{"gene":"SOCS3","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":1999,"finding":"SOCS3 (CIS3) inhibits JAK2 tyrosine kinase activity by two mechanisms: its SH2 domain binds the phosphorylated Y1007 in the activation loop of JAK2 JH1 domain, and its N-terminal kinase inhibitory region (KIR) binds the JH1 domain and directly inhibits kinase activity. Both the SH2 domain and KIR are required for full inhibition, with CIS3-KIR showing stronger binding to JH1 than SOCS1/JAB-KIR.","method":"In vitro kinase assay, binding studies with SH2 domain mutants, chimeric protein analysis, co-immunoprecipitation of endogenous CIS3 with JAK2","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assays combined with mutagenesis and chimeric protein analysis, with mechanistic dissection of both SH2 and KIR contributions","pmids":["10421843"],"is_preprint":false},{"year":1999,"finding":"SOCS3 binds JAK2 in leptin-stimulated cells (co-immunoprecipitation) and inhibits JAK2 tyrosine phosphorylation when overexpressed, thereby acting as a leptin-regulated inhibitor of proximal leptin signaling. SOCS3 expression is induced by leptin specifically (not CIS, SOCS1, or SOCS2) in cells expressing the long-form leptin receptor.","method":"Co-immunoprecipitation of JAK2 with SOCS3 in COS cells; transfection studies showing inhibition of leptin-induced JAK2 phosphorylation; (125)I-leptin binding assay to exclude receptor downregulation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional overexpression assay with receptor surface expression control, single lab","pmids":["10514492"],"is_preprint":false},{"year":2000,"finding":"SOCS3 binds the erythropoietin receptor (EPOR) at a region containing Tyr401 in the cytoplasmic domain, and also binds JAK2; binding to both is required for full suppression of EPO-dependent proliferation and STAT5 activation. Gly45 in the N-terminal region of SOCS3 is critical for EPOR binding but not JAK2 binding, while Leu22 is critical for JAK2 binding; L22D mutant completely loses inhibitory activity.","method":"Co-immunoprecipitation, deletion/point mutagenesis of SOCS3 and EPOR, Ba/F3 cell proliferation assay, STAT5 phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (mutagenesis, Co-IP, functional proliferation and signaling assays) in a single rigorous study","pmids":["10882725"],"is_preprint":false},{"year":2000,"finding":"Insulin induces SOCS3 translocation from an intracellular compartment to the cell membrane, where it colocalizes with the insulin receptor at phosphotyrosine 960; SOCS3 binds the insulin receptor at pY960 (demonstrated by yeast two-hybrid) and competes with Stat5B for this site to inhibit insulin-stimulated Stat5B activation. Colocalization is dependent on IR tyrosine 960 phosphorylation.","method":"Yeast two-hybrid binding assay, confocal microscopy of SOCS3 translocation, IR Y960F mutant cells, Stat5B luciferase reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — yeast two-hybrid plus confocal microscopy plus IR mutant functional analysis, multiple orthogonal methods in one study","pmids":["10821852"],"is_preprint":false},{"year":2001,"finding":"CIS3/SOCS3 plays a negative regulatory role in STAT3 activation in intestinal inflammation; in transgenic mice expressing an activating JAK mutant (F59D-JAB) that overcomes CIS3 inhibition, DSS-induced STAT3 activation and colitis severity were markedly enhanced, demonstrating that CIS3 downregulates STAT3 activity in vivo.","method":"Transgenic mouse model expressing dominant-active JAK mutant overcoming SOCS3 inhibition; DSS-induced colitis model; STAT3 phosphorylation analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with clear phenotypic and molecular readouts, replicated across multiple colitis models","pmids":["11181699"],"is_preprint":false},{"year":2001,"finding":"SOCS1 and SOCS3 promote ubiquitin-mediated degradation of IRS1 and IRS2 via the elongin BC ubiquitin-ligase complex; mutations in the conserved SOCS box abolish interaction with elongin BC without affecting IRS1/2 binding, and these mutants fail to promote IRS ubiquitination/degradation or cause glucose intolerance upon adenoviral liver expression.","method":"Co-immunoprecipitation of endogenous and recombinant IRS1/2; ubiquitination assays; adenoviral overexpression in mouse liver; SOCS box point mutants; glucose tolerance test","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of SOCS box combined with in vivo adenoviral liver reconstitution and glucose tolerance testing, plus Co-IP in multiple cell types","pmids":["12228220"],"is_preprint":false},{"year":1999,"finding":"The SOCS3 promoter contains a STAT1/STAT3 binding element at nucleotides -72 to -64 that is essential for LIF-stimulated SOCS3 promoter activity; SOCS3 overexpression or dominant-negative STAT3 blocks LIF-induced SOCS3 mRNA expression, establishing a negative autoregulatory loop in corticotroph cells.","method":"5' RACE and RNase protection assay to map transcription start site; luciferase promoter deletion/mutation assays; EMSA confirming STAT1/STAT3 binding; stable transfection of dominant-negative STAT3","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — promoter mutagenesis, EMSA, and functional luciferase assays with dominant-negative STAT3, multiple orthogonal methods","pmids":["10359822"],"is_preprint":false},{"year":2002,"finding":"SOCS3 associates with the insulin receptor (IR) and directly inhibits IR autophosphorylation in vitro; ectopic SOCS3 suppresses insulin-dependent IR autophosphorylation, IRS-1 tyrosine phosphorylation, IRS-1 association with PI3K p85, and Akt activation; IL-6-induced SOCS3 in liver coincides with inhibition of hepatic insulin signaling in vivo.","method":"In vitro IR autophosphorylation assay; co-immunoprecipitation of SOCS3 with IR; Western blotting for downstream signaling in HepG2 cells and mouse liver","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus in vivo mouse liver studies plus Co-IP, single lab but multiple orthogonal methods","pmids":["12560330"],"is_preprint":false},{"year":2002,"finding":"SOCS3 and SHP2 both act through gp130 tyrosine 759 to attenuate IL-6 signaling, but by two largely distinct mechanisms: receptor/membrane-targeted SHP2 counteracts IL-6 signaling independently of SOCS3 binding; conversely, SOCS3 inhibits signaling in cells expressing truncated SHP2 not recruited to gp130.","method":"Chimeric receptor constructs targeting SHP2 or SOCS3 independently to gp130; signaling readouts in reconstituted cell systems","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimeric receptor epistasis, single lab, two orthogonal constructs","pmids":["12403768"],"is_preprint":false},{"year":2003,"finding":"SOCS3 interacts with phosphorylated CD28 through its SH2 domain (not the KIR), and a point mutation in the SOCS3 SH2 domain attenuates inhibition of CD28-mediated IL-2 promoter activation; SOCS3 transgenic T cells show reduced CD28-mediated IL-2 production, while SOCS3+/- mice show enhanced IL-2 production.","method":"Co-immunoprecipitation of SOCS3 with phospho-CD28; SOCS3 SH2 domain point mutant; SOCS3 transgenic and heterozygous knockout mice; IL-2 promoter luciferase reporter assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, SH2 domain mutagenesis, and genetic models (transgenic + heterozygous KO) with concordant phenotypes","pmids":["12591901"],"is_preprint":false},{"year":1999,"finding":"LIF induces SOCS3 binding to JAK2 after 60 minutes of stimulation in pituitary corticotroph cells, followed by proteasomal degradation of the complex; SOCS3 overexpression blocks LIF-induced JAK2 tyrosine phosphorylation; SHP-1 is constitutively associated with JAK2 and mediates early dephosphorylation, while SOCS3 mediates later inhibition.","method":"Co-immunoprecipitation of SOCS3 with JAK2; SOCS3 overexpression blocking JAK2 phosphorylation; proteasome inhibitor rescue; SOCS3 deletion construct functional mapping","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional overexpression with proteasome inhibitor, single lab","pmids":["10545526"],"is_preprint":false},{"year":2003,"finding":"Restoration of SOCS3 expression in lung cancer cells where SOCS3 was silenced by CpG methylation resulted in downregulation of active STAT3, induction of apoptosis, and growth suppression, demonstrating SOCS3 tumor suppressor function through JAK/STAT inhibition.","method":"SOCS3 re-expression in methylation-silenced cell lines; STAT3 phosphorylation Western blot; apoptosis and growth assays; methylation-specific PCR","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function reconstitution with defined molecular readout, single lab, multiple cancer cell lines","pmids":["14617776"],"is_preprint":false},{"year":2003,"finding":"SOCS3 interacts with the IGF-I receptor (IGFIR) constitutively in vitro and in intact cells; SOCS3 binds activated IGFIR and IR cytoplasmic domains in yeast two-hybrid assay and GST pull-down; SOCS3 is tyrosine-phosphorylated by IGF-I stimulation, suggesting it is a direct substrate of the IGFIR kinase.","method":"Yeast two-hybrid assay; GST pull-down; co-immunoprecipitation of FLAG-SOCS3 with IGFIR in HEK293 cells; anti-phosphotyrosine immunoprecipitation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by GST pull-down and Co-IP, single lab","pmids":["11071852"],"is_preprint":false},{"year":2004,"finding":"IFN-γ induces SOCS3 via a STAT1-binding element (SBE) at -72/-64 in the SOCS3 promoter; mutation of the SBE abolishes IFN-γ responsiveness; IFN-γ promotes STAT1 (not STAT3) binding to the SBE in macrophages; IFN-γ-induced SOCS3 expression is intact in STAT3-deficient fibroblasts.","method":"Promoter deletion/point mutation luciferase assays; EMSA; IFN-γ treatment of macrophages, J774 cells, and STAT3-deficient fibroblasts; Western blotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — promoter mutagenesis, EMSA, and STAT3-KO cell validation with multiple orthogonal methods","pmids":["14742442"],"is_preprint":false},{"year":2005,"finding":"Resistin markedly induces SOCS3 gene expression in 3T3-L1 adipocytes and increases SOCS3 protein association with the insulin receptor; inhibition of SOCS function prevents resistin from antagonizing insulin action, establishing SOCS3 induction as a mediator of resistin-induced insulin resistance.","method":"RT-PCR and Western blot for SOCS3 induction; Co-IP of SOCS3 with IR; SOCS inhibition functional rescue of insulin signaling","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus SOCS inhibition rescue experiment, single lab","pmids":["15684405"],"is_preprint":false},{"year":2007,"finding":"SOCS3 regulates CXCL12-induced FAK phosphorylation through the ubiquitin-proteasome pathway during B lymphopoiesis; CXCL12 triggers increased FAK ubiquitination in mature (high SOCS3) but not progenitor (low SOCS3) B cells; SOCS3 overexpression in pro-B cells impairs CXCL12-induced FAK phosphorylation and adhesion; SOCS3-deficient mature B cells show prolonged FAK phosphorylation and adhesion to VCAM-1.","method":"FAK ubiquitination assay; SOCS3 overexpression in pro-B cells; conditional SOCS3 knockout (Cre(MMTV)Socs3fl/fl) mature B cells; VCAM-1 adhesion assay; flow cytometry of BM compartments","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and overexpression with ubiquitination assay and functional adhesion readouts, multiple orthogonal methods","pmids":["18031698"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of a ternary complex of SOCS3, JAK2 kinase domain, and a fragment of the IL-6 receptor β-chain (gp130) shows that SOCS3 binds JAK2 and receptor simultaneously using two opposing surfaces; the SOCS3 SH2 domain phosphotyrosine-binding groove is occupied by the receptor, while JAK2 binds a non-canonical surface in a phospho-independent manner; the kinase inhibitory region (KIR) of SOCS3 occludes the substrate-binding groove of JAK2, blocking substrate association.","method":"X-ray crystallography of ternary SOCS3/JAK2/gp130 complex; biochemical substrate association assays; structure-guided mutagenesis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biochemical validation, definitive mechanistic study replicated by multiple subsequent reviews","pmids":["23454976"],"is_preprint":false},{"year":2014,"finding":"SOCS3 selectively inhibits JAK1, JAK2, and TYK2 (but not JAK3) through a three-residue 'GQM' motif in the kinase domain of these JAKs; SOCS3 binds JAK and gp130 simultaneously and inhibits JAK activity in an ATP-independent manner by partially occluding the kinase substrate-binding groove with its KIR.","method":"Biochemical binding studies; mutagenesis of the GQM motif; structural and biochemical analyses building on the SOCS3/JAK2/gp130 crystal structure","journal":"Seminars in immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biochemical and structural analysis, single lab, review-style but incorporating primary biochemical data","pmids":["24418198"],"is_preprint":false},{"year":2015,"finding":"SOCS3 promotes K48-linked polyubiquitination of TBK1 at Lys341 and Lys344, leading to proteasomal degradation of TBK1; SOCS3 directly associates with TBK1 and colocalizes in the cytoplasm; both the BOX domain of SOCS3 and Ser172 phosphorylation of TBK1 are required for this ubiquitination and degradation; SOCS3 thereby inhibits IRF3 phosphorylation and IFN-β transcription and facilitates influenza virus replication.","method":"Co-immunoprecipitation of SOCS3 with TBK1; K48-ubiquitin linkage-specific assay; SOCS3 overexpression and knockdown; SOCS3 BOX domain mutant; TBK1 Lys341/344 and Ser172 mutants; IRF3 phosphorylation and IFN-β reporter assays; viral RNA quantification","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of both SOCS3 BOX domain and TBK1 ubiquitination sites, combined with K48-specific ubiquitin assay and functional antiviral readouts, multiple orthogonal methods","pmids":["25939384"],"is_preprint":false},{"year":2011,"finding":"Simultaneous deletion of both PTEN and SOCS3 in adult retinal ganglion cells enables robust and sustained long-distance axon regeneration, whereas deletion of either alone produces only transient regeneration; PTEN and SOCS3 regulate independent pathways (mTOR and JAK/STAT3, respectively) that act synergistically.","method":"Conditional knockout mice (PTEN-/- and SOCS3-/- single and double deletion in RGCs); optic nerve crush model; gene expression analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with double KO, clear sustained regeneration phenotype, combined with gene expression pathway analysis","pmids":["22056987"],"is_preprint":false},{"year":2012,"finding":"SOCS3-deficient macrophages (LysMCre-SOCS3fl/fl) exhibit enhanced and prolonged activation of JAK/STAT1 and STAT3 pathways, higher M1 proinflammatory gene expression due to enhanced transcriptional activation and chromatin modifications, and stronger capacity to induce Th1 and Th17 differentiation; SOCS3 deficiency exacerbates LPS-induced sepsis with enhanced STAT1/3 activation.","method":"Conditional myeloid SOCS3 knockout mice; LPS sepsis model; cytokine ELISA; STAT phosphorylation Western blot; Th1/Th17 differentiation assay; chromatin modification analysis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined molecular mechanism (STAT activation, chromatin changes) and multiple in vivo and in vitro readouts","pmids":["22925925"],"is_preprint":false},{"year":2018,"finding":"Ezh2 suppresses SOCS3 expression via H3K27 trimethylation of the Socs3 locus in macrophages/microglia; Ezh2 deficiency stimulates SOCS3 expression, which enhances K48-linked ubiquitination and degradation of TRAF6, thereby compromising TLR-induced MyD88-dependent NF-κB activation; silencing SOCS3 restores macrophage activation in Ezh2-deficient mice.","method":"Conditional Ezh2 KO macrophages; ChIP for H3K27me3 at Socs3 locus; TRAF6 ubiquitination assay; SOCS3 siRNA rescue experiment; DSS colitis and EAE models","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, ubiquitination assay, and genetic rescue (SOCS3 silencing in Ezh2 KO) with in vivo validation in two disease models","pmids":["29626115"],"is_preprint":false},{"year":2012,"finding":"Bcr-Abl tyrosine-phosphorylates SOCS3 primarily at Tyr221, which binds Bcr-Abl; this phosphorylation diminishes SOCS3's inhibitory effects on JAK/STAT5 signaling; mutation of Tyr221 phosphorylation site impairs Bcl-XL expression, sensitizes leukemic cells to apoptosis, and significantly blocks Bcr-Abl-mediated tumorigenesis in nude mice and bone marrow transformation.","method":"Co-immunoprecipitation of phospho-SOCS3 with Bcr-Abl; site-directed mutagenesis of SOCS3 Y221; JAK/STAT5 phosphorylation assays; nude mouse tumorigenesis assay; murine bone marrow transformation assay","journal":"Neoplasia (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific phosphorylation site with in vitro signaling and in vivo tumorigenesis validation, multiple orthogonal methods","pmids":["22787435"],"is_preprint":false},{"year":2019,"finding":"SOCS3 inhibits NF-κB p65 expression and activity by interacting with it and inducing ubiquitin-dependent proteasomal degradation of p65; the SH2 domain of SOCS3 is critical for the SOCS3-p65 interaction and p65 degradation; SOCS3 expression promotes HIV-1 replication, and HIV-1 downregulates SOCS3 early in infection to promote inflammatory responses.","method":"Co-immunoprecipitation of SOCS3 with p65; SOCS3 SH2 domain mutant; ubiquitination and proteasomal degradation assays; overexpression and knockdown experiments; HIV-1 replication assays","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with SH2 mutant and ubiquitination assay, single lab","pmids":["30766526"],"is_preprint":false},{"year":2006,"finding":"SOCS3 is required to terminate residual STAT3 activation postnatally (after P0) in retinal cells; SOCS3 deficiency fails to shut down STAT3 activity, thereby delaying Rhodopsin expression and rod photoreceptor cell differentiation; SOCS3 protein expression is post-transcriptionally suppressed during late embryogenesis (mRNA is constant but protein absent) and released postnatally to fine-tune STAT3.","method":"Conditional SOCS3 knockout retina; immunofluorescence for STAT3 phosphorylation; Rhodopsin and Crx expression analysis; comparison of mRNA vs. protein levels","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with molecular signaling readout, single lab, clear phenotype","pmids":["17198696"],"is_preprint":false},{"year":2021,"finding":"Endothelial SOCS3 has a very short protein half-life (< 20 minutes) regulated by ubiquitination and proteasomal degradation; inhibition of SOCS3 ubiquitination and proteasomal degradation leads to protein accumulation and stronger inhibition of IL-6 signaling and barrier function; loss of endothelial SOCS3 causes LPS-induced type I IFN-like gene program, prothrombotic/proadhesive gene expression, NETosis, and lethal kidney failure.","method":"Conditional endothelial SOCS3 knockout mice (SOCS3iEKO); pulse-chase half-life experiments in HUVECs; proteasome inhibitor studies; LPS challenge model; gene expression analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — pulse-chase protein stability assays combined with proteasome inhibitor rescue and conditional KO with defined in vivo phenotype","pmids":["34138760"],"is_preprint":false},{"year":2020,"finding":"SOCS3 absence in myeloid cells leads to substantial accumulation of microglia/macrophages during ocular neovascularization and increased Spp1 gene expression; SPP1 is identified as a direct transcriptional target of STAT3; pharmaceutical SOCS3 activation or SPP1 blockade reduces pathological neovascularization, establishing a SOCS3/STAT3/SPP1 axis in retinal angiogenesis.","method":"Myeloid-specific SOCS3 conditional KO; single-cell RNA sequencing; STAT3 ChIP on SPP1 promoter; pharmacological SOCS3 activation; SPP1 blocking antibody in angiogenesis mouse model","journal":"Molecular therapy : the journal of the American Society of Gene Therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO plus ChIP plus pharmacological rescue, single lab","pmids":["38504518"],"is_preprint":false},{"year":2020,"finding":"DNMT1-mediated hypermethylation of the SOCS3 promoter leads to SOCS3 downregulation in diabetic cardiac fibrosis; high glucose increases DNMT1 expression in cardiac fibroblasts; reduced SOCS3 enables STAT3 activation to promote cardiac fibroblast activation and collagen deposition; genetic or pharmacological DNMT1 inactivation reverses the activated fibroblast phenotype.","method":"Western blot and qPCR in diabetic cardiac fibroblasts; methylation-specific PCR; DNMT1 genetic knockdown; STAT3 phosphorylation assays; collagen deposition assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — methylation-specific PCR plus DNMT1 knockdown rescue with functional fibroblast phenotype readouts, single lab","pmids":["32989761"],"is_preprint":false},{"year":2005,"finding":"SOCS3 overexpression in Th2 cells specifically inhibits IFN-α-mediated growth inhibition without affecting STAT3 activation, growth, or apoptosis in CTCL tumor cells; dominant-negative STAT3 reduces SOCS3 expression and increases IFN-α-mediated growth inhibition, showing STAT3-driven constitutive SOCS3 expression protects tumor cells from IFN-α.","method":"SOCS3 overexpression in CTCL cells; dominant-negative STAT3 transfection; cell growth and apoptosis assays; IFN-α sensitivity assay","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression and dominant-negative experiments with defined functional readout, single lab","pmids":["15618960"],"is_preprint":false},{"year":2005,"finding":"SOCS3 overexpression in primary CD4+ T cells decreases proliferation, FoxP3 and CTLA-4 expression, and suppressive function of regulatory T cells; naturally occurring Treg cells are deficient in SOCS3 protein expression compared with effector T cells, allowing them to respond rapidly to IL-2 and IL-6.","method":"SOCS3 overexpression in Treg cells; flow cytometry for FoxP3/CTLA-4; T cell suppression assay; comparison of SOCS3 levels in Treg vs. Th cells","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SOCS3 overexpression with functional suppression assay plus endogenous level comparison, single lab","pmids":["17621372"],"is_preprint":false},{"year":2005,"finding":"SOCS3 negatively regulates HGF-induced keratinocyte migration by inhibiting STAT3 phosphorylation; dominant-negative STAT3 abolishes HGF-induced migration; SOCS3 overexpression abolishes HGF-induced STAT3 phosphorylation and keratinocyte migration.","method":"Transfection of dominant-negative STAT3 and SOCS3 overexpression constructs; STAT3 phosphorylation Western blot; keratinocyte migration assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression and dominant-negative with functional migration assay plus molecular readout, single lab","pmids":["15629435"],"is_preprint":false},{"year":2008,"finding":"OSM-induced SOCS3 expression in astrocytes requires STAT3 activation and AP-1 element, two GAS elements, and a GC-rich region in the SOCS3 promoter; ERK1/2 and JNK pathways also contribute; OSM stimulation leads to time-dependent recruitment of STAT3, c-Fos, c-Jun, Sp1, CBP, and p300 to the endogenous SOCS3 promoter.","method":"SOCS3 promoter deletion/mutation luciferase assays; siRNA against STAT3; dominant-negative STAT3; ChIP assay for promoter occupancy by multiple transcription factors","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis, STAT3 siRNA/DN, and ChIP in primary astrocytes, single lab","pmids":["18571793"],"is_preprint":false},{"year":2023,"finding":"PTK6 binds to SOCS3 and SOCS3 downregulates PTK6 expression; PTK6 upregulates mTOR phosphorylation to inhibit autophagy in uveal melanoma cells; SOCS3 overexpression partially rescues PTK6-induced promotion of cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation of PTK6 with SOCS3; overexpression and knockdown experiments; mTOR phosphorylation Western blot; autophagy assays; proliferation/migration/invasion assays","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — Co-IP with functional rescue, single lab, mechanism partially defined","pmids":["36690663"],"is_preprint":false}],"current_model":"SOCS3 is a cytokine-inducible feedback inhibitor of JAK/STAT signaling that functions by simultaneously binding specific cytokine receptors (e.g., gp130 at pY759, EPOR at pY401, IR at pY960) via its SH2 domain and inhibiting JAK1/2/TYK2 (but not JAK3) catalytic activity via its kinase inhibitory region (KIR), which occludes the JAK substrate-binding groove; additionally, SOCS3 promotes ubiquitin-mediated proteasomal degradation of target proteins (IRS1/2, TBK1, TRAF6, p65) through its SOCS box, which recruits the elongin BC E3 ligase complex, and its own protein levels are tightly controlled by proteasomal degradation with a half-life of less than 20 minutes, while its gene expression is transcriptionally induced by STAT1 (via IFN-γ) and STAT3 (via IL-6 family cytokines and leptin) binding to a conserved element at -72/-64 in its promoter."},"narrative":{"mechanistic_narrative":"SOCS3 is a cytokine-inducible feedback inhibitor of JAK/STAT signaling that terminates receptor-proximal kinase activity and targets signaling components for proteasomal destruction [PMID:10421843, PMID:23454976, PMID:22925925]. It inhibits JAK2 through a dual mechanism in which its SH2 domain engages the kinase while its N-terminal kinase inhibitory region (KIR) directly suppresses catalytic activity [PMID:10421843]; structural analysis of a SOCS3/JAK2/gp130 ternary complex resolved how SOCS3 binds receptor and kinase simultaneously on opposing surfaces—the SH2 phosphotyrosine groove occupied by receptor while the KIR occludes the JAK substrate-binding groove in an ATP-independent manner [PMID:23454976], a mechanism extended to selective inhibition of JAK1, JAK2, and TYK2 but not JAK3 via a 'GQM' motif in the kinase domain [PMID:24418198]. SOCS3 docks onto defined receptor phosphotyrosines—gp130/IL-6R, the erythropoietin receptor at Tyr401, and the insulin receptor at pY960—where it competes with STATs and attenuates downstream activation [PMID:10882725, PMID:10821852, PMID:23454976]. Through its SOCS box, SOCS3 recruits the elongin BC E3 ligase complex to drive ubiquitin-mediated proteasomal degradation of substrates including IRS1/IRS2, and independent studies establish K48-linked ubiquitination of TBK1, TRAF6, NF-κB p65, and FAK as effector arms that dampen insulin, antiviral, and inflammatory signaling [PMID:12228220, PMID:25939384, PMID:29626115, PMID:30766526, PMID:18031698]. SOCS3 transcription is induced through a conserved STAT element at -72/-64 in its promoter, bound by STAT3 downstream of IL-6-family cytokines and leptin and by STAT1 downstream of IFN-γ, forming a negative autoregulatory loop [PMID:10359822, PMID:14742442, PMID:10514492]; its protein levels are additionally constrained by a half-life of under 20 minutes set by ubiquitin/proteasome turnover [PMID:34138760]. Functionally, SOCS3 restrains STAT3-driven inflammation in vivo, limits M1 macrophage and Th1/Th17 responses, acts as a brake on tumor cell survival, and regulates tissue processes from photoreceptor differentiation to axon regeneration where it acts in parallel with the PTEN/mTOR pathway [PMID:11181699, PMID:22925925, PMID:14617776, PMID:17198696, PMID:22056987].","teleology":[{"year":1999,"claim":"Established the core biochemical mechanism of SOCS3 inhibition, answering how a single protein blocks a JAK kinase.","evidence":"In vitro kinase assays, SH2/KIR mutants, and chimeric protein analysis with endogenous CIS3/JAK2 Co-IP","pmids":["10421843"],"confidence":"High","gaps":["Did not resolve the structural basis of KIR-mediated inhibition","Receptor-context dependence of inhibition not addressed"]},{"year":1999,"claim":"Defined SOCS3 transcription as a STAT-driven negative autoregulatory loop, explaining how cytokine signaling self-limits.","evidence":"Transcription start mapping, promoter mutagenesis, EMSA, and dominant-negative STAT3 in corticotrophs","pmids":["10359822","10545526"],"confidence":"High","gaps":["Did not distinguish STAT1 vs STAT3 contributions at the element","Chromatin context of induction not addressed"]},{"year":2000,"claim":"Showed SOCS3 engages specific receptor phosphotyrosines (EPOR Tyr401, IR pY960) in addition to JAK, explaining receptor selectivity and STAT competition.","evidence":"Yeast two-hybrid, point/deletion mutagenesis, confocal imaging of translocation, and STAT5/STAT5B functional assays","pmids":["10882725","10821852"],"confidence":"High","gaps":["Affinity ranking across different receptors not established","Did not address simultaneous receptor and JAK binding geometry"]},{"year":2001,"claim":"Provided in vivo genetic proof that SOCS3 restrains STAT3 activity, moving the mechanism from cell culture to physiology.","evidence":"Transgenic mice expressing a JAK mutant overcoming SOCS3 inhibition in a DSS colitis model","pmids":["11181699"],"confidence":"High","gaps":["Indirect (used JAK mutant rather than SOCS3 deletion)","Cell-type-specific contributions not resolved"]},{"year":2002,"claim":"Identified the SOCS box/elongin BC degradation arm, showing SOCS3 acts not only as a kinase inhibitor but as an adaptor for proteasomal turnover of substrates like IRS1/2.","evidence":"SOCS box point mutants, ubiquitination assays, adenoviral liver expression and glucose tolerance testing","pmids":["12228220","12560330"],"confidence":"High","gaps":["Did not enumerate the full substrate repertoire","Relative contribution of kinase inhibition vs degradation not quantified"]},{"year":2003,"claim":"Extended SOCS3 targeting beyond cytokine receptors to CD28 and IGF-I receptor, and established its tumor-suppressor role via STAT3, broadening the functional scope.","evidence":"Co-IP, SH2 mutants, transgenic/heterozygous mouse T cells, and re-expression in methylation-silenced cancer lines","pmids":["12591901","11071852","14617776"],"confidence":"High","gaps":["IGFIR interaction functional consequence not fully resolved","Tumor suppression mechanism limited to STAT3 readout"]},{"year":2004,"claim":"Resolved that IFN-γ induces SOCS3 through STAT1 (not STAT3) at the same -72/-64 element, clarifying input-specific transcriptional control.","evidence":"Promoter mutagenesis, EMSA, and IFN-γ treatment of STAT3-deficient fibroblasts","pmids":["14742442"],"confidence":"High","gaps":["Did not address co-regulatory factors at the element","Kinetics of STAT1 vs STAT3 occupancy not compared"]},{"year":2012,"claim":"Showed SOCS3 itself is regulated by tyrosine phosphorylation (Bcr-Abl at Tyr221), revealing a mechanism by which oncogenic kinases neutralize the inhibitor.","evidence":"Co-IP of phospho-SOCS3, Y221 mutagenesis, STAT5 assays, and nude-mouse/bone-marrow transformation","pmids":["22787435"],"confidence":"High","gaps":["Whether other kinases phosphorylate Tyr221 unknown","Structural effect of phosphorylation on KIR not defined"]},{"year":2013,"claim":"Definitively explained the structural logic of dual binding and KIR-mediated inhibition via the SOCS3/JAK2/gp130 ternary crystal structure.","evidence":"X-ray crystallography with biochemical substrate-association assays and structure-guided mutagenesis","pmids":["23454976"],"confidence":"High","gaps":["Did not capture the full-length JAK or membrane context","Dynamics of ternary assembly not resolved"]},{"year":2014,"claim":"Mapped JAK selectivity to a 'GQM' kinase-domain motif, explaining why SOCS3 spares JAK3.","evidence":"Biochemical binding and GQM-motif mutagenesis building on the ternary structure","pmids":["24418198"],"confidence":"Medium","gaps":["Single-lab biochemical analysis","Cellular validation of motif requirement limited"]},{"year":2015,"claim":"Established TBK1 as a SOCS3 ubiquitination substrate, defining an antiviral/innate-immune effector arm distinct from JAK/STAT.","evidence":"K48-specific ubiquitination assays, SOCS3 BOX and TBK1 Lys/Ser mutants, IRF3/IFN-β readouts and viral RNA quantification","pmids":["25939384"],"confidence":"High","gaps":["Did not establish E3 ligase identity for TBK1 in this context","In vivo significance during infection not tested here"]},{"year":2018,"claim":"Showed SOCS3 controls TLR/NF-κB signaling through TRAF6 degradation and is itself epigenetically silenced by Ezh2/H3K27me3, integrating chromatin control with inflammatory output.","evidence":"ChIP for H3K27me3, TRAF6 ubiquitination assay, SOCS3 siRNA rescue in Ezh2-KO macrophages, and colitis/EAE models","pmids":["29626115"],"confidence":"High","gaps":["Direct vs indirect SOCS3-TRAF6 interaction not fully resolved","Generality of Ezh2 control across cell types unknown"]},{"year":2019,"claim":"Extended SOCS3-mediated degradation to NF-κB p65 via the SH2 domain, defining a further branch of inflammatory restraint relevant to viral infection.","evidence":"Co-IP, SOCS3 SH2 mutant, ubiquitination/degradation assays, and HIV-1 replication assays","pmids":["30766526"],"confidence":"Medium","gaps":["Single-lab study without reciprocal in vivo validation","Mechanism of SH2 binding to p65 phosphosite undefined"]},{"year":2021,"claim":"Quantified the rapid proteasomal turnover of SOCS3 protein (<20 min half-life) and tied its stability to the strength of IL-6 signaling control in endothelium.","evidence":"Pulse-chase in HUVECs, proteasome inhibitor studies, and conditional endothelial SOCS3-KO LPS challenge","pmids":["34138760"],"confidence":"High","gaps":["E3 ligase driving SOCS3 turnover not identified","Signals that stabilize SOCS3 not defined"]},{"year":2020,"claim":"Demonstrated tissue-level consequences of SOCS3/STAT3 control, including a STAT3/SPP1 axis in myeloid cells driving pathological angiogenesis and DNMT1-driven SOCS3 silencing in cardiac fibrosis.","evidence":"Myeloid SOCS3 conditional KO, scRNA-seq, STAT3 ChIP on SPP1, methylation-specific PCR, and DNMT1 knockdown","pmids":["38504518","32989761"],"confidence":"Medium","gaps":["Causal link from SOCS3 loss to specific STAT3 targets partly indirect","Single-lab disease-model findings"]},{"year":2011,"claim":"Placed SOCS3 in a parallel-pathway framework with PTEN/mTOR governing CNS axon regeneration, defining a non-cytokine developmental role.","evidence":"Single and double conditional KO of PTEN and SOCS3 in retinal ganglion cells with optic nerve crush","pmids":["22056987","17198696"],"confidence":"High","gaps":["Downstream effectors of SOCS3/STAT3 in regeneration not pinpointed","Whether degradation or kinase inhibition dominates here unknown"]},{"year":null,"claim":"The E3 ligase and signals that set SOCS3's own ultrashort half-life, and a unified accounting of when SOCS3 acts by kinase inhibition versus substrate degradation, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No ligase identified for SOCS3 autoturnover","Relative weighting of KIR inhibition vs SOCS-box degradation across contexts undefined","Stabilizing post-translational signals uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,16,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,16,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,18,21]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[5,18,23]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,16,2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[20,21,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,18,23]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,13,31]}],"complexes":["elongin BC E3 ubiquitin ligase complex"],"partners":["JAK2","IL6ST","EPOR","INSR","IRS1","TBK1","TRAF6","RELA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14543","full_name":"Suppressor of cytokine signaling 3","aliases":["Cytokine-inducible SH2 protein 3","CIS-3","STAT-induced STAT inhibitor 3","SSI-3"],"length_aa":225,"mass_kda":24.8,"function":"SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. SOCS3 is involved in negative regulation of cytokines that signal through the JAK/STAT pathway. Inhibits cytokine signal transduction by binding to tyrosine kinase receptors including IL6ST/gp130, LIF, erythropoietin, insulin, IL12, GCSF and leptin receptors. Binding to JAK2 inhibits its kinase activity and regulates IL6 signaling. Suppresses fetal liver erythropoiesis. Regulates onset and maintenance of allergic responses mediated by T-helper type 2 cells (By similarity). Probable 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 (PubMed:15601820)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O14543/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SOCS3","classification":"Not Classified","n_dependent_lines":167,"n_total_lines":1208,"dependency_fraction":0.1382450331125828},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SOCS3","total_profiled":1310},"omim":[{"mim_id":"621051","title":"PARALEMMIN 3; PALM3","url":"https://www.omim.org/entry/621051"},{"mim_id":"615952","title":"AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 1; ADMIO1","url":"https://www.omim.org/entry/615952"},{"mim_id":"614798","title":"PELLINO E3 UBIQUITIN PROTEIN LIGASE 2; PELI2","url":"https://www.omim.org/entry/614798"},{"mim_id":"612839","title":"TET METHYLCYTOSINE DIOXYGENASE 2; TET2","url":"https://www.omim.org/entry/612839"},{"mim_id":"612472","title":"METHYLTRANSFERASE 3, N6-ADENOSINE-METHYLTRANSFERASE COMPLEX CATALYTIC SUBUNIT; METTL3","url":"https://www.omim.org/entry/612472"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adipose tissue","ntpm":480.4}],"url":"https://www.proteinatlas.org/search/SOCS3"},"hgnc":{"alias_symbol":["SSI-3","CIS3","SOCS-3","Cish3"],"prev_symbol":[]},"alphafold":{"accession":"O14543","domains":[{"cath_id":"3.30.505.10","chopping":"21-131_164-185","consensus_level":"medium","plddt":81.5826,"start":21,"end":185},{"cath_id":"-","chopping":"186-225","consensus_level":"medium","plddt":70.7205,"start":186,"end":225}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14543","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14543-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14543-F1-predicted_aligned_error_v6.png","plddt_mean":71.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SOCS3","jax_strain_url":"https://www.jax.org/strain/search?query=SOCS3"},"sequence":{"accession":"O14543","fasta_url":"https://rest.uniprot.org/uniprotkb/O14543.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14543/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14543"}},"corpus_meta":[{"pmid":"12228220","id":"PMC_12228220","title":"SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12228220","citation_count":702,"is_preprint":false},{"pmid":"22056987","id":"PMC_22056987","title":"Sustained axon regeneration induced by co-deletion of PTEN and SOCS3.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22056987","citation_count":615,"is_preprint":false},{"pmid":"10514492","id":"PMC_10514492","title":"The role of SOCS-3 in leptin signaling and leptin resistance.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10514492","citation_count":494,"is_preprint":false},{"pmid":"12560330","id":"PMC_12560330","title":"Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12560330","citation_count":476,"is_preprint":false},{"pmid":"24600449","id":"PMC_24600449","title":"SOCS3, a Major Regulator of Infection and Inflammation.","date":"2014","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24600449","citation_count":459,"is_preprint":false},{"pmid":"11181699","id":"PMC_11181699","title":"CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation.","date":"2001","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11181699","citation_count":410,"is_preprint":false},{"pmid":"22925925","id":"PMC_22925925","title":"SOCS3 deficiency promotes M1 macrophage polarization and inflammation.","date":"2012","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/22925925","citation_count":386,"is_preprint":false},{"pmid":"10821852","id":"PMC_10821852","title":"SOCS-3 is an insulin-induced negative regulator of insulin signaling.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10821852","citation_count":366,"is_preprint":false},{"pmid":"11748261","id":"PMC_11748261","title":"Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis.","date":"2001","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/11748261","citation_count":328,"is_preprint":false},{"pmid":"10421843","id":"PMC_10421843","title":"Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain.","date":"1999","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/10421843","citation_count":325,"is_preprint":false},{"pmid":"14617776","id":"PMC_14617776","title":"SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/14617776","citation_count":319,"is_preprint":false},{"pmid":"12847520","id":"PMC_12847520","title":"SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12847520","citation_count":292,"is_preprint":false},{"pmid":"10882725","id":"PMC_10882725","title":"CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10882725","citation_count":260,"is_preprint":false},{"pmid":"23454976","id":"PMC_23454976","title":"SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition.","date":"2013","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23454976","citation_count":244,"is_preprint":false},{"pmid":"10359822","id":"PMC_10359822","title":"Autoregulation of pituitary corticotroph SOCS-3 expression: characterization of the murine SOCS-3 promoter.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10359822","citation_count":243,"is_preprint":false},{"pmid":"19643666","id":"PMC_19643666","title":"SOCS1 and SOCS3 in the control of CNS immunity.","date":"2009","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19643666","citation_count":237,"is_preprint":false},{"pmid":"16007096","id":"PMC_16007096","title":"Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis.","date":"2005","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16007096","citation_count":220,"is_preprint":false},{"pmid":"15684405","id":"PMC_15684405","title":"Activation of SOCS-3 by resistin.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15684405","citation_count":209,"is_preprint":false},{"pmid":"12403768","id":"PMC_12403768","title":"SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12403768","citation_count":184,"is_preprint":false},{"pmid":"10515892","id":"PMC_10515892","title":"Interleukin-10 (IL-10) selectively enhances CIS3/SOCS3 mRNA expression in human neutrophils: evidence for an IL-10-induced pathway that is independent of STAT protein activation.","date":"1999","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10515892","citation_count":180,"is_preprint":false},{"pmid":"17241887","id":"PMC_17241887","title":"Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing.","date":"2006","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/17241887","citation_count":180,"is_preprint":false},{"pmid":"16710471","id":"PMC_16710471","title":"SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis.","date":"2006","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/16710471","citation_count":175,"is_preprint":false},{"pmid":"24418198","id":"PMC_24418198","title":"Inhibition of IL-6 family cytokines by SOCS3.","date":"2014","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24418198","citation_count":170,"is_preprint":false},{"pmid":"29626115","id":"PMC_29626115","title":"Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3.","date":"2018","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29626115","citation_count":152,"is_preprint":false},{"pmid":"18713987","id":"PMC_18713987","title":"Expression and functional significance of SOCS-1 and SOCS-3 in astrocytes.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18713987","citation_count":112,"is_preprint":false},{"pmid":"30341772","id":"PMC_30341772","title":"The roles of SOCS3 and STAT3 in bacterial infection and inflammatory diseases.","date":"2018","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30341772","citation_count":111,"is_preprint":false},{"pmid":"11159537","id":"PMC_11159537","title":"STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma.","date":"2001","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11159537","citation_count":103,"is_preprint":false},{"pmid":"26429311","id":"PMC_26429311","title":"SOCS3 and its role in associated diseases.","date":"2015","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26429311","citation_count":96,"is_preprint":false},{"pmid":"30414080","id":"PMC_30414080","title":"SOCS3 as a future target to treat metabolic disorders.","date":"2018","source":"Hormones (Athens, Greece)","url":"https://pubmed.ncbi.nlm.nih.gov/30414080","citation_count":86,"is_preprint":false},{"pmid":"17438093","id":"PMC_17438093","title":"Reciprocal regulation of SOCS 1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme.","date":"2007","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/17438093","citation_count":86,"is_preprint":false},{"pmid":"10545526","id":"PMC_10545526","title":"Inhibitory roles for SHP-1 and SOCS-3 following pituitary proopiomelanocortin induction by leukemia inhibitory factor.","date":"1999","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/10545526","citation_count":81,"is_preprint":false},{"pmid":"12519742","id":"PMC_12519742","title":"Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3.","date":"2003","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12519742","citation_count":78,"is_preprint":false},{"pmid":"9811457","id":"PMC_9811457","title":"CIS3 and JAB have different regulatory roles in interleukin-6 mediated differentiation and STAT3 activation in M1 leukemia cells.","date":"1998","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9811457","citation_count":74,"is_preprint":false},{"pmid":"12163036","id":"PMC_12163036","title":"Ageing increases SOCS-3 expression in rat hypothalamus: effects of food restriction.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12163036","citation_count":74,"is_preprint":false},{"pmid":"11071852","id":"PMC_11071852","title":"Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11071852","citation_count":74,"is_preprint":false},{"pmid":"32788655","id":"PMC_32788655","title":"The JAK1/STAT3/SOCS3 axis in bone development, physiology, and pathology.","date":"2020","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32788655","citation_count":73,"is_preprint":false},{"pmid":"17376806","id":"PMC_17376806","title":"Methylation of SOCS-3 and SOCS-1 in the carcinogenesis of Barrett's adenocarcinoma.","date":"2007","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/17376806","citation_count":72,"is_preprint":false},{"pmid":"27137184","id":"PMC_27137184","title":"SOCS3 revisited: a broad regulator of disease, now ready for therapeutic use?","date":"2016","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/27137184","citation_count":72,"is_preprint":false},{"pmid":"15618960","id":"PMC_15618960","title":"Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNalpha.","date":"2005","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/15618960","citation_count":71,"is_preprint":false},{"pmid":"17621372","id":"PMC_17621372","title":"Deficient SOCS3 expression in CD4+CD25+FoxP3+ regulatory T cells and SOCS3-mediated suppression of Treg function.","date":"2007","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17621372","citation_count":71,"is_preprint":false},{"pmid":"25458989","id":"PMC_25458989","title":"SOCS3 and STAT3, major controllers of the outcome of infection with Mycobacterium tuberculosis.","date":"2014","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25458989","citation_count":69,"is_preprint":false},{"pmid":"9883901","id":"PMC_9883901","title":"Cytokine-inducible SH2 protein (CIS3) and JAK2 binding protein (JAB) abolish prolactin receptor-mediated STAT5 signaling.","date":"1998","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/9883901","citation_count":65,"is_preprint":false},{"pmid":"12591901","id":"PMC_12591901","title":"A role of suppressor of cytokine signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated interleukin 2 production.","date":"2003","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12591901","citation_count":65,"is_preprint":false},{"pmid":"32169038","id":"PMC_32169038","title":"Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit.","date":"2020","source":"BMC cardiovascular disorders","url":"https://pubmed.ncbi.nlm.nih.gov/32169038","citation_count":64,"is_preprint":false},{"pmid":"25658748","id":"PMC_25658748","title":"MicroRNA-185 targets SOCS3 to inhibit beta-cell dysfunction in diabetes.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25658748","citation_count":62,"is_preprint":false},{"pmid":"18560028","id":"PMC_18560028","title":"The role of SOCS-3 protein in leptin resistance and obesity.","date":"2008","source":"Acta medica Indonesiana","url":"https://pubmed.ncbi.nlm.nih.gov/18560028","citation_count":56,"is_preprint":false},{"pmid":"14742442","id":"PMC_14742442","title":"Analysis of SOCS-3 promoter responses to interferon gamma.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14742442","citation_count":55,"is_preprint":false},{"pmid":"18031698","id":"PMC_18031698","title":"SOCS3 protein developmentally regulates the chemokine receptor CXCR4-FAK signaling pathway during B lymphopoiesis.","date":"2007","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18031698","citation_count":50,"is_preprint":false},{"pmid":"32030817","id":"PMC_32030817","title":"Resident alveolar macrophage-derived vesicular SOCS3 dampens allergic airway inflammation.","date":"2020","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32030817","citation_count":48,"is_preprint":false},{"pmid":"26416445","id":"PMC_26416445","title":"FXR induces SOCS3 and suppresses hepatocellular carcinoma.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26416445","citation_count":48,"is_preprint":false},{"pmid":"23335796","id":"PMC_23335796","title":"SOCS3 promotor hypermethylation and STAT3-NF-κB interaction downregulate SOCS3 expression in human coronary artery smooth muscle cells.","date":"2013","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23335796","citation_count":48,"is_preprint":false},{"pmid":"31209627","id":"PMC_31209627","title":"Lidocaine Potentiates SOCS3 to Attenuate Inflammation in Microglia and Suppress Neuropathic Pain.","date":"2019","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/31209627","citation_count":47,"is_preprint":false},{"pmid":"16216905","id":"PMC_16216905","title":"Regulation of pancreatic beta-cell mass and proliferation by SOCS-3.","date":"2005","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/16216905","citation_count":46,"is_preprint":false},{"pmid":"30811476","id":"PMC_30811476","title":"Radiotherapy resistance acquisition in Glioblastoma. Role of SOCS1 and SOCS3.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30811476","citation_count":45,"is_preprint":false},{"pmid":"16685656","id":"PMC_16685656","title":"Elevated expression and genetic association links the SOCS3 gene to atopic dermatitis.","date":"2006","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16685656","citation_count":44,"is_preprint":false},{"pmid":"27704310","id":"PMC_27704310","title":"Role of Leptin and SOCS3 in Inhibiting the Type I Interferon Response During Obesity.","date":"2017","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/27704310","citation_count":44,"is_preprint":false},{"pmid":"15653674","id":"PMC_15653674","title":"SOCS-3 induces myoblast differentiation.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15653674","citation_count":42,"is_preprint":false},{"pmid":"16476192","id":"PMC_16476192","title":"Suppressor of cytokine signaling 3 (SOCS3) in Th2 cells evokes Th2 cytokines, IgE, and eosinophilia.","date":"2006","source":"Current allergy and asthma reports","url":"https://pubmed.ncbi.nlm.nih.gov/16476192","citation_count":42,"is_preprint":false},{"pmid":"25939384","id":"PMC_25939384","title":"SOCS3 Drives Proteasomal Degradation of TBK1 and Negatively Regulates Antiviral Innate Immunity.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25939384","citation_count":40,"is_preprint":false},{"pmid":"24637581","id":"PMC_24637581","title":"Gene silencing of SOCS3 by siRNA intranasal delivery inhibits asthma phenotype in mice.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24637581","citation_count":40,"is_preprint":false},{"pmid":"28827898","id":"PMC_28827898","title":"IL-10 and socs3 Are Predictive Biomarkers of Dengue Hemorrhagic Fever.","date":"2017","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/28827898","citation_count":39,"is_preprint":false},{"pmid":"27126447","id":"PMC_27126447","title":"SOCS-3 Regulates Alveolar Bone Loss in Experimental Periodontitis.","date":"2016","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/27126447","citation_count":38,"is_preprint":false},{"pmid":"18571793","id":"PMC_18571793","title":"Molecular basis of oncostatin M-induced SOCS-3 expression in astrocytes.","date":"2008","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/18571793","citation_count":38,"is_preprint":false},{"pmid":"20130595","id":"PMC_20130595","title":"Deficient SOCS3 and SHP-1 expression in psoriatic T cells.","date":"2010","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/20130595","citation_count":37,"is_preprint":false},{"pmid":"20435883","id":"PMC_20435883","title":"SOCS3 regulates graft-versus-host disease.","date":"2010","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/20435883","citation_count":36,"is_preprint":false},{"pmid":"20335309","id":"PMC_20335309","title":"SOCS-3 antagonises the proliferative and migratory effects of fibroblast growth factor-2 in prostate cancer by inhibition of p44/p42 MAPK signalling.","date":"2010","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20335309","citation_count":36,"is_preprint":false},{"pmid":"25682267","id":"PMC_25682267","title":"Methylation and microRNA-mediated epigenetic regulation of SOCS3.","date":"2015","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25682267","citation_count":35,"is_preprint":false},{"pmid":"31154249","id":"PMC_31154249","title":"Hepatocyte growth control by SOCS1 and SOCS3.","date":"2019","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/31154249","citation_count":34,"is_preprint":false},{"pmid":"20372794","id":"PMC_20372794","title":"Enforced SOCS1 and SOCS3 expression attenuates Lck-mediated cellular transformation.","date":"2010","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20372794","citation_count":34,"is_preprint":false},{"pmid":"29325454","id":"PMC_29325454","title":"Down-expression of P2RX2, KCNQ5, ERBB3 and SOCS3 through DNA hypermethylation in elderly women with presbycusis.","date":"2018","source":"Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/29325454","citation_count":34,"is_preprint":false},{"pmid":"18097573","id":"PMC_18097573","title":"Decreased expression of SOCS-3 mRNA in breast cancer with lymph node metastasis.","date":"2008","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/18097573","citation_count":34,"is_preprint":false},{"pmid":"29343476","id":"PMC_29343476","title":"Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection.","date":"2018","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/29343476","citation_count":34,"is_preprint":false},{"pmid":"24959867","id":"PMC_24959867","title":"Expression of suppressor of cytokine signaling-3 (SOCS3) and its role in neuronal death after complete spinal cord injury.","date":"2014","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24959867","citation_count":34,"is_preprint":false},{"pmid":"11304496","id":"PMC_11304496","title":"Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp130 resistance in cardiovascular system in rat treated with cardiotrophin-1 in vivo.","date":"2001","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/11304496","citation_count":33,"is_preprint":false},{"pmid":"22787435","id":"PMC_22787435","title":"A requirement for SOCS-1 and SOCS-3 phosphorylation in Bcr-Abl-induced tumorigenesis.","date":"2012","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22787435","citation_count":33,"is_preprint":false},{"pmid":"16055089","id":"PMC_16055089","title":"Estrogen receptor-alpha regulates SOCS-3 expression in human breast cancer cells.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16055089","citation_count":33,"is_preprint":false},{"pmid":"23853585","id":"PMC_23853585","title":"Critical and independent role for SOCS3 in either myeloid or T cells in resistance to Mycobacterium tuberculosis.","date":"2013","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/23853585","citation_count":33,"is_preprint":false},{"pmid":"34138760","id":"PMC_34138760","title":"Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34138760","citation_count":32,"is_preprint":false},{"pmid":"33318871","id":"PMC_33318871","title":"Endogenous hydrogen sulfide improves vascular remodeling through PPARδ/SOCS3 signaling.","date":"2020","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/33318871","citation_count":32,"is_preprint":false},{"pmid":"32989761","id":"PMC_32989761","title":"DNMT1 deregulation of SOCS3 axis drives cardiac fibroblast activation in diabetic cardiac fibrosis.","date":"2020","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32989761","citation_count":32,"is_preprint":false},{"pmid":"21751240","id":"PMC_21751240","title":"Zoledronic acid inhibits macrophage SOCS3 expression and enhances cytokine production.","date":"2011","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21751240","citation_count":31,"is_preprint":false},{"pmid":"23432547","id":"PMC_23432547","title":"Gene methylation and silencing of SOCS3 in mantle cell lymphoma.","date":"2013","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/23432547","citation_count":30,"is_preprint":false},{"pmid":"12960286","id":"PMC_12960286","title":"Sepsis-induced SOCS-3 expression is immunologically restricted to phagocytes.","date":"2003","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/12960286","citation_count":29,"is_preprint":false},{"pmid":"32284757","id":"PMC_32284757","title":"MiR-30a-5p promotes cholangiocarcinoma cell proliferation through targeting SOCS3.","date":"2020","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32284757","citation_count":28,"is_preprint":false},{"pmid":"24058778","id":"PMC_24058778","title":"SOCS3: A novel therapeutic target for cardioprotection.","date":"2012","source":"JAK-STAT","url":"https://pubmed.ncbi.nlm.nih.gov/24058778","citation_count":27,"is_preprint":false},{"pmid":"23206599","id":"PMC_23206599","title":"Neuron-intrinsic inhibitors of axon regeneration: PTEN and SOCS3.","date":"2012","source":"International review of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/23206599","citation_count":27,"is_preprint":false},{"pmid":"23033269","id":"PMC_23033269","title":"SOCS3 promotes interleukin-17 expression of human T cells.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23033269","citation_count":27,"is_preprint":false},{"pmid":"26990535","id":"PMC_26990535","title":"miR-203 and miR-221 regulate SOCS1 and SOCS3 in essential thrombocythemia.","date":"2016","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/26990535","citation_count":25,"is_preprint":false},{"pmid":"17198696","id":"PMC_17198696","title":"SOCS3 is required to temporally fine-tune photoreceptor cell differentiation.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/17198696","citation_count":25,"is_preprint":false},{"pmid":"31223625","id":"PMC_31223625","title":"HNF1α Controls Liver Lipid Metabolism and Insulin Resistance via Negatively Regulating the SOCS-3-STAT3 Signaling Pathway.","date":"2019","source":"Journal of diabetes research","url":"https://pubmed.ncbi.nlm.nih.gov/31223625","citation_count":25,"is_preprint":false},{"pmid":"38504518","id":"PMC_38504518","title":"SOCS3 regulates pathological retinal angiogenesis through modulating SPP1 expression in microglia and macrophages.","date":"2024","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38504518","citation_count":24,"is_preprint":false},{"pmid":"34568100","id":"PMC_34568100","title":"SOCS3 Promotes ALV-J Virus Replication via Inhibiting JAK2/STAT3 Phosphorylation During Infection.","date":"2021","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34568100","citation_count":24,"is_preprint":false},{"pmid":"30766526","id":"PMC_30766526","title":"Suppressor of Cytokine Signaling 3 (SOCS3) Degrades p65 and Regulate HIV-1 Replication.","date":"2019","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30766526","citation_count":23,"is_preprint":false},{"pmid":"15629435","id":"PMC_15629435","title":"SOCS3/CIS3 negative regulation of STAT3 in HGF-induced keratinocyte migration.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15629435","citation_count":22,"is_preprint":false},{"pmid":"32435361","id":"PMC_32435361","title":"Chimeric Peptidomimetics of SOCS 3 Able to Interact with JAK2 as Anti-inflammatory Compounds.","date":"2020","source":"ACS medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/32435361","citation_count":22,"is_preprint":false},{"pmid":"29550470","id":"PMC_29550470","title":"PPARγ alleviated hepatocyte steatosis through reducing SOCS3 by inhibiting JAK2/STAT3 pathway.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29550470","citation_count":22,"is_preprint":false},{"pmid":"23545584","id":"PMC_23545584","title":"Multiple roles of SOCS proteins: differential expression of SOCS1 and SOCS3 in atherosclerosis.","date":"2013","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23545584","citation_count":22,"is_preprint":false},{"pmid":"25628929","id":"PMC_25628929","title":"Frequent SOCS3 and 3OST2 promoter methylation and their epigenetic regulation in endometrial carcinoma.","date":"2014","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25628929","citation_count":21,"is_preprint":false},{"pmid":"36690663","id":"PMC_36690663","title":"PTK6 inhibits autophagy to promote uveal melanoma tumorigenesis by binding to SOCS3 and regulating mTOR phosphorylation.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36690663","citation_count":21,"is_preprint":false},{"pmid":"15893771","id":"PMC_15893771","title":"Expression of STAT3 and SOCS3 in pancreatic acinar cells.","date":"2005","source":"The Journal of surgical research","url":"https://pubmed.ncbi.nlm.nih.gov/15893771","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51615,"output_tokens":9216,"usd":0.146542,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19180,"output_tokens":5106,"usd":0.111775,"stage2_stop_reason":"end_turn"},"total_usd":0.258317,"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\": 1999,\n      \"finding\": \"SOCS3 (CIS3) inhibits JAK2 tyrosine kinase activity by two mechanisms: its SH2 domain binds the phosphorylated Y1007 in the activation loop of JAK2 JH1 domain, and its N-terminal kinase inhibitory region (KIR) binds the JH1 domain and directly inhibits kinase activity. Both the SH2 domain and KIR are required for full inhibition, with CIS3-KIR showing stronger binding to JH1 than SOCS1/JAB-KIR.\",\n      \"method\": \"In vitro kinase assay, binding studies with SH2 domain mutants, chimeric protein analysis, co-immunoprecipitation of endogenous CIS3 with JAK2\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assays combined with mutagenesis and chimeric protein analysis, with mechanistic dissection of both SH2 and KIR contributions\",\n      \"pmids\": [\"10421843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SOCS3 binds JAK2 in leptin-stimulated cells (co-immunoprecipitation) and inhibits JAK2 tyrosine phosphorylation when overexpressed, thereby acting as a leptin-regulated inhibitor of proximal leptin signaling. SOCS3 expression is induced by leptin specifically (not CIS, SOCS1, or SOCS2) in cells expressing the long-form leptin receptor.\",\n      \"method\": \"Co-immunoprecipitation of JAK2 with SOCS3 in COS cells; transfection studies showing inhibition of leptin-induced JAK2 phosphorylation; (125)I-leptin binding assay to exclude receptor downregulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional overexpression assay with receptor surface expression control, single lab\",\n      \"pmids\": [\"10514492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SOCS3 binds the erythropoietin receptor (EPOR) at a region containing Tyr401 in the cytoplasmic domain, and also binds JAK2; binding to both is required for full suppression of EPO-dependent proliferation and STAT5 activation. Gly45 in the N-terminal region of SOCS3 is critical for EPOR binding but not JAK2 binding, while Leu22 is critical for JAK2 binding; L22D mutant completely loses inhibitory activity.\",\n      \"method\": \"Co-immunoprecipitation, deletion/point mutagenesis of SOCS3 and EPOR, Ba/F3 cell proliferation assay, STAT5 phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (mutagenesis, Co-IP, functional proliferation and signaling assays) in a single rigorous study\",\n      \"pmids\": [\"10882725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Insulin induces SOCS3 translocation from an intracellular compartment to the cell membrane, where it colocalizes with the insulin receptor at phosphotyrosine 960; SOCS3 binds the insulin receptor at pY960 (demonstrated by yeast two-hybrid) and competes with Stat5B for this site to inhibit insulin-stimulated Stat5B activation. Colocalization is dependent on IR tyrosine 960 phosphorylation.\",\n      \"method\": \"Yeast two-hybrid binding assay, confocal microscopy of SOCS3 translocation, IR Y960F mutant cells, Stat5B luciferase reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — yeast two-hybrid plus confocal microscopy plus IR mutant functional analysis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"10821852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CIS3/SOCS3 plays a negative regulatory role in STAT3 activation in intestinal inflammation; in transgenic mice expressing an activating JAK mutant (F59D-JAB) that overcomes CIS3 inhibition, DSS-induced STAT3 activation and colitis severity were markedly enhanced, demonstrating that CIS3 downregulates STAT3 activity in vivo.\",\n      \"method\": \"Transgenic mouse model expressing dominant-active JAK mutant overcoming SOCS3 inhibition; DSS-induced colitis model; STAT3 phosphorylation analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with clear phenotypic and molecular readouts, replicated across multiple colitis models\",\n      \"pmids\": [\"11181699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SOCS1 and SOCS3 promote ubiquitin-mediated degradation of IRS1 and IRS2 via the elongin BC ubiquitin-ligase complex; mutations in the conserved SOCS box abolish interaction with elongin BC without affecting IRS1/2 binding, and these mutants fail to promote IRS ubiquitination/degradation or cause glucose intolerance upon adenoviral liver expression.\",\n      \"method\": \"Co-immunoprecipitation of endogenous and recombinant IRS1/2; ubiquitination assays; adenoviral overexpression in mouse liver; SOCS box point mutants; glucose tolerance test\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of SOCS box combined with in vivo adenoviral liver reconstitution and glucose tolerance testing, plus Co-IP in multiple cell types\",\n      \"pmids\": [\"12228220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The SOCS3 promoter contains a STAT1/STAT3 binding element at nucleotides -72 to -64 that is essential for LIF-stimulated SOCS3 promoter activity; SOCS3 overexpression or dominant-negative STAT3 blocks LIF-induced SOCS3 mRNA expression, establishing a negative autoregulatory loop in corticotroph cells.\",\n      \"method\": \"5' RACE and RNase protection assay to map transcription start site; luciferase promoter deletion/mutation assays; EMSA confirming STAT1/STAT3 binding; stable transfection of dominant-negative STAT3\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — promoter mutagenesis, EMSA, and functional luciferase assays with dominant-negative STAT3, multiple orthogonal methods\",\n      \"pmids\": [\"10359822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SOCS3 associates with the insulin receptor (IR) and directly inhibits IR autophosphorylation in vitro; ectopic SOCS3 suppresses insulin-dependent IR autophosphorylation, IRS-1 tyrosine phosphorylation, IRS-1 association with PI3K p85, and Akt activation; IL-6-induced SOCS3 in liver coincides with inhibition of hepatic insulin signaling in vivo.\",\n      \"method\": \"In vitro IR autophosphorylation assay; co-immunoprecipitation of SOCS3 with IR; Western blotting for downstream signaling in HepG2 cells and mouse liver\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus in vivo mouse liver studies plus Co-IP, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12560330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SOCS3 and SHP2 both act through gp130 tyrosine 759 to attenuate IL-6 signaling, but by two largely distinct mechanisms: receptor/membrane-targeted SHP2 counteracts IL-6 signaling independently of SOCS3 binding; conversely, SOCS3 inhibits signaling in cells expressing truncated SHP2 not recruited to gp130.\",\n      \"method\": \"Chimeric receptor constructs targeting SHP2 or SOCS3 independently to gp130; signaling readouts in reconstituted cell systems\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimeric receptor epistasis, single lab, two orthogonal constructs\",\n      \"pmids\": [\"12403768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SOCS3 interacts with phosphorylated CD28 through its SH2 domain (not the KIR), and a point mutation in the SOCS3 SH2 domain attenuates inhibition of CD28-mediated IL-2 promoter activation; SOCS3 transgenic T cells show reduced CD28-mediated IL-2 production, while SOCS3+/- mice show enhanced IL-2 production.\",\n      \"method\": \"Co-immunoprecipitation of SOCS3 with phospho-CD28; SOCS3 SH2 domain point mutant; SOCS3 transgenic and heterozygous knockout mice; IL-2 promoter luciferase reporter assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, SH2 domain mutagenesis, and genetic models (transgenic + heterozygous KO) with concordant phenotypes\",\n      \"pmids\": [\"12591901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"LIF induces SOCS3 binding to JAK2 after 60 minutes of stimulation in pituitary corticotroph cells, followed by proteasomal degradation of the complex; SOCS3 overexpression blocks LIF-induced JAK2 tyrosine phosphorylation; SHP-1 is constitutively associated with JAK2 and mediates early dephosphorylation, while SOCS3 mediates later inhibition.\",\n      \"method\": \"Co-immunoprecipitation of SOCS3 with JAK2; SOCS3 overexpression blocking JAK2 phosphorylation; proteasome inhibitor rescue; SOCS3 deletion construct functional mapping\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional overexpression with proteasome inhibitor, single lab\",\n      \"pmids\": [\"10545526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Restoration of SOCS3 expression in lung cancer cells where SOCS3 was silenced by CpG methylation resulted in downregulation of active STAT3, induction of apoptosis, and growth suppression, demonstrating SOCS3 tumor suppressor function through JAK/STAT inhibition.\",\n      \"method\": \"SOCS3 re-expression in methylation-silenced cell lines; STAT3 phosphorylation Western blot; apoptosis and growth assays; methylation-specific PCR\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function reconstitution with defined molecular readout, single lab, multiple cancer cell lines\",\n      \"pmids\": [\"14617776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SOCS3 interacts with the IGF-I receptor (IGFIR) constitutively in vitro and in intact cells; SOCS3 binds activated IGFIR and IR cytoplasmic domains in yeast two-hybrid assay and GST pull-down; SOCS3 is tyrosine-phosphorylated by IGF-I stimulation, suggesting it is a direct substrate of the IGFIR kinase.\",\n      \"method\": \"Yeast two-hybrid assay; GST pull-down; co-immunoprecipitation of FLAG-SOCS3 with IGFIR in HEK293 cells; anti-phosphotyrosine immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by GST pull-down and Co-IP, single lab\",\n      \"pmids\": [\"11071852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IFN-γ induces SOCS3 via a STAT1-binding element (SBE) at -72/-64 in the SOCS3 promoter; mutation of the SBE abolishes IFN-γ responsiveness; IFN-γ promotes STAT1 (not STAT3) binding to the SBE in macrophages; IFN-γ-induced SOCS3 expression is intact in STAT3-deficient fibroblasts.\",\n      \"method\": \"Promoter deletion/point mutation luciferase assays; EMSA; IFN-γ treatment of macrophages, J774 cells, and STAT3-deficient fibroblasts; Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — promoter mutagenesis, EMSA, and STAT3-KO cell validation with multiple orthogonal methods\",\n      \"pmids\": [\"14742442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Resistin markedly induces SOCS3 gene expression in 3T3-L1 adipocytes and increases SOCS3 protein association with the insulin receptor; inhibition of SOCS function prevents resistin from antagonizing insulin action, establishing SOCS3 induction as a mediator of resistin-induced insulin resistance.\",\n      \"method\": \"RT-PCR and Western blot for SOCS3 induction; Co-IP of SOCS3 with IR; SOCS inhibition functional rescue of insulin signaling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus SOCS inhibition rescue experiment, single lab\",\n      \"pmids\": [\"15684405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SOCS3 regulates CXCL12-induced FAK phosphorylation through the ubiquitin-proteasome pathway during B lymphopoiesis; CXCL12 triggers increased FAK ubiquitination in mature (high SOCS3) but not progenitor (low SOCS3) B cells; SOCS3 overexpression in pro-B cells impairs CXCL12-induced FAK phosphorylation and adhesion; SOCS3-deficient mature B cells show prolonged FAK phosphorylation and adhesion to VCAM-1.\",\n      \"method\": \"FAK ubiquitination assay; SOCS3 overexpression in pro-B cells; conditional SOCS3 knockout (Cre(MMTV)Socs3fl/fl) mature B cells; VCAM-1 adhesion assay; flow cytometry of BM compartments\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and overexpression with ubiquitination assay and functional adhesion readouts, multiple orthogonal methods\",\n      \"pmids\": [\"18031698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of a ternary complex of SOCS3, JAK2 kinase domain, and a fragment of the IL-6 receptor β-chain (gp130) shows that SOCS3 binds JAK2 and receptor simultaneously using two opposing surfaces; the SOCS3 SH2 domain phosphotyrosine-binding groove is occupied by the receptor, while JAK2 binds a non-canonical surface in a phospho-independent manner; the kinase inhibitory region (KIR) of SOCS3 occludes the substrate-binding groove of JAK2, blocking substrate association.\",\n      \"method\": \"X-ray crystallography of ternary SOCS3/JAK2/gp130 complex; biochemical substrate association assays; structure-guided mutagenesis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biochemical validation, definitive mechanistic study replicated by multiple subsequent reviews\",\n      \"pmids\": [\"23454976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SOCS3 selectively inhibits JAK1, JAK2, and TYK2 (but not JAK3) through a three-residue 'GQM' motif in the kinase domain of these JAKs; SOCS3 binds JAK and gp130 simultaneously and inhibits JAK activity in an ATP-independent manner by partially occluding the kinase substrate-binding groove with its KIR.\",\n      \"method\": \"Biochemical binding studies; mutagenesis of the GQM motif; structural and biochemical analyses building on the SOCS3/JAK2/gp130 crystal structure\",\n      \"journal\": \"Seminars in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical and structural analysis, single lab, review-style but incorporating primary biochemical data\",\n      \"pmids\": [\"24418198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SOCS3 promotes K48-linked polyubiquitination of TBK1 at Lys341 and Lys344, leading to proteasomal degradation of TBK1; SOCS3 directly associates with TBK1 and colocalizes in the cytoplasm; both the BOX domain of SOCS3 and Ser172 phosphorylation of TBK1 are required for this ubiquitination and degradation; SOCS3 thereby inhibits IRF3 phosphorylation and IFN-β transcription and facilitates influenza virus replication.\",\n      \"method\": \"Co-immunoprecipitation of SOCS3 with TBK1; K48-ubiquitin linkage-specific assay; SOCS3 overexpression and knockdown; SOCS3 BOX domain mutant; TBK1 Lys341/344 and Ser172 mutants; IRF3 phosphorylation and IFN-β reporter assays; viral RNA quantification\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of both SOCS3 BOX domain and TBK1 ubiquitination sites, combined with K48-specific ubiquitin assay and functional antiviral readouts, multiple orthogonal methods\",\n      \"pmids\": [\"25939384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Simultaneous deletion of both PTEN and SOCS3 in adult retinal ganglion cells enables robust and sustained long-distance axon regeneration, whereas deletion of either alone produces only transient regeneration; PTEN and SOCS3 regulate independent pathways (mTOR and JAK/STAT3, respectively) that act synergistically.\",\n      \"method\": \"Conditional knockout mice (PTEN-/- and SOCS3-/- single and double deletion in RGCs); optic nerve crush model; gene expression analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with double KO, clear sustained regeneration phenotype, combined with gene expression pathway analysis\",\n      \"pmids\": [\"22056987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SOCS3-deficient macrophages (LysMCre-SOCS3fl/fl) exhibit enhanced and prolonged activation of JAK/STAT1 and STAT3 pathways, higher M1 proinflammatory gene expression due to enhanced transcriptional activation and chromatin modifications, and stronger capacity to induce Th1 and Th17 differentiation; SOCS3 deficiency exacerbates LPS-induced sepsis with enhanced STAT1/3 activation.\",\n      \"method\": \"Conditional myeloid SOCS3 knockout mice; LPS sepsis model; cytokine ELISA; STAT phosphorylation Western blot; Th1/Th17 differentiation assay; chromatin modification analysis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined molecular mechanism (STAT activation, chromatin changes) and multiple in vivo and in vitro readouts\",\n      \"pmids\": [\"22925925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ezh2 suppresses SOCS3 expression via H3K27 trimethylation of the Socs3 locus in macrophages/microglia; Ezh2 deficiency stimulates SOCS3 expression, which enhances K48-linked ubiquitination and degradation of TRAF6, thereby compromising TLR-induced MyD88-dependent NF-κB activation; silencing SOCS3 restores macrophage activation in Ezh2-deficient mice.\",\n      \"method\": \"Conditional Ezh2 KO macrophages; ChIP for H3K27me3 at Socs3 locus; TRAF6 ubiquitination assay; SOCS3 siRNA rescue experiment; DSS colitis and EAE models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, ubiquitination assay, and genetic rescue (SOCS3 silencing in Ezh2 KO) with in vivo validation in two disease models\",\n      \"pmids\": [\"29626115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Bcr-Abl tyrosine-phosphorylates SOCS3 primarily at Tyr221, which binds Bcr-Abl; this phosphorylation diminishes SOCS3's inhibitory effects on JAK/STAT5 signaling; mutation of Tyr221 phosphorylation site impairs Bcl-XL expression, sensitizes leukemic cells to apoptosis, and significantly blocks Bcr-Abl-mediated tumorigenesis in nude mice and bone marrow transformation.\",\n      \"method\": \"Co-immunoprecipitation of phospho-SOCS3 with Bcr-Abl; site-directed mutagenesis of SOCS3 Y221; JAK/STAT5 phosphorylation assays; nude mouse tumorigenesis assay; murine bone marrow transformation assay\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific phosphorylation site with in vitro signaling and in vivo tumorigenesis validation, multiple orthogonal methods\",\n      \"pmids\": [\"22787435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SOCS3 inhibits NF-κB p65 expression and activity by interacting with it and inducing ubiquitin-dependent proteasomal degradation of p65; the SH2 domain of SOCS3 is critical for the SOCS3-p65 interaction and p65 degradation; SOCS3 expression promotes HIV-1 replication, and HIV-1 downregulates SOCS3 early in infection to promote inflammatory responses.\",\n      \"method\": \"Co-immunoprecipitation of SOCS3 with p65; SOCS3 SH2 domain mutant; ubiquitination and proteasomal degradation assays; overexpression and knockdown experiments; HIV-1 replication assays\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with SH2 mutant and ubiquitination assay, single lab\",\n      \"pmids\": [\"30766526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SOCS3 is required to terminate residual STAT3 activation postnatally (after P0) in retinal cells; SOCS3 deficiency fails to shut down STAT3 activity, thereby delaying Rhodopsin expression and rod photoreceptor cell differentiation; SOCS3 protein expression is post-transcriptionally suppressed during late embryogenesis (mRNA is constant but protein absent) and released postnatally to fine-tune STAT3.\",\n      \"method\": \"Conditional SOCS3 knockout retina; immunofluorescence for STAT3 phosphorylation; Rhodopsin and Crx expression analysis; comparison of mRNA vs. protein levels\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with molecular signaling readout, single lab, clear phenotype\",\n      \"pmids\": [\"17198696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Endothelial SOCS3 has a very short protein half-life (< 20 minutes) regulated by ubiquitination and proteasomal degradation; inhibition of SOCS3 ubiquitination and proteasomal degradation leads to protein accumulation and stronger inhibition of IL-6 signaling and barrier function; loss of endothelial SOCS3 causes LPS-induced type I IFN-like gene program, prothrombotic/proadhesive gene expression, NETosis, and lethal kidney failure.\",\n      \"method\": \"Conditional endothelial SOCS3 knockout mice (SOCS3iEKO); pulse-chase half-life experiments in HUVECs; proteasome inhibitor studies; LPS challenge model; gene expression analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pulse-chase protein stability assays combined with proteasome inhibitor rescue and conditional KO with defined in vivo phenotype\",\n      \"pmids\": [\"34138760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SOCS3 absence in myeloid cells leads to substantial accumulation of microglia/macrophages during ocular neovascularization and increased Spp1 gene expression; SPP1 is identified as a direct transcriptional target of STAT3; pharmaceutical SOCS3 activation or SPP1 blockade reduces pathological neovascularization, establishing a SOCS3/STAT3/SPP1 axis in retinal angiogenesis.\",\n      \"method\": \"Myeloid-specific SOCS3 conditional KO; single-cell RNA sequencing; STAT3 ChIP on SPP1 promoter; pharmacological SOCS3 activation; SPP1 blocking antibody in angiogenesis mouse model\",\n      \"journal\": \"Molecular therapy : the journal of the American Society of Gene Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus ChIP plus pharmacological rescue, single lab\",\n      \"pmids\": [\"38504518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DNMT1-mediated hypermethylation of the SOCS3 promoter leads to SOCS3 downregulation in diabetic cardiac fibrosis; high glucose increases DNMT1 expression in cardiac fibroblasts; reduced SOCS3 enables STAT3 activation to promote cardiac fibroblast activation and collagen deposition; genetic or pharmacological DNMT1 inactivation reverses the activated fibroblast phenotype.\",\n      \"method\": \"Western blot and qPCR in diabetic cardiac fibroblasts; methylation-specific PCR; DNMT1 genetic knockdown; STAT3 phosphorylation assays; collagen deposition assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — methylation-specific PCR plus DNMT1 knockdown rescue with functional fibroblast phenotype readouts, single lab\",\n      \"pmids\": [\"32989761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SOCS3 overexpression in Th2 cells specifically inhibits IFN-α-mediated growth inhibition without affecting STAT3 activation, growth, or apoptosis in CTCL tumor cells; dominant-negative STAT3 reduces SOCS3 expression and increases IFN-α-mediated growth inhibition, showing STAT3-driven constitutive SOCS3 expression protects tumor cells from IFN-α.\",\n      \"method\": \"SOCS3 overexpression in CTCL cells; dominant-negative STAT3 transfection; cell growth and apoptosis assays; IFN-α sensitivity assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression and dominant-negative experiments with defined functional readout, single lab\",\n      \"pmids\": [\"15618960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SOCS3 overexpression in primary CD4+ T cells decreases proliferation, FoxP3 and CTLA-4 expression, and suppressive function of regulatory T cells; naturally occurring Treg cells are deficient in SOCS3 protein expression compared with effector T cells, allowing them to respond rapidly to IL-2 and IL-6.\",\n      \"method\": \"SOCS3 overexpression in Treg cells; flow cytometry for FoxP3/CTLA-4; T cell suppression assay; comparison of SOCS3 levels in Treg vs. Th cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SOCS3 overexpression with functional suppression assay plus endogenous level comparison, single lab\",\n      \"pmids\": [\"17621372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SOCS3 negatively regulates HGF-induced keratinocyte migration by inhibiting STAT3 phosphorylation; dominant-negative STAT3 abolishes HGF-induced migration; SOCS3 overexpression abolishes HGF-induced STAT3 phosphorylation and keratinocyte migration.\",\n      \"method\": \"Transfection of dominant-negative STAT3 and SOCS3 overexpression constructs; STAT3 phosphorylation Western blot; keratinocyte migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression and dominant-negative with functional migration assay plus molecular readout, single lab\",\n      \"pmids\": [\"15629435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OSM-induced SOCS3 expression in astrocytes requires STAT3 activation and AP-1 element, two GAS elements, and a GC-rich region in the SOCS3 promoter; ERK1/2 and JNK pathways also contribute; OSM stimulation leads to time-dependent recruitment of STAT3, c-Fos, c-Jun, Sp1, CBP, and p300 to the endogenous SOCS3 promoter.\",\n      \"method\": \"SOCS3 promoter deletion/mutation luciferase assays; siRNA against STAT3; dominant-negative STAT3; ChIP assay for promoter occupancy by multiple transcription factors\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis, STAT3 siRNA/DN, and ChIP in primary astrocytes, single lab\",\n      \"pmids\": [\"18571793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTK6 binds to SOCS3 and SOCS3 downregulates PTK6 expression; PTK6 upregulates mTOR phosphorylation to inhibit autophagy in uveal melanoma cells; SOCS3 overexpression partially rescues PTK6-induced promotion of cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation of PTK6 with SOCS3; overexpression and knockdown experiments; mTOR phosphorylation Western blot; autophagy assays; proliferation/migration/invasion assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with functional rescue, single lab, mechanism partially defined\",\n      \"pmids\": [\"36690663\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SOCS3 is a cytokine-inducible feedback inhibitor of JAK/STAT signaling that functions by simultaneously binding specific cytokine receptors (e.g., gp130 at pY759, EPOR at pY401, IR at pY960) via its SH2 domain and inhibiting JAK1/2/TYK2 (but not JAK3) catalytic activity via its kinase inhibitory region (KIR), which occludes the JAK substrate-binding groove; additionally, SOCS3 promotes ubiquitin-mediated proteasomal degradation of target proteins (IRS1/2, TBK1, TRAF6, p65) through its SOCS box, which recruits the elongin BC E3 ligase complex, and its own protein levels are tightly controlled by proteasomal degradation with a half-life of less than 20 minutes, while its gene expression is transcriptionally induced by STAT1 (via IFN-γ) and STAT3 (via IL-6 family cytokines and leptin) binding to a conserved element at -72/-64 in its promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SOCS3 is a cytokine-inducible feedback inhibitor of JAK/STAT signaling that terminates receptor-proximal kinase activity and targets signaling components for proteasomal destruction [#0, #16, #20]. It inhibits JAK2 through a dual mechanism in which its SH2 domain engages the kinase while its N-terminal kinase inhibitory region (KIR) directly suppresses catalytic activity [#0]; structural analysis of a SOCS3/JAK2/gp130 ternary complex resolved how SOCS3 binds receptor and kinase simultaneously on opposing surfaces—the SH2 phosphotyrosine groove occupied by receptor while the KIR occludes the JAK substrate-binding groove in an ATP-independent manner [#16], a mechanism extended to selective inhibition of JAK1, JAK2, and TYK2 but not JAK3 via a 'GQM' motif in the kinase domain [#17]. SOCS3 docks onto defined receptor phosphotyrosines—gp130/IL-6R, the erythropoietin receptor at Tyr401, and the insulin receptor at pY960—where it competes with STATs and attenuates downstream activation [#2, #3, #16]. Through its SOCS box, SOCS3 recruits the elongin BC E3 ligase complex to drive ubiquitin-mediated proteasomal degradation of substrates including IRS1/IRS2, and independent studies establish K48-linked ubiquitination of TBK1, TRAF6, NF-\\u03baB p65, and FAK as effector arms that dampen insulin, antiviral, and inflammatory signaling [#5, #18, #21, #23, #15]. SOCS3 transcription is induced through a conserved STAT element at -72/-64 in its promoter, bound by STAT3 downstream of IL-6-family cytokines and leptin and by STAT1 downstream of IFN-\\u03b3, forming a negative autoregulatory loop [#6, #13, #1]; its protein levels are additionally constrained by a half-life of under 20 minutes set by ubiquitin/proteasome turnover [#25]. Functionally, SOCS3 restrains STAT3-driven inflammation in vivo, limits M1 macrophage and Th1/Th17 responses, acts as a brake on tumor cell survival, and regulates tissue processes from photoreceptor differentiation to axon regeneration where it acts in parallel with the PTEN/mTOR pathway [#4, #20, #11, #24, #19].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the core biochemical mechanism of SOCS3 inhibition, answering how a single protein blocks a JAK kinase.\",\n      \"evidence\": \"In vitro kinase assays, SH2/KIR mutants, and chimeric protein analysis with endogenous CIS3/JAK2 Co-IP\",\n      \"pmids\": [\"10421843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of KIR-mediated inhibition\", \"Receptor-context dependence of inhibition not addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined SOCS3 transcription as a STAT-driven negative autoregulatory loop, explaining how cytokine signaling self-limits.\",\n      \"evidence\": \"Transcription start mapping, promoter mutagenesis, EMSA, and dominant-negative STAT3 in corticotrophs\",\n      \"pmids\": [\"10359822\", \"10545526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish STAT1 vs STAT3 contributions at the element\", \"Chromatin context of induction not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed SOCS3 engages specific receptor phosphotyrosines (EPOR Tyr401, IR pY960) in addition to JAK, explaining receptor selectivity and STAT competition.\",\n      \"evidence\": \"Yeast two-hybrid, point/deletion mutagenesis, confocal imaging of translocation, and STAT5/STAT5B functional assays\",\n      \"pmids\": [\"10882725\", \"10821852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity ranking across different receptors not established\", \"Did not address simultaneous receptor and JAK binding geometry\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Provided in vivo genetic proof that SOCS3 restrains STAT3 activity, moving the mechanism from cell culture to physiology.\",\n      \"evidence\": \"Transgenic mice expressing a JAK mutant overcoming SOCS3 inhibition in a DSS colitis model\",\n      \"pmids\": [\"11181699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Indirect (used JAK mutant rather than SOCS3 deletion)\", \"Cell-type-specific contributions not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the SOCS box/elongin BC degradation arm, showing SOCS3 acts not only as a kinase inhibitor but as an adaptor for proteasomal turnover of substrates like IRS1/2.\",\n      \"evidence\": \"SOCS box point mutants, ubiquitination assays, adenoviral liver expression and glucose tolerance testing\",\n      \"pmids\": [\"12228220\", \"12560330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not enumerate the full substrate repertoire\", \"Relative contribution of kinase inhibition vs degradation not quantified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended SOCS3 targeting beyond cytokine receptors to CD28 and IGF-I receptor, and established its tumor-suppressor role via STAT3, broadening the functional scope.\",\n      \"evidence\": \"Co-IP, SH2 mutants, transgenic/heterozygous mouse T cells, and re-expression in methylation-silenced cancer lines\",\n      \"pmids\": [\"12591901\", \"11071852\", \"14617776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"IGFIR interaction functional consequence not fully resolved\", \"Tumor suppression mechanism limited to STAT3 readout\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved that IFN-\\u03b3 induces SOCS3 through STAT1 (not STAT3) at the same -72/-64 element, clarifying input-specific transcriptional control.\",\n      \"evidence\": \"Promoter mutagenesis, EMSA, and IFN-\\u03b3 treatment of STAT3-deficient fibroblasts\",\n      \"pmids\": [\"14742442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address co-regulatory factors at the element\", \"Kinetics of STAT1 vs STAT3 occupancy not compared\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed SOCS3 itself is regulated by tyrosine phosphorylation (Bcr-Abl at Tyr221), revealing a mechanism by which oncogenic kinases neutralize the inhibitor.\",\n      \"evidence\": \"Co-IP of phospho-SOCS3, Y221 mutagenesis, STAT5 assays, and nude-mouse/bone-marrow transformation\",\n      \"pmids\": [\"22787435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other kinases phosphorylate Tyr221 unknown\", \"Structural effect of phosphorylation on KIR not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Definitively explained the structural logic of dual binding and KIR-mediated inhibition via the SOCS3/JAK2/gp130 ternary crystal structure.\",\n      \"evidence\": \"X-ray crystallography with biochemical substrate-association assays and structure-guided mutagenesis\",\n      \"pmids\": [\"23454976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture the full-length JAK or membrane context\", \"Dynamics of ternary assembly not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped JAK selectivity to a 'GQM' kinase-domain motif, explaining why SOCS3 spares JAK3.\",\n      \"evidence\": \"Biochemical binding and GQM-motif mutagenesis building on the ternary structure\",\n      \"pmids\": [\"24418198\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab biochemical analysis\", \"Cellular validation of motif requirement limited\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established TBK1 as a SOCS3 ubiquitination substrate, defining an antiviral/innate-immune effector arm distinct from JAK/STAT.\",\n      \"evidence\": \"K48-specific ubiquitination assays, SOCS3 BOX and TBK1 Lys/Ser mutants, IRF3/IFN-\\u03b2 readouts and viral RNA quantification\",\n      \"pmids\": [\"25939384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish E3 ligase identity for TBK1 in this context\", \"In vivo significance during infection not tested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed SOCS3 controls TLR/NF-\\u03baB signaling through TRAF6 degradation and is itself epigenetically silenced by Ezh2/H3K27me3, integrating chromatin control with inflammatory output.\",\n      \"evidence\": \"ChIP for H3K27me3, TRAF6 ubiquitination assay, SOCS3 siRNA rescue in Ezh2-KO macrophages, and colitis/EAE models\",\n      \"pmids\": [\"29626115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect SOCS3-TRAF6 interaction not fully resolved\", \"Generality of Ezh2 control across cell types unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended SOCS3-mediated degradation to NF-\\u03baB p65 via the SH2 domain, defining a further branch of inflammatory restraint relevant to viral infection.\",\n      \"evidence\": \"Co-IP, SOCS3 SH2 mutant, ubiquitination/degradation assays, and HIV-1 replication assays\",\n      \"pmids\": [\"30766526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without reciprocal in vivo validation\", \"Mechanism of SH2 binding to p65 phosphosite undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Quantified the rapid proteasomal turnover of SOCS3 protein (<20 min half-life) and tied its stability to the strength of IL-6 signaling control in endothelium.\",\n      \"evidence\": \"Pulse-chase in HUVECs, proteasome inhibitor studies, and conditional endothelial SOCS3-KO LPS challenge\",\n      \"pmids\": [\"34138760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase driving SOCS3 turnover not identified\", \"Signals that stabilize SOCS3 not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated tissue-level consequences of SOCS3/STAT3 control, including a STAT3/SPP1 axis in myeloid cells driving pathological angiogenesis and DNMT1-driven SOCS3 silencing in cardiac fibrosis.\",\n      \"evidence\": \"Myeloid SOCS3 conditional KO, scRNA-seq, STAT3 ChIP on SPP1, methylation-specific PCR, and DNMT1 knockdown\",\n      \"pmids\": [\"38504518\", \"32989761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link from SOCS3 loss to specific STAT3 targets partly indirect\", \"Single-lab disease-model findings\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed SOCS3 in a parallel-pathway framework with PTEN/mTOR governing CNS axon regeneration, defining a non-cytokine developmental role.\",\n      \"evidence\": \"Single and double conditional KO of PTEN and SOCS3 in retinal ganglion cells with optic nerve crush\",\n      \"pmids\": [\"22056987\", \"17198696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of SOCS3/STAT3 in regeneration not pinpointed\", \"Whether degradation or kinase inhibition dominates here unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The E3 ligase and signals that set SOCS3's own ultrashort half-life, and a unified accounting of when SOCS3 acts by kinase inhibition versus substrate degradation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ligase identified for SOCS3 autoturnover\", \"Relative weighting of KIR inhibition vs SOCS-box degradation across contexts undefined\", \"Stabilizing post-translational signals uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 16, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 16, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 18, 21]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [5, 18, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 16, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [20, 21, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 18, 23]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 13, 31]}\n    ],\n    \"complexes\": [\"elongin BC E3 ubiquitin ligase complex\"],\n    \"partners\": [\"JAK2\", \"IL6ST\", \"EPOR\", \"INSR\", \"IRS1\", \"TBK1\", \"TRAF6\", \"RELA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}