-stimulated enhancer of zeste homolog-2 (EZH2) forces suppression of deptor to cause glomerular mesangial cell pathology.","date":"2021","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/34224844","citation_count":16,"is_preprint":false},{"pmid":"29969188","id":"PMC_29969188","title":"DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation.","date":"2018","source":"American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons","url":"https://pubmed.ncbi.nlm.nih.gov/29969188","citation_count":14,"is_preprint":false},{"pmid":"28616583","id":"PMC_28616583","title":"MNK inversely regulates TELO2 vs. DEPTOR to control mTORC1 signaling.","date":"2017","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28616583","citation_count":14,"is_preprint":false},{"pmid":"33995662","id":"PMC_33995662","title":"DEPTOR stabilizes ErbB2 to promote the proliferation and survival of ErbB2-positive breast cancer cells.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33995662","citation_count":13,"is_preprint":false},{"pmid":"32702393","id":"PMC_32702393","title":"DEPTOR is a microRNA-155 target regulating migration and cytokine production in diffuse large B-cell lymphoma cells.","date":"2020","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/32702393","citation_count":13,"is_preprint":false},{"pmid":"32916025","id":"PMC_32916025","title":"DEPTOR Prevents Osteoarthritis Development Via Interplay With TRC8 to Reduce Endoplasmic Reticulum Stress in Chondrocytes.","date":"2020","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/32916025","citation_count":13,"is_preprint":false},{"pmid":"33854045","id":"PMC_33854045","title":"Nuclear ErbB2 represses DEPTOR transcription to inhibit autophagy in breast cancer cells.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33854045","citation_count":13,"is_preprint":false},{"pmid":"33865870","id":"PMC_33865870","title":"Structural Basis of DEPTOR to Recognize Phosphatidic Acid Using its Tandem DEP Domains.","date":"2021","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33865870","citation_count":13,"is_preprint":false},{"pmid":"34519269","id":"PMC_34519269","title":"Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34519269","citation_count":12,"is_preprint":false},{"pmid":"27097662","id":"PMC_27097662","title":"DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance.","date":"2016","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27097662","citation_count":12,"is_preprint":false},{"pmid":"39702468","id":"PMC_39702468","title":"Deptor protects against myocardial ischemia-reperfusion injury by regulating the mTOR signaling and autophagy.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/39702468","citation_count":11,"is_preprint":false},{"pmid":"28267437","id":"PMC_28267437","title":"Different functions of DEPTOR in modulating sensitivity to chemotherapy for esophageal squamous cell carcinoma.","date":"2017","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/28267437","citation_count":11,"is_preprint":false},{"pmid":"26742010","id":"PMC_26742010","title":"Regulator of cullins-1 expression knockdown suppresses the malignant progression of muscle-invasive transitional cell carcinoma by regulating mTOR/DEPTOR pathway.","date":"2016","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26742010","citation_count":11,"is_preprint":false},{"pmid":"26558456","id":"PMC_26558456","title":"Androgen receptor functions as a negative transcriptional regulator of DEPTOR, mTOR inhibitor.","date":"2015","source":"The Journal of toxicological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26558456","citation_count":10,"is_preprint":false},{"pmid":"34634301","id":"PMC_34634301","title":"Tyrosine phosphorylation of DEPTOR functions as a molecular switch to activate mTOR signaling.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34634301","citation_count":10,"is_preprint":false},{"pmid":"28349073","id":"PMC_28349073","title":"DEPTOR-mTOR Signaling Is Critical for Lipid Metabolism and Inflammation Homeostasis of Lymphocytes in Human PBMC Culture.","date":"2017","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/28349073","citation_count":10,"is_preprint":false},{"pmid":"26717892","id":"PMC_26717892","title":"Cul1 promotes melanoma cell proliferation by promoting DEPTOR degradation and enhancing cap-dependent translation.","date":"2015","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/26717892","citation_count":9,"is_preprint":false},{"pmid":"28916338","id":"PMC_28916338","title":"Structure-activity relationship study of small molecule inhibitors of the DEPTOR-mTOR interaction.","date":"2017","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/28916338","citation_count":9,"is_preprint":false},{"pmid":"34644502","id":"PMC_34644502","title":"Design, Synthesis, and Biological Evaluation of Icaritin Derivatives as Novel Putative DEPTOR Inhibitors for Multiple Myeloma Treatment.","date":"2021","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34644502","citation_count":9,"is_preprint":false},{"pmid":"31395691","id":"PMC_31395691","title":"A Novel Therapeutic Induces DEPTOR Degradation in Multiple Myeloma Cells with Resulting Tumor Cytotoxicity.","date":"2019","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/31395691","citation_count":8,"is_preprint":false},{"pmid":"32934682","id":"PMC_32934682","title":"Metformin attenuates renal interstitial fibrosis through upregulation of Deptor in unilateral ureteral obstruction in rats.","date":"2020","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32934682","citation_count":8,"is_preprint":false},{"pmid":"27144580","id":"PMC_27144580","title":"Chemopreventive Effect of Dietary Glutamineon Colitis-Associated Colorectal Cancer Is Associated with Modulation of the DEPTOR/mTOR Signaling Pathway.","date":"2016","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/27144580","citation_count":8,"is_preprint":false},{"pmid":"33416146","id":"PMC_33416146","title":"Regulatory role of DEPTOR‑mediated cellular autophagy and mitochondrial reactive oxygen species in angiogenesis in multiple myeloma.","date":"2020","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33416146","citation_count":7,"is_preprint":false},{"pmid":"35216969","id":"PMC_35216969","title":"Turnover of the mTOR inhibitor, DEPTOR, and downstream AKT phosphorylation in multiple myeloma cells, is dependent on ERK1-mediated phosphorylation.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35216969","citation_count":6,"is_preprint":false},{"pmid":"27179948","id":"PMC_27179948","title":"p65 down-regulates DEPTOR expression in response to LPS stimulation in hepatocytes.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27179948","citation_count":6,"is_preprint":false},{"pmid":"36090478","id":"PMC_36090478","title":"Stabilization of DEPTOR sensitizes hypopharyngeal cancer to radiotherapy via targeting degradation.","date":"2022","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/36090478","citation_count":6,"is_preprint":false},{"pmid":"33477144","id":"PMC_33477144","title":"Downregulation of miR-96-5p Inhibits mTOR/NF-κb Signaling Pathway via DEPTOR in Allergic Rhinitis.","date":"2021","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33477144","citation_count":6,"is_preprint":false},{"pmid":"33412518","id":"PMC_33412518","title":"Function of Deptor and its roles in hematological malignancies.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33412518","citation_count":5,"is_preprint":false},{"pmid":"40042094","id":"PMC_40042094","title":"Trophoblast-specific Deptor knockdown enhances trophoblast nutrient transport and fetal growth in mice.","date":"2025","source":"Acta physiologica (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40042094","citation_count":5,"is_preprint":false},{"pmid":"26871578","id":"PMC_26871578","title":"DEPTOR promoter genetic variants and insulin resistance in obese children and adolescents.","date":"2016","source":"Pediatric diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/26871578","citation_count":5,"is_preprint":false},{"pmid":"38365163","id":"PMC_38365163","title":"miR-193b-5p promotes GCRV replication by inhibiting autophagy via targeting deptor in grass carp (Ctenopharyngodon idellus).","date":"2024","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38365163","citation_count":5,"is_preprint":false},{"pmid":"34122519","id":"PMC_34122519","title":"DEPTOR in Skeletal Development and Diseases.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34122519","citation_count":4,"is_preprint":false},{"pmid":"36535626","id":"PMC_36535626","title":"DEPTOR loss impairs brown adipocyte development in vitro but has limited impacts in mice.","date":"2022","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/36535626","citation_count":4,"is_preprint":false},{"pmid":"39533404","id":"PMC_39533404","title":"DEPTOR attenuates asthma progression by suppressing endoplasmic reticulum stress through SOD1.","date":"2024","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/39533404","citation_count":4,"is_preprint":false},{"pmid":"40133007","id":"PMC_40133007","title":"Lentivirus-Mediated Trophoblast-Specific Deptor Knockdown Increases Transplacental System A and System L Amino Acid Transport and Fetal Growth in Mice.","date":"2025","source":"Function (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40133007","citation_count":4,"is_preprint":false},{"pmid":"34431457","id":"PMC_34431457","title":"Exploring novel and potent molecules for disrupting DEPTOR-mTOR interaction through structure-steered screening, extra-exactitude molecular docking, prime binding free energy estimation and voguish molecular dynamics.","date":"2021","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/34431457","citation_count":4,"is_preprint":false},{"pmid":"35923131","id":"PMC_35923131","title":"DFNA5 inhibits colorectal cancer proliferation by suppressing the mTORC1/2 signaling pathways via upregulation of DEPTOR.","date":"2022","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/35923131","citation_count":4,"is_preprint":false},{"pmid":"32376551","id":"PMC_32376551","title":"[MicroRNA-671-3p suppresses proliferation and invasion of breast cancer cells by targeting DEPTOR].","date":"2020","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/32376551","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50169,"output_tokens":9255,"usd":0.144666,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19845,"output_tokens":5197,"usd":0.114575,"stage2_stop_reason":"end_turn"},"total_usd":0.259241,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"DEPTOR directly interacts with mTOR and functions as an endogenous inhibitor of both mTORC1 and mTORC2 kinase activities. Loss of DEPTOR activates S6K1, Akt, and SGK1, while DEPTOR overexpression suppresses S6K1 but, by relieving mTORC1-to-PI3K feedback inhibition, activates Akt.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, overexpression with downstream signaling readouts (S6K1, Akt, SGK1 phosphorylation)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, loss-of-function and gain-of-function with multiple orthogonal downstream readouts; foundational paper replicated extensively by independent labs\",\n      \"pmids\": [\"19446321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DEPTOR is a physiological substrate of SCF(βTrCP) E3 ubiquitin ligase. Upon growth factor stimulation, RSK1 and S6K1 phosphorylate DEPTOR, enabling recognition by βTrCP via its degron sequence, leading to ubiquitination and proteasomal degradation. DEPTOR half-life is shortened by βTrCP and extended by a dominant-negative βTrCP mutant or RSK1/S6K1 inhibition.\",\n      \"method\": \"In vitro ubiquitination assay, co-immunoprecipitation, dominant-negative mutant expression, degron site mutagenesis, half-life measurement\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of ubiquitination, mutagenesis of degron, replicated independently by two concurrent papers (PMID:22017875, 22017877)\",\n      \"pmids\": [\"22017876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"mTOR and casein kinase I (CKI) cooperate to phosphorylate DEPTOR, generating a phosphodegron recognized by βTrCP, driving SCF(βTrCP)-dependent proteasomal degradation. This creates a positive feedback loop in which mTOR promotes its own activation by destroying its inhibitor DEPTOR.\",\n      \"method\": \"Phosphorylation assays, co-immunoprecipitation, βTrCP depletion, degron mutation, mTOR inhibitor treatment with signaling readouts\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation assay, mutagenesis, replicated by two concurrent independent labs (PMID:22017876, 22017877)\",\n      \"pmids\": [\"22017875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DEPTOR is phosphorylated on three serines in a conserved degron by CK1α (after a priming phosphorylation by mTORC1 or mTORC2) in response to mitogens, facilitating binding and ubiquitylation by βTrCP and consequent proteasomal degradation. Blocking this pathway via βTrCP knockdown or a stable DEPTOR mutant unable to bind βTrCP results in mTOR inhibition.\",\n      \"method\": \"Phosphorylation-site mapping, mutagenesis, βTrCP knockdown, stable mutant expression, CK1α involvement established by kinase assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis, in vitro kinase assays, replicated by two concurrent independent labs (PMID:22017875, 22017876)\",\n      \"pmids\": [\"22017877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR. The inhibitory effect of RSV on leucine-stimulated mTORC1 activation was greatly reduced when DEPTOR was suppressed by RNAi, establishing DEPTOR-dependence of this mechanism.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, pharmacological treatment with downstream signaling readouts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP showing enhanced mTOR/DEPTOR association plus RNAi epistasis, single lab, two orthogonal methods\",\n      \"pmids\": [\"20851890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM and biochemical analysis revealed that both structured regions of DEPTOR — the PDZ domain and the DEP domain tandem (DEPt) — engage mTOR. The PDZ domain binds with a mildly activating effect and acts as an anchor for DEPt, which allosterically suppresses mTOR activation. DEPTOR is itself phosphorylated by mTOR in a substrate-like mode, rationalizing inhibition of non-stimulated mTOR at higher DEPTOR concentrations.\",\n      \"method\": \"Cryo-EM structure determination, biochemical binding assays, domain mutagenesis, kinase assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structural determination combined with biochemical and mutagenesis validation in a single rigorous study; independently corroborated by concurrent structural paper PMID:34519269\",\n      \"pmids\": [\"34519268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Reconstitution of mTORC1 with DEPTOR showed DEPTOR is a partial inhibitor of mTORC1. DEPTOR's PDZ domain interacts with the mTOR FAT region and the unstructured linker preceding the PDZ binds the mTOR FRB domain. The linker and PDZ form the minimal inhibitory unit; the N-terminal tandem DEP domains also contribute. mTORC1 activated by RHEB or oncogenic mutation is more potently inhibited by DEPTOR. mTORC1 prevents DEPTOR inhibition by phosphorylating DEPTOR (mutual antagonism).\",\n      \"method\": \"In vitro reconstitution, structural analysis, domain mutagenesis, kinase assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with structural analyses and mutagenesis, two concurrent independent structural papers (PMID:34519268)\",\n      \"pmids\": [\"34519269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structure (1.5 Å) of DEPTOR's N-terminal tandem DEP domains shows a dumbbell-shaped structure with an 18-amino-acid DDEX motif at the end of DEP2 that interacts with DEP1 to stabilize the structure. Biochemical studies showed the tandem DEP domains directly interact with phosphatidic acid via two distinct positively charged patches, providing a structural basis for DEPTOR dissociation from mTORC1 upon phosphatidic acid stimulation.\",\n      \"method\": \"X-ray crystallography (1.5 Å resolution), biochemical binding assays with phosphatidic acid\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure combined with biochemical validation of lipid binding\",\n      \"pmids\": [\"33865870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"OTUB1 directly interacts with DEPTOR via its N-terminal domain and deubiquitinates DEPTOR to stabilize it, in a Cys-91-independent but Asp-88-dependent (non-canonical) manner. The OTUB1-DEPTOR interaction is enhanced by amino acid treatment. OTUB1 suppresses amino acid-induced mTORC1 activation in a DEPTOR-dependent manner, thereby controlling autophagy, cell proliferation, and cell size.\",\n      \"method\": \"Deubiquitination assay, co-immunoprecipitation, domain mutagenesis (Cys-91, Asp-88), siRNA knockdown with signaling readouts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro deubiquitination assay plus reciprocal Co-IP and mutagenesis, single lab\",\n      \"pmids\": [\"29382726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"p38γ and p38δ phosphorylate DEPTOR, leading to its degradation and subsequent mTOR activation, thereby promoting cardiac hypertrophy. Hearts from mice lacking p38γ/δ have high DEPTOR levels and low mTOR pathway activity. shRNA-mediated knockdown of Deptor reverted the small-heart phenotype of p38γ/δ knockout mice.\",\n      \"method\": \"In vivo mouse knockout model, shRNA knockdown, cardiomyocyte-specific overexpression, phosphorylation assays, genetic epistasis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double knockout rescue, in vivo KO with defined cardiac phenotype, multiple orthogonal methods across independent experiments\",\n      \"pmids\": [\"26795633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBE2C couples with APC/C(CDH1) E3 ligase to promote ubiquitylation and degradation of DEPTOR, leading to mTORC signaling activation and promotion of cell cycle progression. KrasG12D-induced UBE2C expression drives DEPTOR degradation; Deptor deletion fully rescued the tumor inhibitory effect of Ube2c deletion in a KrasG12D lung tumor model, establishing DEPTOR as the key downstream effector.\",\n      \"method\": \"Ubiquitination assay, co-immunoprecipitation, genetic mouse models (Ube2c deletion, Deptor deletion, KrasG12D), epistasis rescue experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with Deptor deletion rescuing Ube2c KO phenotype, combined with biochemical ubiquitination assays; multiple orthogonal methods\",\n      \"pmids\": [\"36548081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DEPTOR functions as a nuclear protein in multiple myeloma cells, capable of binding DNA and regulating transcription. Nuclear DEPTOR sustains expression of genes involved in the ER network, and DEPTOR depletion induces ER stress and synergizes with proteasome inhibitor bortezomib.\",\n      \"method\": \"Subcellular fractionation, chromatin immunoprecipitation, siRNA knockdown, ER stress marker analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation plus ChIP demonstrating nuclear localization and DNA binding, single lab, two orthogonal methods\",\n      \"pmids\": [\"27655709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The ESCRT pathway mediates CXCR4-promoted lysosomal degradation of DEPTOR. CXCR4 stimulates DEPTOR degradation via Gαi and PI3K signaling and via the ESCRT machinery; depletion of ESCRTs by siRNA leads to increased DEPTOR levels and attenuated CXCR4-promoted Akt activation, consistent with decreased mTORC2 activity.\",\n      \"method\": \"siRNA knockdown of ESCRT components, pharmacological inhibition of Gαi and PI3K, western blot for DEPTOR levels and Akt phosphorylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis with pharmacological confirmation, single lab, two orthogonal approaches\",\n      \"pmids\": [\"25605718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TGF-β-stimulated Smad3 acts as a key node to suppress DEPTOR abundance, thereby releasing mTORC1/2 inhibition and driving mesangial cell hypertrophy. Sustained (not acute) mTOR activation is required for DEPTOR suppression. Knockdown of Smad3 prevented TGF-β-induced DEPTOR suppression; overexpression of Smad3 decreased DEPTOR; knockdown of DEPTOR reversed Smad7-mediated inhibition of TGF-β-induced hypertrophy.\",\n      \"method\": \"siRNA knockdown, overexpression, mTOR inhibitor (PP242), western blot for DEPTOR levels and mTORC1/2 activity, protein synthesis and cell size assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via siRNA plus pharmacological inhibition, single lab, multiple orthogonal manipulations\",\n      \"pmids\": [\"23362262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GNMT (glycine N-methyltransferase) interacts with DEPTOR/DEPDC6; FRET assay demonstrated that the C-terminal half of GNMT interacts with the PDZ domain of DEPDC6/DEPTOR.\",\n      \"method\": \"Yeast two-hybrid screening, fluorescence resonance energy transfer (FRET) assay, knockdown and overexpression with signaling readouts\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET plus yeast two-hybrid with domain mapping, single lab\",\n      \"pmids\": [\"22160218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Baf60c induces expression of DEPTOR via the Baf60c-Six4 transcriptional complex, and DEPTOR then mediates activation of Akt (by relieving mTORC1 negative feedback to PI3K) and glycolytic metabolism in a cell-autonomous manner in skeletal muscle.\",\n      \"method\": \"Transgenic muscle-specific overexpression, ChIP for Baf60c-Six4 binding to Deptor promoter, siRNA knockdown epistasis, metabolic phenotyping in vivo\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model plus ChIP and cell-autonomous epistasis with multiple orthogonal readouts\",\n      \"pmids\": [\"23563706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tyrosine 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. SYK (spleen tyrosine kinase) was identified as the kinase responsible for DEPTOR Tyr289 phosphorylation in an ephrin receptor-dependent manner, as established by proximity biotinylation assays and functional validation.\",\n      \"method\": \"Site-directed mutagenesis (Y289), proximity biotinylation (BioID), co-immunoprecipitation, pharmacological inhibition, mTOR signaling readouts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of phosphorylation site combined with proximity biotinylation identification of kinase, single lab\",\n      \"pmids\": [\"34634301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ERK1 phosphorylates DEPTOR at serine 235 (S235), regulating DEPTOR stability. An S235 phosphomimetic DEPTOR mutant was resistant to proteasomal degradation. S235 phosphorylation enables USP-7 deubiquitinase association with DEPTOR; inhibition of USP-7 results in DEPTOR polyubiquitination and degradation. ERK1-mediated S235 phosphorylation of DEPTOR maintains Akt activity in multiple myeloma cells.\",\n      \"method\": \"In vitro kinase assay (ERK1), mutagenesis (S235A and S235D), co-immunoprecipitation for USP-7, proteasome inhibitor rescue, ERK1 knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis confirming S235 regulation, single lab\",\n      \"pmids\": [\"35216969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NOTCH1 directly binds to and activates the human DEPTOR promoter in T-ALL cells, transcriptionally upregulating DEPTOR expression. DEPTOR depletion inhibited Akt activation, abolished cellular proliferation, attenuated glycolytic metabolism, and enhanced cell death in T-ALL cells.\",\n      \"method\": \"Chromatin immunoprecipitation, NOTCH1 overexpression/knockdown with DEPTOR promoter reporter, siRNA knockdown with proliferation/metabolism/apoptosis readouts, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct NOTCH1 binding to DEPTOR promoter, combined with functional knockdown experiments, single lab\",\n      \"pmids\": [\"27593934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DEPTOR directly interacts with c-Myc (via Wnt/β-catenin/c-Myc signaling), and c-Myc binds the DEPTOR promoter to transcriptionally regulate DEPTOR expression in colorectal cancer cells. Inhibition of Wnt/β-catenin or c-Myc knockdown decreased DEPTOR expression; c-Myc overexpression increased it.\",\n      \"method\": \"Chromatin immunoprecipitation (c-Myc binding to DEPTOR promoter), siRNA/shRNA knockdown, luciferase reporter, in vitro and in vivo tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing direct c-Myc binding to DEPTOR promoter, combined with loss/gain-of-function and reporter assays, single lab\",\n      \"pmids\": [\"29666061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"p53 directly binds to the DEPTOR promoter and transactivates DEPTOR expression. Deletion of the p53-binding site on the DEPTOR promoter by CRISPR-Cas9 decreases DEPTOR expression and promotes cell proliferation via Akt signaling. Upon doxorubicin treatment, p53 induces DEPTOR expression leading to cancer cell resistance.\",\n      \"method\": \"Chromatin immunoprecipitation, CRISPR-Cas9 deletion of p53-binding site, luciferase reporter, western blot for downstream signaling\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus CRISPR-Cas9 functional deletion of binding site, single lab, two orthogonal methods\",\n      \"pmids\": [\"33184290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Androgen receptor (AR) functions as a negative transcriptional regulator of DEPTOR. DHT treatment repressed DEPTOR mRNA in LNCaP cells in a time-dependent manner, reversed by the AR antagonist bicalutamide. ChIP assay demonstrated AR binds to an AR-responsive element-like region within the 4th intron of the DEPTOR gene, accompanied by reduced acetylated histone H3.\",\n      \"method\": \"RT-PCR, ChIP assay, pharmacological (DHT, bicalutamide), siRNA knockdown with mTORC1 readouts\",\n      \"journal\": \"The Journal of toxicological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing direct AR binding to DEPTOR gene, combined with pharmacological manipulation, single lab\",\n      \"pmids\": [\"26558456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"p65/NF-κB directly binds the DEPTOR promoter at a -145/-127 region and represses DEPTOR transcription in response to LPS stimulation. Progressive deletions and mutations of the promoter, plus ChIP assays, confirmed this NF-κB binding site is essential for DEPTOR promoter activity.\",\n      \"method\": \"Chromatin immunoprecipitation, promoter deletion/mutation analysis, luciferase reporter, NF-κB inhibitor (PDTC) and IκBα overexpression\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus promoter mutagenesis with reporter assay, single lab\",\n      \"pmids\": [\"27179948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TNFAIP3 (A20) interacts with and stabilizes DEPTOR via its zinc-finger domains; the TNFAIP3-DEPTOR complex rapidly promotes autophagy after LPS treatment to prevent NLRP3 inflammasome formation in monocytes. This interaction was established by GST pull-down, yeast two-hybrid, confocal microscopy, and co-immunoprecipitation.\",\n      \"method\": \"GST pull-down, yeast two-hybrid, co-immunoprecipitation, confocal microscopy, siRNA knockdown with autophagy and inflammasome readouts\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding assays (GST pull-down, co-IP, Y2H) plus functional epistasis, single lab\",\n      \"pmids\": [\"29940800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DEPTOR directly interacts with ErbB2 at the cell membrane, disrupting ErbB2 polyubiquitination and degradation by β-TrCP. DEPTOR knockdown destabilizes ErbB2, shortens its protein half-life, and inactivates ErbB2-PI3K-AKT-mTOR signaling. A constitutively active ErbB2 mutant fully rescued the reduction in cell proliferation and survival caused by DEPTOR knockdown.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, subcellular fractionation, ubiquitination assay, half-life measurement, constitutively active mutant rescue, siRNA knockdown\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with subcellular fractionation and ubiquitination assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33995662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nuclear ErbB2 directly binds to a consensus sequence in the DEPTOR promoter to repress its transcription. ErbB2 kinase activity is required for its nuclear translocation and transcriptional repression of DEPTOR. Repression of DEPTOR by nuclear ErbB2 inhibits autophagy induction by activating mTORC1.\",\n      \"method\": \"Chromatin immunoprecipitation, ErbB2 nuclear translocation experiments (kinase-dead mutant), DEPTOR promoter reporter, autophagy assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus kinase-dead mutant demonstrating kinase requirement, single lab\",\n      \"pmids\": [\"33854045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DEPTOR binds transcriptional coactivator TAZ and inhibits its transactivation properties, thereby repressing RUNX2 transcriptional activity and elevating PPARγ gene transcription in BMSCs, promoting adipogenesis over osteogenesis. TAZ knockdown in BMSCs abolished the beneficial effects of Deptor ablation on bone-fat balance in mice.\",\n      \"method\": \"Co-immunoprecipitation, TAZ knockdown epistasis, in vivo mouse model of osteoporosis, western blot for RUNX2/PPARγ targets\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing DEPTOR-TAZ interaction plus TAZ epistasis rescue, single lab\",\n      \"pmids\": [\"35609371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DEPTOR interplays with TRC8 E3 ubiquitin ligase in chondrocytes, promoting TRC8 auto-ubiquitination and TRC8 degradation by the ubiquitin-proteasome system. Loss of DEPTOR leads to TRC8 accumulation, excessive ER stress, chondrocyte apoptosis, and osteoarthritis progression, independent of mTOR signaling.\",\n      \"method\": \"Proteomics analysis, co-immunoprecipitation, ubiquitination assay, conditional DEPTOR knockout mice, intra-articular lentivirus injection, ER stress inhibitor rescue\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo conditional KO with ER stress inhibitor epistasis, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"32916025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DEPTOR expression in CD4+ T regulatory cells stabilizes Foxp3 expression, shifts metabolism toward oxidative phosphorylation, increases Treg survival and suppressive function. In vivo, induced DEPTOR expression in CD4+ T regulatory cells (not effectors) mediates prolonged cardiac allograft survival in a fully MHC-mismatched transplant model.\",\n      \"method\": \"Conditional knock-in mouse model, in vitro T cell differentiation/metabolism assays, in vivo cardiac allograft transplant model, Foxp3 stability analysis\",\n      \"journal\": \"American journal of transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knock-in model with defined immunological phenotype and metabolic readouts, single lab\",\n      \"pmids\": [\"29969188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Liver-specific DEPTOR knockout mice showed sustained mTORC1 activation upon fasting and a reduction in circulating glucose and hepatic glycogen during fasting. Acute rapamycin treatment normalized glycemia, establishing that hepatic DEPTOR accelerates mTORC1 inhibition during the transition to fasting. Loss of DEPTOR also increased oxidative metabolism in hepatocytes, associated with increased cytochrome c expression.\",\n      \"method\": \"Conditional knockout mouse model (Albumin-cre), metabolic phenotyping, rapamycin rescue experiment, hepatocyte oxidative metabolism assays\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined metabolic phenotype and pharmacological rescue, single lab\",\n      \"pmids\": [\"28462079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DEPTOR is a stemness factor that maintains pluripotency in embryonic stem cells by limiting mTOR activity. DEPTOR levels dramatically decrease with ESC differentiation, and knockdown of DEPTOR is sufficient to promote ESC differentiation, accompanied by a corresponding increase in mTORC1 activity.\",\n      \"method\": \"shRNA knockdown, western blot for DEPTOR and mTORC1 activity during differentiation, pluripotency marker analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined differentiation phenotype correlated with mTORC1 activation, single lab\",\n      \"pmids\": [\"25258312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DEPTOR directly binds to the kinase domain of EGFR via its PDZ domain to inactivate EGFR signaling. DEPTOR depletion not only directly activates mTORC1/2 but also relieves EGFR inhibition, further activating mTOR signals and inducing EMT via ZEB1 and SLUG upregulation. In vivo, Deptor deletion accelerated KrasG12D;p53fl/fl-induced lung tumorigenesis via EGFR-mTOR signals.\",\n      \"method\": \"Co-immunoprecipitation (PDZ domain binding to EGFR kinase domain), domain mutagenesis, in vivo KrasG12D;p53fl/fl;Deptor-KO mouse model, signaling readouts\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus in vivo genetic model, single lab\",\n      \"pmids\": [\"34320372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DEPTOR depletion in prostate cancer cells activates both mTORC1 and mTORC2, induces AKT-dependent EMT, and promotes β-catenin nuclear translocation. In a Deptor-KO mouse model, Deptor knockout accelerated Pten loss-induced prostate tumorigenesis via mTOR signaling activation. Abrogation of mTOR or AKT activation rescued the biological consequences of DEPTOR depletion.\",\n      \"method\": \"Conditional knockout mouse model (Deptor-KO x Pten-loss), siRNA knockdown, pharmacological inhibitors of mTOR and AKT as epistasis tools, migration/invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis in mouse tumor model plus pharmacological rescue, single lab\",\n      \"pmids\": [\"31685947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RPS27L silencing shortens the protein half-life of β-TrCP (the DEPTOR E3 ligase receptor), leading to DEPTOR accumulation, mTORC1 inactivation, and autophagy induction. Simultaneous DEPTOR silencing partially rescued mTORC1 inactivation and autophagy caused by RPS27L loss, establishing DEPTOR as a causal mediator of this pathway.\",\n      \"method\": \"siRNA knockdown, half-life measurement of β-TrCP, DEPTOR and mTORC1 signaling readouts, double knockdown epistasis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiment (double knockdown rescue) plus mechanistic half-life measurements, single lab\",\n      \"pmids\": [\"30425236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DEPTOR is a cell-autonomous pro-adipogenic factor. DEPTOR is induced by glucocorticoids during adipogenesis, and its overexpression promotes while its suppression blocks adipogenesis. DEPTOR activates the proadipogenic Akt/PKB-PPARγ axis by dampening mTORC1-mediated negative feedback inhibition of insulin signaling.\",\n      \"method\": \"Transgenic mouse overexpression model, siRNA knockdown, adipogenesis assays, signaling readouts for Akt/PPARγ, glucocorticoid treatment\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model combined with in vitro loss-of-function and mechanistic signaling studies, single lab\",\n      \"pmids\": [\"22883231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Trophoblast-specific Deptor knockdown activates placental mTORC1 and mTORC2 signaling, increases trophoblast plasma membrane LAT1 and SNAT2 amino acid transporter expression and activity, and stimulates in vivo transplacental system A and L amino acid transport and fetal growth. In human FGR placentas, DEPTOR protein expression is higher and negatively correlated with birth weight and system A amino acid transporter activity.\",\n      \"method\": \"Lentiviral shRNA trophoblast-specific knockdown in mice, mTOR signaling readouts, transporter expression/activity assays, in vivo transplacental transport measurement\",\n      \"journal\": \"Function (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — trophoblast-specific in vivo KD with functional transport assays and signaling readouts, single lab, corroborated by concurrent independent paper (PMID:40042094)\",\n      \"pmids\": [\"40133007\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DEPTOR is a constitutive inhibitory subunit of both mTORC1 and mTORC2 that binds mTOR through a bipartite interface involving its PDZ domain (contacting the FAT region) and DEP domain tandem (allosterically suppressing kinase activation); it is regulated by a phosphorylation-driven destruction cycle in which mTOR, CK1α, RSK1, S6K1, p38γ/δ, and ERK1 sequentially phosphorylate DEPTOR to generate a phosphodegron recognized by the SCF(βTrCP) E3 ligase for ubiquitination and proteasomal degradation, while OTUB1 and USP-7 (stabilized by S235 phosphorylation) antagonize this destruction; additional non-canonical interactions include binding to EGFR (via PDZ domain), ErbB2, TAZ, TRC8, and TNFAIP3, nuclear localization with transcriptional regulatory activity, and sensitivity to phosphatidic acid at its tandem DEP domains, collectively positioning DEPTOR as a multifunctional hub that coordinates mTOR activity with PI3K/Akt feedback, autophagy, adipogenesis, cardiac hypertrophy, immune function, placental nutrient transport, and stem cell pluripotency.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DEPTOR is an endogenous inhibitory subunit of both mTORC1 and mTORC2 that sets the cellular threshold for mTOR signaling and the PI3K/Akt feedback loop downstream of it [#0]. It engages mTOR through a bipartite interface: a PDZ domain (with its preceding unstructured linker) binds the mTOR FAT and FRB regions and acts as an anchor, while the N-terminal tandem DEP domains allosterically suppress kinase activation, with mTORC1 reciprocally phosphorylating DEPTOR in a substrate-like mode to relieve inhibition [#5, #6, #7]. Loss of DEPTOR activates S6K1, Akt, and SGK1, whereas its accumulation suppresses mTORC1 and, by relieving mTORC1-to-PI3K feedback, can paradoxically activate Akt [#0]. DEPTOR abundance is governed by a phosphorylation-driven destruction cycle: priming by mTOR followed by CK1\\u03b1, together with RSK1, S6K1, p38\\u03b3/\\u03b4 and ERK1, generates a phosphodegron recognized by SCF(\\u03b2TrCP) for ubiquitination and proteasomal degradation, creating a positive feedback loop in which active mTOR destroys its own inhibitor [#1, #2, #3, #9, #17]; APC/C(CDH1) via UBE2C provides an additional degradative input, while OTUB1 and USP-7 (the latter recruited upon ERK1-mediated S235 phosphorylation) deubiquitinate and stabilize DEPTOR [#10, #8, #17]. The tandem DEP domains also bind phosphatidic acid, providing a lipid-sensing route for DEPTOR dissociation from mTORC1 [#7]. Through these activities DEPTOR controls autophagy, adipogenesis, cardiac and mesangial hypertrophy, hepatic fasting metabolism, embryonic stem cell pluripotency, regulatory T cell function, and placental amino acid transport and fetal growth [#9, #23, #29, #30, #28, #34, #35]. Beyond its mTOR-centered role, DEPTOR also acts as a nuclear DNA-binding transcriptional regulator and engages non-canonical partners including EGFR and ErbB2 (via its PDZ domain), TAZ, and the E3 ligase TRC8 in mTOR-independent functions [#11, #31, #24, #26, #27]. Its expression is set by a wide transcriptional network including NOTCH1, c-Myc, p53, androgen receptor, NF-\\u03baB, and the Baf60c-Six4 complex [#18, #19, #20, #21, #22, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established the founding mechanistic identity of DEPTOR as an mTOR-binding protein that inhibits both mTOR complexes, defining its place in the mTOR/PI3K/Akt signaling axis.\",\n      \"evidence\": \"Reciprocal Co-IP with mTOR plus RNAi and overexpression read out on S6K1, Akt, and SGK1 phosphorylation\",\n      \"pmids\": [\"19446321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of inhibition not defined\", \"Did not resolve how DEPTOR levels are regulated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how DEPTOR levels are controlled, showing growth factor signaling triggers SCF(\\u03b2TrCP)-mediated degradation through a multi-kinase phosphodegron, creating a feedback loop coupling mTOR activity to destruction of its own inhibitor.\",\n      \"evidence\": \"In vitro ubiquitination and kinase assays, degron mutagenesis, \\u03b2TrCP depletion and dominant-negative expression, half-life measurement (three concurrent independent papers; kinases RSK1, S6K1, mTOR priming, CK1\\u03b1)\",\n      \"pmids\": [\"22017876\", \"22017875\", \"22017877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address deubiquitinating opposition to degradation\", \"In vivo physiological relevance of the loop not yet tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked a pharmacological mTOR inhibitor to DEPTOR, showing resveratrol acts in part by promoting the mTOR-DEPTOR interaction.\",\n      \"evidence\": \"Co-IP showing enhanced mTOR/DEPTOR association plus RNAi epistasis on leucine-stimulated mTORC1\",\n      \"pmids\": [\"20851890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which resveratrol enhances binding unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a physiological output of DEPTOR by showing it is a pro-adipogenic factor that activates the Akt-PPAR\\u03b3 axis through relief of mTORC1 feedback.\",\n      \"evidence\": \"Transgenic overexpression, siRNA knockdown, adipogenesis and signaling assays with glucocorticoid induction\",\n      \"pmids\": [\"22883231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional partners in adipocytes not defined here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected upstream signaling to DEPTOR abundance in tissue hypertrophy, showing TGF-\\u03b2/Smad3 and Baf60c-Six4 transcriptionally set DEPTOR levels to tune mTOR output and metabolism.\",\n      \"evidence\": \"siRNA/overexpression epistasis with mTOR inhibitor in mesangial cells; transgenic muscle model plus ChIP for the Baf60c-Six4 complex on the Deptor promoter\",\n      \"pmids\": [\"23362262\", \"23563706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How multiple transcriptional inputs are integrated unknown\", \"Tissue-specific relevance of each input untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended DEPTOR function to stem cell biology, showing it maintains pluripotency by restraining mTOR activity.\",\n      \"evidence\": \"shRNA knockdown with pluripotency markers and mTORC1 activity during ESC differentiation\",\n      \"pmids\": [\"25258312\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking mTOR restraint to pluripotency network not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified non-degradative and non-cytoplasmic functions \\u2014 a p38\\u03b3/\\u03b4 degradation route driving cardiac hypertrophy, and a nuclear DNA-binding transcriptional role sustaining the ER gene network.\",\n      \"evidence\": \"In vivo p38\\u03b3/\\u03b4 knockout with shRNA rescue of cardiac phenotype; subcellular fractionation and ChIP in myeloma cells\",\n      \"pmids\": [\"26795633\", \"27655709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear DEPTOR DNA-binding specificity and direct targets incompletely mapped\", \"Relationship between nuclear and mTOR-bound pools unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the stabilizing arm of DEPTOR turnover and additional protein partners, with OTUB1 and TNFAIP3 stabilizing DEPTOR to control mTORC1, autophagy, and inflammasome activity.\",\n      \"evidence\": \"In vitro deubiquitination, GST pull-down, Y2H, Co-IP, and confocal microscopy with functional autophagy/inflammasome readouts\",\n      \"pmids\": [\"29382726\", \"29940800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-canonical OTUB1 catalytic mechanism on DEPTOR not fully resolved\", \"Single lab for each partner\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Delivered the structural mechanism of inhibition: cryo-EM, reconstitution, and crystallography showed a bipartite PDZ-plus-tandem-DEP engagement of mTOR, substrate-like phosphorylation by mTOR, and phosphatidic acid binding by the DEP domains as a dissociation switch.\",\n      \"evidence\": \"Cryo-EM and in vitro reconstitution of mTORC1 with DEPTOR (two concurrent papers), 1.5 \\u00c5 crystal structure of tandem DEP domains with lipid-binding assays\",\n      \"pmids\": [\"34519268\", \"34519269\", \"33865870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of DEPTOR bound within intact mTORC2 not resolved\", \"Cellular conditions controlling phosphatidic-acid-driven dissociation untested in vivo\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the regulatory and non-canonical interaction repertoire, identifying SYK/ephrin-driven Tyr289 phosphorylation that weakens mTOR binding, and PDZ-mediated control of EGFR and ErbB2 receptor signaling and stability.\",\n      \"evidence\": \"Site mutagenesis with BioID; Co-IP with domain mapping, subcellular fractionation, ubiquitination assays, and in vivo Kras;p53 lung tumor models\",\n      \"pmids\": [\"34634301\", \"34320372\", \"33995662\", \"33854045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between receptor-binding and mTOR-inhibitory pools unclear\", \"Single lab for each interaction\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the transcriptional network setting DEPTOR levels (NOTCH1, c-Myc, p53, androgen receptor, NF-\\u03baB) and defined ERK1-S235 phosphorylation that recruits USP-7 to stabilize DEPTOR, plus a TAZ-binding adipogenic mechanism.\",\n      \"evidence\": \"ChIP, promoter reporters, and CRISPR binding-site deletion across multiple cancer models; in vitro ERK1 kinase assay with phosphomimetic mutants and USP-7 Co-IP; Co-IP and epistasis for TAZ\",\n      \"pmids\": [\"27593934\", \"29666061\", \"33184290\", \"26558456\", \"27179948\", \"35216969\", \"35609371\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How competing transcriptional inputs are integrated in a given cell type unknown\", \"Each regulatory link rests on a single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established DEPTOR as the key downstream effector of additional degradation machinery in vivo, with APC/C(CDH1)/UBE2C-driven turnover required for Kras-induced tumorigenesis.\",\n      \"evidence\": \"Ubiquitination assays plus genetic mouse epistasis (Deptor deletion rescuing Ube2c-loss phenotype in KrasG12D lung tumors)\",\n      \"pmids\": [\"36548081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-cycle timing of APC/C-dependent DEPTOR turnover not resolved\", \"Relationship to the \\u03b2TrCP route during tumorigenesis unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated an organismal physiological role at the maternal-fetal interface, with trophoblast DEPTOR restraining placental mTOR signaling, amino acid transport, and fetal growth, and elevated DEPTOR in human fetal growth restriction.\",\n      \"evidence\": \"Trophoblast-specific shRNA knockdown in mice with transporter activity and transplacental transport assays, plus human FGR placental correlation (corroborated by concurrent paper)\",\n      \"pmids\": [\"40133007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal direction of elevated DEPTOR in human FGR not established\", \"Upstream signals driving placental DEPTOR levels unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct DEPTOR pools \\u2014 mTOR-inhibitory, nuclear/transcriptional, and receptor-binding \\u2014 are partitioned and coordinated within a single cell, and which functions are mTOR-dependent versus independent, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling cytoplasmic, nuclear, and membrane functions\", \"Stoichiometry of DEPTOR within mTORC1 vs mTORC2 in vivo unknown\", \"Physiological triggers selecting among degradation and stabilization routes unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [24, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 3, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 23, 25, 33]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [29, 34, 35]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11, 18, 19, 20]}\n    ],\n    \"complexes\": [\"mTORC1\", \"mTORC2\"],\n    \"partners\": [\"MTOR\", \"BTRC\", \"OTUB1\", \"USP7\", \"EGFR\", \"ERBB2\", \"WWTR1\", \"RNF139\"]\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}