{"gene":"SOCS6","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2002,"finding":"SOCS6 binds to elongins B and C through its SOCS box, consistent with function as an E3 ubiquitin ligase. The SOCS6 SH2 domain preferentially binds phosphopeptides with valine at pY+1 and hydrophobic residues at pY+2 and pY+3. SOCS6 SH2 domain interacts with a protein complex consisting of IRS-4, IRS-2, and the p85 regulatory subunit of PI3-kinase.","method":"Biochemical binding assays (phosphopeptide binding specificity), co-immunoprecipitation, and SOCS-6 knockout mice","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical binding assays with phosphopeptide specificity mapping plus genetic knockout model, multiple orthogonal methods in a single rigorous study","pmids":["12052866"],"is_preprint":false},{"year":2004,"finding":"After insulin stimulation, SOCS6 interacts with the monomeric p85 subunit of class-Ia PI3-kinase but not with p85/p110 dimers, and this interaction improves downstream Akt/PKB signaling. SOCS6 protein is transiently induced by insulin and degraded via a proteasome-mediated mechanism.","method":"Co-immunoprecipitation, SOCS6 transgenic mice, proteasome inhibitor experiments, western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, transgenic mouse phenotype, and proteasome inhibitor rescue, single lab with multiple orthogonal methods","pmids":["15123678"],"is_preprint":false},{"year":2006,"finding":"The E3 ubiquitin ligase HOIL-1 interacts with SOCS6 through its Ubl domain, requiring the SH2 and SOCS box domains of SOCS6. HOIL-1 stabilizes SOCS6 and induces ubiquitination and degradation of proteins associated with SOCS6, indicating SOCS6 can engage multiple E3 ubiquitin ligase complexes.","method":"Co-immunoprecipitation, ubiquitination assays, domain deletion analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and domain mapping with ubiquitination assay, single lab, two orthogonal methods","pmids":["16643902"],"is_preprint":false},{"year":2006,"finding":"SOCS6 protein stability is increased by PMA treatment via a PKCδ-Erk pathway. Both Erk and PKCδ activation are required for increased SOCS6 stability, with Erk acting downstream of PKCδ. Stability depends on the N-terminal region of SOCS6.","method":"PMA treatment, pharmacological inhibitors of PKC and Erk, domain deletion analysis, western blot in HEK293T and MCF7 cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological pathway dissection with domain mapping, single lab, two cell lines","pmids":["17210122"],"is_preprint":false},{"year":2007,"finding":"Endogenous and overexpressed SOCS6 localizes to both the nucleus and cytoplasm. Nuclear localization requires the N-terminal region (amino acids 1-210). The C-terminal region of SOCS6 is responsible for decreasing Stat3 protein levels in the nucleus.","method":"GFP-tagged SOCS6 subcellular localization, domain deletion constructs, western blot for Stat3 protein levels","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct imaging of localization with functional domain mapping, single lab, two orthogonal readouts","pmids":["17603019"],"is_preprint":false},{"year":2009,"finding":"SOCS6 acts as a negative regulator of T cell activation by binding specifically to the active form of p56lck (F505) through its kinase domain. SOCS6 is recruited to the immunological synapse upon APC-T cell conjugation, promotes p56lck ubiquitination and proteasomal targeting, and represses TCR-dependent IL-2 promoter activity.","method":"Yeast two-hybrid screening, co-immunoprecipitation, confocal microscopy, ubiquitination assay, IL-2 promoter reporter assay in Jurkat T cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, Co-IP, confocal, ubiquitination assay, reporter assay) in a single rigorous study establishing the full mechanistic chain","pmids":["20007709"],"is_preprint":false},{"year":2010,"finding":"The SH2 domain of SOCS6 directly binds c-KIT at phosphotyrosine Y568. Crystal structure (1.45 Å) of SOCS6 SH2 domain bound to c-KIT peptide (residues 564-574) reveals a highly complementary interface with a large BG loop insertion contributing to substrate interaction (Kd = 0.3 μM). SOCS6 has ubiquitin ligase activity toward c-KIT and promotes c-KIT protein turnover in cells.","method":"Crystal structure determination (1.45 Å), surface plasmon resonance/binding affinity measurement, in vitro ubiquitin ligase assay, cell-based c-KIT turnover assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure with functional validation by in vitro ubiquitin ligase assay and cell-based turnover, multiple orthogonal methods","pmids":["21030588"],"is_preprint":false},{"year":2012,"finding":"SOCS6 is targeted to mitochondria, forms a complex with DRP1 and mitochondrial phosphatase PGAM5, attenuates DRP1 phosphorylation, and promotes DRP1 mitochondrial translocation, leading to mitochondrial fission and intrinsic apoptosis. Mutation analyses show SOCS6-mediated apoptosis is coupled to its ability to induce mitochondrial fission.","method":"Lentiviral knockdown, co-immunoprecipitation of SOCS6-DRP1-PGAM5 complex, mitochondrial fractionation, DRP1 phosphorylation assays, site-directed mutagenesis, apoptosis assays (Bax conformational change, mitochondrial targeting)","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying ternary complex, functional KD, mutagenesis, and subcellular fractionation, multiple orthogonal methods in single rigorous study","pmids":["22955947"],"is_preprint":false},{"year":2012,"finding":"SOCS6 directly binds phosphotyrosines 591 and 919 of Flt3 upon ligand stimulation. SOCS6 enhances ubiquitination of Flt3, promotes receptor internalization and degradation, and weakens Erk1/2 (but not Akt) activation. SOCS6 also becomes tyrosine-phosphorylated upon Flt3 stimulation.","method":"Phosphopeptide fishing, co-immunoprecipitation, stable Ba/F3 and UT-7 transfectants, ubiquitination assay, receptor internalization/degradation assay, proliferation assay with Flt3-ITD","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphopeptide binding mapping combined with cell-based ubiquitination, receptor degradation, and signaling assays, multiple orthogonal methods","pmids":["22952242"],"is_preprint":false},{"year":2009,"finding":"SOCS6 is frequently down-regulated in gastric cancer through allelic loss and promoter hypermethylation. Ectopic SOCS6 expression suppresses cell growth and colony formation by activating the intrinsic apoptotic pathway with decreased mitochondrial membrane potential.","method":"Allelic loss analysis, methylation-specific PCR, ectopic overexpression, colony formation assay, apoptosis assay, mitochondrial membrane potential measurement","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ectopic expression with functional phenotypic readouts and epigenetic mechanism, single lab, multiple methods","pmids":["19646809"],"is_preprint":false},{"year":2014,"finding":"SOCS6 negatively regulates signaling downstream of multiple receptor tyrosine kinases (including c-KIT and Flt3) primarily through its SH2 domain binding phosphorylated receptor substrates and its SOCS box-mediated ubiquitin ligase activity leading to receptor/substrate degradation.","method":"Review/synthesis of prior biochemical and cell-based experiments (Co-IP, ubiquitination assays, cell signaling assays)","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — synthesis of replicated biochemical findings across multiple studies; review paper citing original experimental data","pmids":["25172101"],"is_preprint":false},{"year":2017,"finding":"Combined loss of SOCS6 and SOCS7 in mice recapitulates the cortical layer inversion seen in reelin-deficient mice, with dramatic accumulation of the reelin signaling molecule DAB1 in the cortex. The SH2 domains of SOCS6 and SOCS7 bind DAB1 ex vivo; mutation of DAB1 reduces binding and protects from degradation by SOCS6. Phosphorylated DAB1 is elevated in cortical neurons lacking SOCS6 and SOCS7, indicating SOCS6 terminates reelin signaling by promoting DAB1 degradation.","method":"SOCS6/SOCS7 double-knockout mice, genetic epistasis, ex vivo binding assays, DAB1 mutation analysis, cortical neuron immunostaining","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in double KO mice with direct ex vivo binding assays and mutagenesis establishing the mechanistic chain for DAB1 regulation","pmids":["26503265"],"is_preprint":false},{"year":2018,"finding":"SOCS6 promotes apoptosis and inhibits angiogenesis in prostate cancer cells. RNA-sequencing identified Bcl2 and Hspa1a as downstream targets downregulated by SOCS6 overexpression (apoptosis), and F7, Fak3, and Frzb as angiogenesis-related targets suppressed by SOCS6.","method":"SOCS6 overexpression, in vitro apoptosis/migration/invasion assays, in vivo xenograft with angiogenesis measurement, next-generation RNA sequencing, pathway enrichment analysis, western blot validation","journal":"Current cancer drug targets","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression with RNA-seq target identification and in vivo validation, single lab","pmids":["29295692"],"is_preprint":false},{"year":2021,"finding":"SOCS6 promotes radiosensitivity in esophageal squamous cell carcinoma cells and reduces cancer stem cell properties. The mechanism involves ubiquitylation and degradation of c-Kit, confirmed by co-immunoprecipitation and ubiquitin blotting. SOCS6 and c-Kit co-localize in the cytoplasm.","method":"SOCS6 overexpression, colony formation assay, flow cytometry (CSC markers), immunofluorescence/confocal co-localization, co-immunoprecipitation, ubiquitin blotting, xenograft mouse model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with ubiquitin blotting and in vivo validation, replicates prior c-KIT ubiquitination mechanism in new cellular context","pmids":["33712005"],"is_preprint":false},{"year":2021,"finding":"SOCS6 deficiency in esophageal squamous cell carcinoma confers radioresistance by increasing radiation-induced G2/M arrest, enhancing DNA damage repair, and inhibiting radiation-induced apoptosis. Transcriptome sequencing shows SOCS6 transcription is partially p53-dependent.","method":"SOCS6 knockdown (RNAi), clonogenic survival assay, cell cycle analysis, DNA damage repair assays, apoptosis assay, transcriptome sequencing, in vivo xenograft irradiation model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with multiple mechanistic readouts and transcriptomic analysis, single lab","pmids":["33689885"],"is_preprint":false},{"year":2020,"finding":"BC-box motif in SOCS6 (SLQYLCRFVI, the elongin BC binding site) mediates neuronal differentiation of somatic stem cells. Peptide delivery of the BC-box motif induces GABAergic neuronal differentiation via ubiquitination of JAK2 and inhibition of the JAK2-STAT3 pathway.","method":"Intracellular peptide delivery, neuronal differentiation assays (GABA marker expression), JAK2 ubiquitination assay, STAT3 pathway analysis, in vivo transplantation into ischemic rodent model","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — peptide-based functional assay with JAK2 ubiquitination readout; single lab, limited biochemical follow-up of direct mechanism","pmids":["32668737"],"is_preprint":false},{"year":2025,"finding":"SOCS6 promotes ubiquitin-proteasomal degradation of SLC7A11 (the cystine/glutamate transporter xCT), reducing intracellular glutathione and increasing ROS and Fe2+ accumulation to drive ferroptosis in ovarian cancer cells. SOCS6 also suppresses de novo fatty acid synthesis by downregulating FASN and ACC.","method":"SOCS6 overexpression, co-immunoprecipitation, ubiquitination assay, ferroptosis induction (erastin), GSH/ROS/Fe2+ measurement, western blot for lipid metabolism enzymes, xenograft mouse model","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assay identifying SLC7A11 as substrate, functional readouts, single lab","pmids":["41061872"],"is_preprint":false},{"year":2025,"finding":"FTO (m6A demethylase) selectively binds and demethylates N6-methyladenosine modifications within the coding sequence of SOCS6 mRNA in keratinocytes, reducing SOCS6 mRNA stability and protein expression, which activates inflammatory programs. IL-1β, S100A8, and S100A9 are downstream effectors of this FTO/SOCS6-m6A axis.","method":"Transcriptomic and epitranscriptomic (m6A) sequencing, RNA immunoprecipitation (RIP), MeRIP to map m6A on SOCS6 mRNA, FTO knockdown in vivo and in vitro, mRNA stability assays, western blot","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epitranscriptomic mapping (MeRIP) with functional validation in vivo and in vitro, single lab with multiple orthogonal methods","pmids":["41644088"],"is_preprint":false},{"year":2025,"finding":"lncRNA CASC2 stabilizes SOCS6 mRNA by recruiting the RNA-binding protein U2AF2. This CASC2/U2AF2/SOCS6 axis in retinal pigment epithelium-derived exosomes inhibits M1 macrophage polarization and promotes M2 polarization in diabetic retinopathy.","method":"RNA immunoprecipitation (RIP), dual-luciferase reporter assay, U2AF2 knockdown, mRNA stability assay, exosome isolation/transfer, macrophage polarization flow cytometry, in vivo diabetic rat model","journal":"Diabetic medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP identifies U2AF2-SOCS6 mRNA interaction, functional exosome transfer experiments, single lab","pmids":["40065730"],"is_preprint":false},{"year":2014,"finding":"SOCS6 silencing (via miR-494-3p overexpression) activates STAT3 signaling and promotes megakaryocyte differentiation of hematopoietic stem/progenitor cells. SOCS6 was confirmed as a direct miR-494-3p target by luciferase assay; SOCS6 silencing alone mimics the megakaryocyte hyperplasia phenotype of primary myelofibrosis.","method":"miRNA overexpression in CD34+ HSPCs, gene expression profiling, luciferase reporter assay, western blot for SOCS6 and STAT3, megakaryocyte differentiation assays, miR-494-3p inhibition in PMF HSPCs","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function (SOCS6 siRNA) phenocopies miRNA overexpression in primary cells, confirmed target by luciferase, single lab","pmids":["28423484"],"is_preprint":false}],"current_model":"SOCS6 is a multifunctional E3 ubiquitin ligase adaptor whose SH2 domain binds phosphorylated substrates (including c-KIT pY568, Flt3 pY591/pY919, p56lck active form, DAB1, and SLC7A11) and whose SOCS box recruits elongin BC (and HOIL-1) to promote substrate ubiquitination and proteasomal degradation; it also localizes to mitochondria where it forms a complex with DRP1 and PGAM5 to promote mitochondrial fission and intrinsic apoptosis, negatively regulates JAK-STAT signaling (including via nuclear Stat3 degradation and STAT3 pathway suppression), terminates reelin signaling in cortical neurons by targeting DAB1 for degradation, and its own stability is regulated post-translationally via PKCδ-Erk-dependent mechanisms and m6A-mediated mRNA stability controlled by FTO."},"narrative":{"mechanistic_narrative":"SOCS6 is a substrate-recruiting adaptor of the elongin BC-based E3 ubiquitin ligase machinery that uses its SH2 domain to capture phosphotyrosine-bearing signaling proteins and its C-terminal SOCS box to drive their ubiquitination and proteasomal degradation, thereby terminating diverse tyrosine-kinase signaling outputs [PMID:12052866, PMID:25172101]. Its SH2 domain has a defined phosphopeptide preference (valine at pY+1, hydrophobic residues at pY+2/+3) and directly engages activated receptor tyrosine kinases including c-KIT at pY568 and Flt3 at pY591/pY919, promoting receptor ubiquitination, internalization/turnover, and attenuation of downstream Erk signaling [PMID:12052866, PMID:21030588, PMID:22952242]; a 1.45 Å crystal structure of the SH2 domain bound to a c-KIT phosphopeptide defines a high-affinity, BG-loop-mediated interface [PMID:21030588]. The same SH2/SOCS-box logic targets the active form of p56lck at the immunological synapse to restrain TCR-driven IL-2 induction [PMID:20007709] and degrades phosphorylated DAB1 in cortical neurons to terminate reelin signaling, with combined Socs6/Socs7 loss recapitulating reelin-deficient cortical layer inversion [PMID:26503265]. Beyond its ligase-adaptor role, SOCS6 localizes to both nucleus and cytoplasm and to mitochondria, where it forms a complex with DRP1 and the phosphatase PGAM5, attenuates DRP1 phosphorylation to promote DRP1 mitochondrial translocation, mitochondrial fission, and intrinsic apoptosis [PMID:17603019, PMID:22955947]. Through these activities SOCS6 acts broadly as a growth-suppressive and pro-apoptotic factor, and its abundance is set post-transcriptionally by a PKCδ-Erk-dependent stability mechanism and by RNA-level control through m6A demethylation and RNA-binding-protein-mediated mRNA stabilization [PMID:17210122, PMID:22955947, PMID:41644088, PMID:40065730].","teleology":[{"year":2002,"claim":"Established the core biochemical identity of SOCS6 as an E3 ligase adaptor by showing the SOCS box binds elongins B/C and defining the SH2 phosphopeptide-binding specificity, framing how SOCS6 would later recognize substrates.","evidence":"Phosphopeptide binding specificity assays, Co-IP, and SOCS6 knockout mice","pmids":["12052866"],"confidence":"High","gaps":["Physiological substrates not yet identified","No in vivo phenotype linking elongin BC binding to substrate degradation"]},{"year":2004,"claim":"Showed SOCS6 is itself an insulin-responsive, proteasome-regulated protein that engages the PI3K regulatory subunit p85, implicating it in metabolic receptor signaling and revealing its own turnover is controlled.","evidence":"Co-IP, SOCS6 transgenic mice, proteasome inhibitor experiments","pmids":["15123678"],"confidence":"High","gaps":["Identity of the ligase degrading SOCS6 not defined","Mechanism by which p85 binding improves Akt signaling unresolved"]},{"year":2006,"claim":"Demonstrated SOCS6 can engage E3 machinery beyond elongin BC (HOIL-1 via its Ubl domain) and that its stability is set by a PKCδ-Erk pathway acting on its N-terminus, establishing multi-ligase engagement and post-translational regulation of SOCS6 levels.","evidence":"Co-IP, ubiquitination and domain-deletion assays; PMA treatment with PKC/Erk inhibitors","pmids":["16643902","17210122"],"confidence":"Medium","gaps":["Functional significance of HOIL-1 versus elongin BC engagement unclear","Direct PKCδ/Erk target site on SOCS6 not mapped"]},{"year":2007,"claim":"Defined SOCS6 subcellular distribution (nucleus and cytoplasm) and a domain division of labor in which the N-terminus directs nuclear localization and the C-terminus lowers nuclear Stat3, connecting SOCS6 to JAK-STAT regulation.","evidence":"GFP-tagged localization, domain-deletion constructs, Stat3 western blot","pmids":["17603019"],"confidence":"Medium","gaps":["Whether Stat3 reduction is via direct ubiquitination not shown","Nuclear function of SOCS6 not mechanistically defined"]},{"year":2009,"claim":"Linked SOCS6 to tumor suppression by showing it is epigenetically silenced in gastric cancer and that restoring it triggers intrinsic apoptosis, providing the first functional growth-suppressive readout.","evidence":"Allelic loss/methylation analysis, ectopic expression, colony formation and mitochondrial membrane potential assays","pmids":["19646809"],"confidence":"Medium","gaps":["Molecular trigger of apoptosis by SOCS6 not identified at this stage","No defined substrate connecting SOCS6 to the apoptotic pathway"]},{"year":2009,"claim":"Showed SOCS6 is a negative regulator of T cell activation that selectively binds the active form of p56lck at the immunological synapse to drive its ubiquitination and repress IL-2 induction, providing a complete SH2-to-degradation mechanistic chain for an immune substrate.","evidence":"Yeast two-hybrid, Co-IP, confocal microscopy, ubiquitination and IL-2 reporter assays in Jurkat cells","pmids":["20007709"],"confidence":"High","gaps":["In vivo T cell phenotype not established","Whether other TCR-proximal kinases are also targeted unknown"]},{"year":2010,"claim":"Provided atomic-resolution proof of substrate recognition by solving the SOCS6 SH2 domain bound to c-KIT pY568 and showing SOCS6 ubiquitinates and turns over c-KIT, cementing the receptor-tyrosine-kinase substrate model.","evidence":"1.45 Å crystal structure, binding affinity measurement, in vitro ubiquitin ligase and cell-based turnover assays","pmids":["21030588"],"confidence":"High","gaps":["In vivo consequence of c-KIT regulation by SOCS6 not addressed","Whether degradation requires the full elongin BC complex in cells not shown structurally"]},{"year":2012,"claim":"Extended the RTK-substrate model to Flt3 (binding pY591/pY919, enhancing ubiquitination, internalization and Erk attenuation) and revealed a parallel non-degradative mitochondrial role in which SOCS6/DRP1/PGAM5 complex formation drives fission and intrinsic apoptosis.","evidence":"Phosphopeptide fishing, Co-IP, ubiquitination/internalization assays in Ba/F3 and UT-7 cells; mitochondrial fractionation, DRP1 phosphorylation and apoptosis assays","pmids":["22952242","22955947"],"confidence":"High","gaps":["How SOCS6 attenuates DRP1 phosphorylation mechanistically (recruitment of PGAM5 vs direct) not fully resolved","Relationship between RTK-degradation and mitochondrial functions of SOCS6 unclear"]},{"year":2017,"claim":"Established a developmental substrate in vivo by showing Socs6/Socs7 loss phenocopies reelin deficiency through accumulation of phosphorylated DAB1, demonstrating SOCS6 terminates reelin signaling by SH2-mediated DAB1 binding and degradation.","evidence":"Socs6/Socs7 double-knockout mice, genetic epistasis, ex vivo binding and DAB1 mutation analysis, cortical neuron immunostaining","pmids":["26503265"],"confidence":"High","gaps":["Functional redundancy between SOCS6 and SOCS7 not separated","Direct demonstration of DAB1 ubiquitination by SOCS6 in vivo not shown"]},{"year":2018,"claim":"Broadened the tumor-suppressive program by linking SOCS6 to pro-apoptotic and anti-angiogenic transcriptional outputs in prostate cancer, identifying candidate downstream effectors.","evidence":"SOCS6 overexpression, RNA-seq, in vitro and xenograft angiogenesis/apoptosis assays","pmids":["29295692"],"confidence":"Medium","gaps":["Whether the RNA-seq targets are direct SOCS6 substrates or secondary effects unknown","No degradation substrate identified for the anti-angiogenic effect"]},{"year":2021,"claim":"Connected SOCS6's c-KIT ubiquitination activity to a therapeutic phenotype, showing SOCS6 promotes radiosensitivity and reduces cancer stem cell properties in esophageal carcinoma, while its loss enhances DNA repair and G2/M arrest in a partly p53-dependent manner.","evidence":"Overexpression and knockdown, Co-IP/ubiquitin blotting for c-Kit, clonogenic survival, cell cycle, DNA damage and apoptosis assays, transcriptome sequencing, xenografts","pmids":["33712005","33689885"],"confidence":"Medium","gaps":["Direct mechanism linking c-Kit degradation to DNA repair/cell cycle not defined","Nature of p53-SOCS6 transcriptional dependence unresolved"]},{"year":2020,"claim":"Showed the elongin-BC-binding BC-box motif of SOCS6 is sufficient to drive JAK2 ubiquitination and inhibit JAK2-STAT3 signaling, mechanistically tying SOCS6 to STAT pathway suppression and a neuronal differentiation outcome.","evidence":"Intracellular peptide delivery, JAK2 ubiquitination and STAT3 pathway assays, in vivo transplantation","pmids":["32668737"],"confidence":"Medium","gaps":["Direct binding of full-length SOCS6 to JAK2 not demonstrated","Peptide-based readout may not reflect endogenous regulation"]},{"year":2025,"claim":"Identified new degradation substrates and metabolic outputs, showing SOCS6 ubiquitinates SLC7A11 to drive ferroptosis and suppresses fatty acid synthesis enzymes in ovarian cancer.","evidence":"Overexpression, Co-IP, ubiquitination assay, GSH/ROS/Fe2+ and lipid-enzyme measurements, xenografts","pmids":["41061872"],"confidence":"Medium","gaps":["Whether SLC7A11 binding is SH2/phosphotyrosine-dependent not addressed","Mechanism of FASN/ACC downregulation (direct vs transcriptional) unknown"]},{"year":2025,"claim":"Resolved upstream RNA-level control of SOCS6, showing m6A demethylation by FTO and lncRNA CASC2/U2AF2-mediated stabilization tune SOCS6 mRNA stability to govern inflammatory and macrophage-polarization outcomes.","evidence":"MeRIP/RIP mapping, FTO and U2AF2 knockdown, mRNA stability assays, exosome transfer, in vivo disease models","pmids":["41644088","40065730"],"confidence":"Medium","gaps":["Direct integration of mRNA-level control with SOCS6 protein function not shown","Tissue-specificity of these RNA-regulatory axes unclear"]},{"year":null,"claim":"How SOCS6 partitions between its E3-adaptor degradation function and its non-degradative mitochondrial fission/apoptosis role, and what governs substrate selection across its many phosphotyrosine targets, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model coordinating cytoplasmic, nuclear, and mitochondrial SOCS6 pools","Substrate hierarchy and context-dependence of SH2-mediated targeting undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,6,8,11,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,7,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,13]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,8,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5,6,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,9,16]}],"complexes":["Elongin BC E3 ubiquitin ligase complex","SOCS6-DRP1-PGAM5 mitochondrial complex"],"partners":["KIT","FLT3","LCK","DAB1","DNM1L","PGAM5","SLC7A11","ELOC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14544","full_name":"Suppressor of cytokine signaling 6","aliases":["Cytokine-inducible SH2 protein 4","CIS-4","Suppressor of cytokine signaling 4","SOCS-4"],"length_aa":535,"mass_kda":59.5,"function":"SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. May be a substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (By similarity). Regulates KIT degradation by ubiquitination of the tyrosine-phosphorylated receptor","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O14544/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SOCS6","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SOCS6","total_profiled":1310},"omim":[{"mim_id":"605118","title":"SUPPRESSOR OF CYTOKINE SIGNALING 6; SOCS6","url":"https://www.omim.org/entry/605118"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SOCS6"},"hgnc":{"alias_symbol":["CIS4","SSI4","HSPC060","STATI4","STAI4","Cish4"],"prev_symbol":["SOCS4"]},"alphafold":{"accession":"O14544","domains":[{"cath_id":"3.30.505.10","chopping":"373-497","consensus_level":"high","plddt":84.1933,"start":373,"end":497},{"cath_id":"1.10.750,1.10.750","chopping":"498-535","consensus_level":"medium","plddt":88.5479,"start":498,"end":535}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14544","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14544-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14544-F1-predicted_aligned_error_v6.png","plddt_mean":54.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SOCS6","jax_strain_url":"https://www.jax.org/strain/search?query=SOCS6"},"sequence":{"accession":"O14544","fasta_url":"https://rest.uniprot.org/uniprotkb/O14544.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14544/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14544"}},"corpus_meta":[{"pmid":"27811366","id":"PMC_27811366","title":"MiR-21 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Stearoyl CoA Desaturase 1.","date":"2023","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/37409698","citation_count":2,"is_preprint":false},{"pmid":"37947793","id":"PMC_37947793","title":"Evaluation of trans- and cis-4-[18F]Fluorogabapentin for Brain PET Imaging.","date":"2023","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37947793","citation_count":2,"is_preprint":false},{"pmid":"41311181","id":"PMC_41311181","title":"[Expression and clinical significance of SIRT1 and SOCS6 in gingival tissue of patients with severe chronic periodontitis].","date":"2025","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/41311181","citation_count":1,"is_preprint":false},{"pmid":"41061872","id":"PMC_41061872","title":"Suppressor of cytokine signaling 6 (SOCS6) mediates ubiquitination degradation of SLC7A11 to drive ferroptosis and block lipid metabolism in ovarian cancer cells.","date":"2025","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/41061872","citation_count":1,"is_preprint":false},{"pmid":"39354960","id":"PMC_39354960","title":"Cis-4-[18F]fluoro-L-proline PET/CT molecular imaging quantifying liver collagenogenesis: No existing fibrotic deposition in experimental advanced-stage alcoholic liver fibrosis.","date":"2022","source":"Frontiers in nuclear medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39354960","citation_count":1,"is_preprint":false},{"pmid":"37589228","id":"PMC_37589228","title":"Serum levels of SOCS6 are decreased in diabetic retinopathy and are related to severity of the disease.","date":"2023","source":"Advances in clinical and experimental medicine : official organ Wroclaw Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/37589228","citation_count":0,"is_preprint":false},{"pmid":"41174995","id":"PMC_41174995","title":"Association of SOCS6 Gene Polymorphisms and Promoter Hypermethylation With the Progression of Hepatitis B Virus Infection.","date":"2025","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/41174995","citation_count":0,"is_preprint":false},{"pmid":"41644088","id":"PMC_41644088","title":"FTO/SOCS6-m6A axis epigenetic modification links obesity to atopic dermatitis by regulating keratinocyte function.","date":"2026","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/41644088","citation_count":0,"is_preprint":false},{"pmid":"37732236","id":"PMC_37732236","title":"Evaluation of trans- and cis-4-[18F]fluorogabapentin for brain PET imaging.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37732236","citation_count":0,"is_preprint":false},{"pmid":"37622557","id":"PMC_37622557","title":"Quantification Of Collagenogenesis In Experimental Early-stage Alcoholic Liver Fibrosis Using Cis-4-[18F]fluoro-L-Proline microPET.","date":"2023","source":"Current medical imaging","url":"https://pubmed.ncbi.nlm.nih.gov/37622557","citation_count":0,"is_preprint":false},{"pmid":"41919701","id":"PMC_41919701","title":"Excited-state-dependent chiral pathways in the photoisomerization of cis-4,4'-azopyridine.","date":"2026","source":"The Journal of chemical physics","url":"https://pubmed.ncbi.nlm.nih.gov/41919701","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50735,"output_tokens":5352,"usd":0.116242,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13772,"output_tokens":5172,"usd":0.09908,"stage2_stop_reason":"end_turn"},"total_usd":0.215322,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"SOCS6 binds to elongins B and C through its SOCS box, consistent with function as an E3 ubiquitin ligase. The SOCS6 SH2 domain preferentially binds phosphopeptides with valine at pY+1 and hydrophobic residues at pY+2 and pY+3. SOCS6 SH2 domain interacts with a protein complex consisting of IRS-4, IRS-2, and the p85 regulatory subunit of PI3-kinase.\",\n      \"method\": \"Biochemical binding assays (phosphopeptide binding specificity), co-immunoprecipitation, and SOCS-6 knockout mice\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical binding assays with phosphopeptide specificity mapping plus genetic knockout model, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"12052866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"After insulin stimulation, SOCS6 interacts with the monomeric p85 subunit of class-Ia PI3-kinase but not with p85/p110 dimers, and this interaction improves downstream Akt/PKB signaling. SOCS6 protein is transiently induced by insulin and degraded via a proteasome-mediated mechanism.\",\n      \"method\": \"Co-immunoprecipitation, SOCS6 transgenic mice, proteasome inhibitor experiments, western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, transgenic mouse phenotype, and proteasome inhibitor rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15123678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The E3 ubiquitin ligase HOIL-1 interacts with SOCS6 through its Ubl domain, requiring the SH2 and SOCS box domains of SOCS6. HOIL-1 stabilizes SOCS6 and induces ubiquitination and degradation of proteins associated with SOCS6, indicating SOCS6 can engage multiple E3 ubiquitin ligase complexes.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, domain deletion analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and domain mapping with ubiquitination assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"16643902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SOCS6 protein stability is increased by PMA treatment via a PKCδ-Erk pathway. Both Erk and PKCδ activation are required for increased SOCS6 stability, with Erk acting downstream of PKCδ. Stability depends on the N-terminal region of SOCS6.\",\n      \"method\": \"PMA treatment, pharmacological inhibitors of PKC and Erk, domain deletion analysis, western blot in HEK293T and MCF7 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological pathway dissection with domain mapping, single lab, two cell lines\",\n      \"pmids\": [\"17210122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Endogenous and overexpressed SOCS6 localizes to both the nucleus and cytoplasm. Nuclear localization requires the N-terminal region (amino acids 1-210). The C-terminal region of SOCS6 is responsible for decreasing Stat3 protein levels in the nucleus.\",\n      \"method\": \"GFP-tagged SOCS6 subcellular localization, domain deletion constructs, western blot for Stat3 protein levels\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct imaging of localization with functional domain mapping, single lab, two orthogonal readouts\",\n      \"pmids\": [\"17603019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SOCS6 acts as a negative regulator of T cell activation by binding specifically to the active form of p56lck (F505) through its kinase domain. SOCS6 is recruited to the immunological synapse upon APC-T cell conjugation, promotes p56lck ubiquitination and proteasomal targeting, and represses TCR-dependent IL-2 promoter activity.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, confocal microscopy, ubiquitination assay, IL-2 promoter reporter assay in Jurkat T cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, Co-IP, confocal, ubiquitination assay, reporter assay) in a single rigorous study establishing the full mechanistic chain\",\n      \"pmids\": [\"20007709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The SH2 domain of SOCS6 directly binds c-KIT at phosphotyrosine Y568. Crystal structure (1.45 Å) of SOCS6 SH2 domain bound to c-KIT peptide (residues 564-574) reveals a highly complementary interface with a large BG loop insertion contributing to substrate interaction (Kd = 0.3 μM). SOCS6 has ubiquitin ligase activity toward c-KIT and promotes c-KIT protein turnover in cells.\",\n      \"method\": \"Crystal structure determination (1.45 Å), surface plasmon resonance/binding affinity measurement, in vitro ubiquitin ligase assay, cell-based c-KIT turnover assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure with functional validation by in vitro ubiquitin ligase assay and cell-based turnover, multiple orthogonal methods\",\n      \"pmids\": [\"21030588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SOCS6 is targeted to mitochondria, forms a complex with DRP1 and mitochondrial phosphatase PGAM5, attenuates DRP1 phosphorylation, and promotes DRP1 mitochondrial translocation, leading to mitochondrial fission and intrinsic apoptosis. Mutation analyses show SOCS6-mediated apoptosis is coupled to its ability to induce mitochondrial fission.\",\n      \"method\": \"Lentiviral knockdown, co-immunoprecipitation of SOCS6-DRP1-PGAM5 complex, mitochondrial fractionation, DRP1 phosphorylation assays, site-directed mutagenesis, apoptosis assays (Bax conformational change, mitochondrial targeting)\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying ternary complex, functional KD, mutagenesis, and subcellular fractionation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"22955947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SOCS6 directly binds phosphotyrosines 591 and 919 of Flt3 upon ligand stimulation. SOCS6 enhances ubiquitination of Flt3, promotes receptor internalization and degradation, and weakens Erk1/2 (but not Akt) activation. SOCS6 also becomes tyrosine-phosphorylated upon Flt3 stimulation.\",\n      \"method\": \"Phosphopeptide fishing, co-immunoprecipitation, stable Ba/F3 and UT-7 transfectants, ubiquitination assay, receptor internalization/degradation assay, proliferation assay with Flt3-ITD\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphopeptide binding mapping combined with cell-based ubiquitination, receptor degradation, and signaling assays, multiple orthogonal methods\",\n      \"pmids\": [\"22952242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SOCS6 is frequently down-regulated in gastric cancer through allelic loss and promoter hypermethylation. Ectopic SOCS6 expression suppresses cell growth and colony formation by activating the intrinsic apoptotic pathway with decreased mitochondrial membrane potential.\",\n      \"method\": \"Allelic loss analysis, methylation-specific PCR, ectopic overexpression, colony formation assay, apoptosis assay, mitochondrial membrane potential measurement\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ectopic expression with functional phenotypic readouts and epigenetic mechanism, single lab, multiple methods\",\n      \"pmids\": [\"19646809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SOCS6 negatively regulates signaling downstream of multiple receptor tyrosine kinases (including c-KIT and Flt3) primarily through its SH2 domain binding phosphorylated receptor substrates and its SOCS box-mediated ubiquitin ligase activity leading to receptor/substrate degradation.\",\n      \"method\": \"Review/synthesis of prior biochemical and cell-based experiments (Co-IP, ubiquitination assays, cell signaling assays)\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — synthesis of replicated biochemical findings across multiple studies; review paper citing original experimental data\",\n      \"pmids\": [\"25172101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Combined loss of SOCS6 and SOCS7 in mice recapitulates the cortical layer inversion seen in reelin-deficient mice, with dramatic accumulation of the reelin signaling molecule DAB1 in the cortex. The SH2 domains of SOCS6 and SOCS7 bind DAB1 ex vivo; mutation of DAB1 reduces binding and protects from degradation by SOCS6. Phosphorylated DAB1 is elevated in cortical neurons lacking SOCS6 and SOCS7, indicating SOCS6 terminates reelin signaling by promoting DAB1 degradation.\",\n      \"method\": \"SOCS6/SOCS7 double-knockout mice, genetic epistasis, ex vivo binding assays, DAB1 mutation analysis, cortical neuron immunostaining\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in double KO mice with direct ex vivo binding assays and mutagenesis establishing the mechanistic chain for DAB1 regulation\",\n      \"pmids\": [\"26503265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SOCS6 promotes apoptosis and inhibits angiogenesis in prostate cancer cells. RNA-sequencing identified Bcl2 and Hspa1a as downstream targets downregulated by SOCS6 overexpression (apoptosis), and F7, Fak3, and Frzb as angiogenesis-related targets suppressed by SOCS6.\",\n      \"method\": \"SOCS6 overexpression, in vitro apoptosis/migration/invasion assays, in vivo xenograft with angiogenesis measurement, next-generation RNA sequencing, pathway enrichment analysis, western blot validation\",\n      \"journal\": \"Current cancer drug targets\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression with RNA-seq target identification and in vivo validation, single lab\",\n      \"pmids\": [\"29295692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOCS6 promotes radiosensitivity in esophageal squamous cell carcinoma cells and reduces cancer stem cell properties. The mechanism involves ubiquitylation and degradation of c-Kit, confirmed by co-immunoprecipitation and ubiquitin blotting. SOCS6 and c-Kit co-localize in the cytoplasm.\",\n      \"method\": \"SOCS6 overexpression, colony formation assay, flow cytometry (CSC markers), immunofluorescence/confocal co-localization, co-immunoprecipitation, ubiquitin blotting, xenograft mouse model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with ubiquitin blotting and in vivo validation, replicates prior c-KIT ubiquitination mechanism in new cellular context\",\n      \"pmids\": [\"33712005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOCS6 deficiency in esophageal squamous cell carcinoma confers radioresistance by increasing radiation-induced G2/M arrest, enhancing DNA damage repair, and inhibiting radiation-induced apoptosis. Transcriptome sequencing shows SOCS6 transcription is partially p53-dependent.\",\n      \"method\": \"SOCS6 knockdown (RNAi), clonogenic survival assay, cell cycle analysis, DNA damage repair assays, apoptosis assay, transcriptome sequencing, in vivo xenograft irradiation model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with multiple mechanistic readouts and transcriptomic analysis, single lab\",\n      \"pmids\": [\"33689885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BC-box motif in SOCS6 (SLQYLCRFVI, the elongin BC binding site) mediates neuronal differentiation of somatic stem cells. Peptide delivery of the BC-box motif induces GABAergic neuronal differentiation via ubiquitination of JAK2 and inhibition of the JAK2-STAT3 pathway.\",\n      \"method\": \"Intracellular peptide delivery, neuronal differentiation assays (GABA marker expression), JAK2 ubiquitination assay, STAT3 pathway analysis, in vivo transplantation into ischemic rodent model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — peptide-based functional assay with JAK2 ubiquitination readout; single lab, limited biochemical follow-up of direct mechanism\",\n      \"pmids\": [\"32668737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SOCS6 promotes ubiquitin-proteasomal degradation of SLC7A11 (the cystine/glutamate transporter xCT), reducing intracellular glutathione and increasing ROS and Fe2+ accumulation to drive ferroptosis in ovarian cancer cells. SOCS6 also suppresses de novo fatty acid synthesis by downregulating FASN and ACC.\",\n      \"method\": \"SOCS6 overexpression, co-immunoprecipitation, ubiquitination assay, ferroptosis induction (erastin), GSH/ROS/Fe2+ measurement, western blot for lipid metabolism enzymes, xenograft mouse model\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assay identifying SLC7A11 as substrate, functional readouts, single lab\",\n      \"pmids\": [\"41061872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FTO (m6A demethylase) selectively binds and demethylates N6-methyladenosine modifications within the coding sequence of SOCS6 mRNA in keratinocytes, reducing SOCS6 mRNA stability and protein expression, which activates inflammatory programs. IL-1β, S100A8, and S100A9 are downstream effectors of this FTO/SOCS6-m6A axis.\",\n      \"method\": \"Transcriptomic and epitranscriptomic (m6A) sequencing, RNA immunoprecipitation (RIP), MeRIP to map m6A on SOCS6 mRNA, FTO knockdown in vivo and in vitro, mRNA stability assays, western blot\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epitranscriptomic mapping (MeRIP) with functional validation in vivo and in vitro, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41644088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"lncRNA CASC2 stabilizes SOCS6 mRNA by recruiting the RNA-binding protein U2AF2. This CASC2/U2AF2/SOCS6 axis in retinal pigment epithelium-derived exosomes inhibits M1 macrophage polarization and promotes M2 polarization in diabetic retinopathy.\",\n      \"method\": \"RNA immunoprecipitation (RIP), dual-luciferase reporter assay, U2AF2 knockdown, mRNA stability assay, exosome isolation/transfer, macrophage polarization flow cytometry, in vivo diabetic rat model\",\n      \"journal\": \"Diabetic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP identifies U2AF2-SOCS6 mRNA interaction, functional exosome transfer experiments, single lab\",\n      \"pmids\": [\"40065730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SOCS6 silencing (via miR-494-3p overexpression) activates STAT3 signaling and promotes megakaryocyte differentiation of hematopoietic stem/progenitor cells. SOCS6 was confirmed as a direct miR-494-3p target by luciferase assay; SOCS6 silencing alone mimics the megakaryocyte hyperplasia phenotype of primary myelofibrosis.\",\n      \"method\": \"miRNA overexpression in CD34+ HSPCs, gene expression profiling, luciferase reporter assay, western blot for SOCS6 and STAT3, megakaryocyte differentiation assays, miR-494-3p inhibition in PMF HSPCs\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function (SOCS6 siRNA) phenocopies miRNA overexpression in primary cells, confirmed target by luciferase, single lab\",\n      \"pmids\": [\"28423484\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SOCS6 is a multifunctional E3 ubiquitin ligase adaptor whose SH2 domain binds phosphorylated substrates (including c-KIT pY568, Flt3 pY591/pY919, p56lck active form, DAB1, and SLC7A11) and whose SOCS box recruits elongin BC (and HOIL-1) to promote substrate ubiquitination and proteasomal degradation; it also localizes to mitochondria where it forms a complex with DRP1 and PGAM5 to promote mitochondrial fission and intrinsic apoptosis, negatively regulates JAK-STAT signaling (including via nuclear Stat3 degradation and STAT3 pathway suppression), terminates reelin signaling in cortical neurons by targeting DAB1 for degradation, and its own stability is regulated post-translationally via PKCδ-Erk-dependent mechanisms and m6A-mediated mRNA stability controlled by FTO.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SOCS6 is a substrate-recruiting adaptor of the elongin BC-based E3 ubiquitin ligase machinery that uses its SH2 domain to capture phosphotyrosine-bearing signaling proteins and its C-terminal SOCS box to drive their ubiquitination and proteasomal degradation, thereby terminating diverse tyrosine-kinase signaling outputs [#0, #10]. Its SH2 domain has a defined phosphopeptide preference (valine at pY+1, hydrophobic residues at pY+2/+3) and directly engages activated receptor tyrosine kinases including c-KIT at pY568 and Flt3 at pY591/pY919, promoting receptor ubiquitination, internalization/turnover, and attenuation of downstream Erk signaling [#0, #6, #8]; a 1.45 \\u00c5 crystal structure of the SH2 domain bound to a c-KIT phosphopeptide defines a high-affinity, BG-loop-mediated interface [#6]. The same SH2/SOCS-box logic targets the active form of p56lck at the immunological synapse to restrain TCR-driven IL-2 induction [#5] and degrades phosphorylated DAB1 in cortical neurons to terminate reelin signaling, with combined Socs6/Socs7 loss recapitulating reelin-deficient cortical layer inversion [#11]. Beyond its ligase-adaptor role, SOCS6 localizes to both nucleus and cytoplasm and to mitochondria, where it forms a complex with DRP1 and the phosphatase PGAM5, attenuates DRP1 phosphorylation to promote DRP1 mitochondrial translocation, mitochondrial fission, and intrinsic apoptosis [#4, #7]. Through these activities SOCS6 acts broadly as a growth-suppressive and pro-apoptotic factor, and its abundance is set post-transcriptionally by a PKC\\u03b4-Erk-dependent stability mechanism and by RNA-level control through m6A demethylation and RNA-binding-protein-mediated mRNA stabilization [#3, #7, #17, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the core biochemical identity of SOCS6 as an E3 ligase adaptor by showing the SOCS box binds elongins B/C and defining the SH2 phosphopeptide-binding specificity, framing how SOCS6 would later recognize substrates.\",\n      \"evidence\": \"Phosphopeptide binding specificity assays, Co-IP, and SOCS6 knockout mice\",\n      \"pmids\": [\"12052866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates not yet identified\", \"No in vivo phenotype linking elongin BC binding to substrate degradation\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed SOCS6 is itself an insulin-responsive, proteasome-regulated protein that engages the PI3K regulatory subunit p85, implicating it in metabolic receptor signaling and revealing its own turnover is controlled.\",\n      \"evidence\": \"Co-IP, SOCS6 transgenic mice, proteasome inhibitor experiments\",\n      \"pmids\": [\"15123678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the ligase degrading SOCS6 not defined\", \"Mechanism by which p85 binding improves Akt signaling unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated SOCS6 can engage E3 machinery beyond elongin BC (HOIL-1 via its Ubl domain) and that its stability is set by a PKC\\u03b4-Erk pathway acting on its N-terminus, establishing multi-ligase engagement and post-translational regulation of SOCS6 levels.\",\n      \"evidence\": \"Co-IP, ubiquitination and domain-deletion assays; PMA treatment with PKC/Erk inhibitors\",\n      \"pmids\": [\"16643902\", \"17210122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of HOIL-1 versus elongin BC engagement unclear\", \"Direct PKC\\u03b4/Erk target site on SOCS6 not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined SOCS6 subcellular distribution (nucleus and cytoplasm) and a domain division of labor in which the N-terminus directs nuclear localization and the C-terminus lowers nuclear Stat3, connecting SOCS6 to JAK-STAT regulation.\",\n      \"evidence\": \"GFP-tagged localization, domain-deletion constructs, Stat3 western blot\",\n      \"pmids\": [\"17603019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Stat3 reduction is via direct ubiquitination not shown\", \"Nuclear function of SOCS6 not mechanistically defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked SOCS6 to tumor suppression by showing it is epigenetically silenced in gastric cancer and that restoring it triggers intrinsic apoptosis, providing the first functional growth-suppressive readout.\",\n      \"evidence\": \"Allelic loss/methylation analysis, ectopic expression, colony formation and mitochondrial membrane potential assays\",\n      \"pmids\": [\"19646809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular trigger of apoptosis by SOCS6 not identified at this stage\", \"No defined substrate connecting SOCS6 to the apoptotic pathway\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed SOCS6 is a negative regulator of T cell activation that selectively binds the active form of p56lck at the immunological synapse to drive its ubiquitination and repress IL-2 induction, providing a complete SH2-to-degradation mechanistic chain for an immune substrate.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, confocal microscopy, ubiquitination and IL-2 reporter assays in Jurkat cells\",\n      \"pmids\": [\"20007709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo T cell phenotype not established\", \"Whether other TCR-proximal kinases are also targeted unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided atomic-resolution proof of substrate recognition by solving the SOCS6 SH2 domain bound to c-KIT pY568 and showing SOCS6 ubiquitinates and turns over c-KIT, cementing the receptor-tyrosine-kinase substrate model.\",\n      \"evidence\": \"1.45 \\u00c5 crystal structure, binding affinity measurement, in vitro ubiquitin ligase and cell-based turnover assays\",\n      \"pmids\": [\"21030588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequence of c-KIT regulation by SOCS6 not addressed\", \"Whether degradation requires the full elongin BC complex in cells not shown structurally\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended the RTK-substrate model to Flt3 (binding pY591/pY919, enhancing ubiquitination, internalization and Erk attenuation) and revealed a parallel non-degradative mitochondrial role in which SOCS6/DRP1/PGAM5 complex formation drives fission and intrinsic apoptosis.\",\n      \"evidence\": \"Phosphopeptide fishing, Co-IP, ubiquitination/internalization assays in Ba/F3 and UT-7 cells; mitochondrial fractionation, DRP1 phosphorylation and apoptosis assays\",\n      \"pmids\": [\"22952242\", \"22955947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SOCS6 attenuates DRP1 phosphorylation mechanistically (recruitment of PGAM5 vs direct) not fully resolved\", \"Relationship between RTK-degradation and mitochondrial functions of SOCS6 unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established a developmental substrate in vivo by showing Socs6/Socs7 loss phenocopies reelin deficiency through accumulation of phosphorylated DAB1, demonstrating SOCS6 terminates reelin signaling by SH2-mediated DAB1 binding and degradation.\",\n      \"evidence\": \"Socs6/Socs7 double-knockout mice, genetic epistasis, ex vivo binding and DAB1 mutation analysis, cortical neuron immunostaining\",\n      \"pmids\": [\"26503265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional redundancy between SOCS6 and SOCS7 not separated\", \"Direct demonstration of DAB1 ubiquitination by SOCS6 in vivo not shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Broadened the tumor-suppressive program by linking SOCS6 to pro-apoptotic and anti-angiogenic transcriptional outputs in prostate cancer, identifying candidate downstream effectors.\",\n      \"evidence\": \"SOCS6 overexpression, RNA-seq, in vitro and xenograft angiogenesis/apoptosis assays\",\n      \"pmids\": [\"29295692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the RNA-seq targets are direct SOCS6 substrates or secondary effects unknown\", \"No degradation substrate identified for the anti-angiogenic effect\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected SOCS6's c-KIT ubiquitination activity to a therapeutic phenotype, showing SOCS6 promotes radiosensitivity and reduces cancer stem cell properties in esophageal carcinoma, while its loss enhances DNA repair and G2/M arrest in a partly p53-dependent manner.\",\n      \"evidence\": \"Overexpression and knockdown, Co-IP/ubiquitin blotting for c-Kit, clonogenic survival, cell cycle, DNA damage and apoptosis assays, transcriptome sequencing, xenografts\",\n      \"pmids\": [\"33712005\", \"33689885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking c-Kit degradation to DNA repair/cell cycle not defined\", \"Nature of p53-SOCS6 transcriptional dependence unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed the elongin-BC-binding BC-box motif of SOCS6 is sufficient to drive JAK2 ubiquitination and inhibit JAK2-STAT3 signaling, mechanistically tying SOCS6 to STAT pathway suppression and a neuronal differentiation outcome.\",\n      \"evidence\": \"Intracellular peptide delivery, JAK2 ubiquitination and STAT3 pathway assays, in vivo transplantation\",\n      \"pmids\": [\"32668737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of full-length SOCS6 to JAK2 not demonstrated\", \"Peptide-based readout may not reflect endogenous regulation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified new degradation substrates and metabolic outputs, showing SOCS6 ubiquitinates SLC7A11 to drive ferroptosis and suppresses fatty acid synthesis enzymes in ovarian cancer.\",\n      \"evidence\": \"Overexpression, Co-IP, ubiquitination assay, GSH/ROS/Fe2+ and lipid-enzyme measurements, xenografts\",\n      \"pmids\": [\"41061872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SLC7A11 binding is SH2/phosphotyrosine-dependent not addressed\", \"Mechanism of FASN/ACC downregulation (direct vs transcriptional) unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved upstream RNA-level control of SOCS6, showing m6A demethylation by FTO and lncRNA CASC2/U2AF2-mediated stabilization tune SOCS6 mRNA stability to govern inflammatory and macrophage-polarization outcomes.\",\n      \"evidence\": \"MeRIP/RIP mapping, FTO and U2AF2 knockdown, mRNA stability assays, exosome transfer, in vivo disease models\",\n      \"pmids\": [\"41644088\", \"40065730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct integration of mRNA-level control with SOCS6 protein function not shown\", \"Tissue-specificity of these RNA-regulatory axes unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SOCS6 partitions between its E3-adaptor degradation function and its non-degradative mitochondrial fission/apoptosis role, and what governs substrate selection across its many phosphotyrosine targets, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model coordinating cytoplasmic, nuclear, and mitochondrial SOCS6 pools\", \"Substrate hierarchy and context-dependence of SH2-mediated targeting undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 6, 8, 11, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 7, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 13]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 9, 16]}\n    ],\n    \"complexes\": [\"Elongin BC E3 ubiquitin ligase complex\", \"SOCS6-DRP1-PGAM5 mitochondrial complex\"],\n    \"partners\": [\"KIT\", \"FLT3\", \"LCK\", \"DAB1\", \"DNM1L\", \"PGAM5\", \"SLC7A11\", \"ELOC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}