Affinage

SOCS3

Suppressor of cytokine signaling 3 · UniProt O14543

Length
225 aa
Mass
24.8 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    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

    PMID:10421843

    Open questions at the time
    • Did not resolve the structural basis of KIR-mediated inhibition
    • Receptor-context dependence of inhibition not addressed
  2. 1999 High

    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

    PMID:10359822 PMID:10545526

    Open questions at the time
    • Did not distinguish STAT1 vs STAT3 contributions at the element
    • Chromatin context of induction not addressed
  3. 2000 High

    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

    PMID:10821852 PMID:10882725

    Open questions at the time
    • Affinity ranking across different receptors not established
    • Did not address simultaneous receptor and JAK binding geometry
  4. 2001 High

    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

    PMID:11181699

    Open questions at the time
    • Indirect (used JAK mutant rather than SOCS3 deletion)
    • Cell-type-specific contributions not resolved
  5. 2002 High

    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

    PMID:12228220 PMID:12560330

    Open questions at the time
    • Did not enumerate the full substrate repertoire
    • Relative contribution of kinase inhibition vs degradation not quantified
  6. 2003 High

    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

    PMID:11071852 PMID:12591901 PMID:14617776

    Open questions at the time
    • IGFIR interaction functional consequence not fully resolved
    • Tumor suppression mechanism limited to STAT3 readout
  7. 2004 High

    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

    PMID:14742442

    Open questions at the time
    • Did not address co-regulatory factors at the element
    • Kinetics of STAT1 vs STAT3 occupancy not compared
  8. 2012 High

    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

    PMID:22787435

    Open questions at the time
    • Whether other kinases phosphorylate Tyr221 unknown
    • Structural effect of phosphorylation on KIR not defined
  9. 2013 High

    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

    PMID:23454976

    Open questions at the time
    • Did not capture the full-length JAK or membrane context
    • Dynamics of ternary assembly not resolved
  10. 2014 Medium

    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

    PMID:24418198

    Open questions at the time
    • Single-lab biochemical analysis
    • Cellular validation of motif requirement limited
  11. 2015 High

    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

    PMID:25939384

    Open questions at the time
    • Did not establish E3 ligase identity for TBK1 in this context
    • In vivo significance during infection not tested here
  12. 2018 High

    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

    PMID:29626115

    Open questions at the time
    • Direct vs indirect SOCS3-TRAF6 interaction not fully resolved
    • Generality of Ezh2 control across cell types unknown
  13. 2019 Medium

    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

    PMID:30766526

    Open questions at the time
    • Single-lab study without reciprocal in vivo validation
    • Mechanism of SH2 binding to p65 phosphosite undefined
  14. 2021 High

    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

    PMID:34138760

    Open questions at the time
    • E3 ligase driving SOCS3 turnover not identified
    • Signals that stabilize SOCS3 not defined
  15. 2020 Medium

    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

    PMID:32989761 PMID:38504518

    Open questions at the time
    • Causal link from SOCS3 loss to specific STAT3 targets partly indirect
    • Single-lab disease-model findings
  16. 2011 High

    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

    PMID:17198696 PMID:22056987

    Open questions at the time
    • Downstream effectors of SOCS3/STAT3 in regeneration not pinpointed
    • Whether degradation or kinase inhibition dominates here unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
EPORIL6STINSRIRS1JAK2RELATBK1TRAF6
Complex memberships
elongin BC E3 ubiquitin ligase complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 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. In vitro kinase assay, binding studies with SH2 domain mutants, chimeric protein analysis, co-immunoprecipitation of endogenous CIS3 with JAK2 Genes to cells : devoted to molecular & cellular mechanisms High 10421843
1999 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. 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 The Journal of biological chemistry High 10514492
2000 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. Co-immunoprecipitation, deletion/point mutagenesis of SOCS3 and EPOR, Ba/F3 cell proliferation assay, STAT5 phosphorylation assay The Journal of biological chemistry High 10882725
2000 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. Yeast two-hybrid binding assay, confocal microscopy of SOCS3 translocation, IR Y960F mutant cells, Stat5B luciferase reporter assay The Journal of biological chemistry High 10821852
2001 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. Transgenic mouse model expressing dominant-active JAK mutant overcoming SOCS3 inhibition; DSS-induced colitis model; STAT3 phosphorylation analysis The Journal of experimental medicine High 11181699
2001 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. Co-immunoprecipitation of endogenous and recombinant IRS1/2; ubiquitination assays; adenoviral overexpression in mouse liver; SOCS box point mutants; glucose tolerance test The Journal of biological chemistry High 12228220
1999 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. 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 Proceedings of the National Academy of Sciences of the United States of America High 10359822
2002 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. In vitro IR autophosphorylation assay; co-immunoprecipitation of SOCS3 with IR; Western blotting for downstream signaling in HepG2 cells and mouse liver The Journal of biological chemistry High 12560330
2002 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. Chimeric receptor constructs targeting SHP2 or SOCS3 independently to gp130; signaling readouts in reconstituted cell systems The Journal of biological chemistry Medium 12403768
2003 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. Co-immunoprecipitation of SOCS3 with phospho-CD28; SOCS3 SH2 domain point mutant; SOCS3 transgenic and heterozygous knockout mice; IL-2 promoter luciferase reporter assay The Journal of experimental medicine High 12591901
1999 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. Co-immunoprecipitation of SOCS3 with JAK2; SOCS3 overexpression blocking JAK2 phosphorylation; proteasome inhibitor rescue; SOCS3 deletion construct functional mapping The Journal of clinical investigation Medium 10545526
2003 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. SOCS3 re-expression in methylation-silenced cell lines; STAT3 phosphorylation Western blot; apoptosis and growth assays; methylation-specific PCR Proceedings of the National Academy of Sciences of the United States of America Medium 14617776
2003 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. Yeast two-hybrid assay; GST pull-down; co-immunoprecipitation of FLAG-SOCS3 with IGFIR in HEK293 cells; anti-phosphotyrosine immunoprecipitation Biochemical and biophysical research communications Medium 11071852
2004 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. Promoter deletion/point mutation luciferase assays; EMSA; IFN-γ treatment of macrophages, J774 cells, and STAT3-deficient fibroblasts; Western blotting The Journal of biological chemistry High 14742442
2005 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. RT-PCR and Western blot for SOCS3 induction; Co-IP of SOCS3 with IR; SOCS inhibition functional rescue of insulin signaling Molecular and cellular biology Medium 15684405
2007 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. 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 Immunity High 18031698
2013 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. X-ray crystallography of ternary SOCS3/JAK2/gp130 complex; biochemical substrate association assays; structure-guided mutagenesis Nature structural & molecular biology High 23454976
2014 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. Biochemical binding studies; mutagenesis of the GQM motif; structural and biochemical analyses building on the SOCS3/JAK2/gp130 crystal structure Seminars in immunology Medium 24418198
2015 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. 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 Molecular and cellular biology High 25939384
2011 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. Conditional knockout mice (PTEN-/- and SOCS3-/- single and double deletion in RGCs); optic nerve crush model; gene expression analysis Nature High 22056987
2012 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. Conditional myeloid SOCS3 knockout mice; LPS sepsis model; cytokine ELISA; STAT phosphorylation Western blot; Th1/Th17 differentiation assay; chromatin modification analysis Journal of immunology (Baltimore, Md. : 1950) High 22925925
2018 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. Conditional Ezh2 KO macrophages; ChIP for H3K27me3 at Socs3 locus; TRAF6 ubiquitination assay; SOCS3 siRNA rescue experiment; DSS colitis and EAE models The Journal of experimental medicine High 29626115
2012 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. 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 Neoplasia (New York, N.Y.) High 22787435
2019 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. Co-immunoprecipitation of SOCS3 with p65; SOCS3 SH2 domain mutant; ubiquitination and proteasomal degradation assays; overexpression and knockdown experiments; HIV-1 replication assays Frontiers in microbiology Medium 30766526
2006 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. Conditional SOCS3 knockout retina; immunofluorescence for STAT3 phosphorylation; Rhodopsin and Crx expression analysis; comparison of mRNA vs. protein levels Developmental biology Medium 17198696
2021 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. Conditional endothelial SOCS3 knockout mice (SOCS3iEKO); pulse-chase half-life experiments in HUVECs; proteasome inhibitor studies; LPS challenge model; gene expression analysis JCI insight High 34138760
2020 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. Myeloid-specific SOCS3 conditional KO; single-cell RNA sequencing; STAT3 ChIP on SPP1 promoter; pharmacological SOCS3 activation; SPP1 blocking antibody in angiogenesis mouse model Molecular therapy : the journal of the American Society of Gene Therapy Medium 38504518
2020 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. Western blot and qPCR in diabetic cardiac fibroblasts; methylation-specific PCR; DNMT1 genetic knockdown; STAT3 phosphorylation assays; collagen deposition assays Journal of cellular physiology Medium 32989761
2005 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. SOCS3 overexpression in CTCL cells; dominant-negative STAT3 transfection; cell growth and apoptosis assays; IFN-α sensitivity assay Leukemia Medium 15618960
2005 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. SOCS3 overexpression in Treg cells; flow cytometry for FoxP3/CTLA-4; T cell suppression assay; comparison of SOCS3 levels in Treg vs. Th cells European journal of immunology Medium 17621372
2005 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. Transfection of dominant-negative STAT3 and SOCS3 overexpression constructs; STAT3 phosphorylation Western blot; keratinocyte migration assay Biochemical and biophysical research communications Medium 15629435
2008 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. SOCS3 promoter deletion/mutation luciferase assays; siRNA against STAT3; dominant-negative STAT3; ChIP assay for promoter occupancy by multiple transcription factors Glia Medium 18571793
2023 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. Co-immunoprecipitation of PTK6 with SOCS3; overexpression and knockdown experiments; mTOR phosphorylation Western blot; autophagy assays; proliferation/migration/invasion assays Cell death & disease Low 36690663

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. The Journal of biological chemistry 702 12228220
2011 Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature 615 22056987
1999 The role of SOCS-3 in leptin signaling and leptin resistance. The Journal of biological chemistry 494 10514492
2003 Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. The Journal of biological chemistry 476 12560330
2014 SOCS3, a Major Regulator of Infection and Inflammation. Frontiers in immunology 459 24600449
2001 CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. The Journal of experimental medicine 410 11181699
2012 SOCS3 deficiency promotes M1 macrophage polarization and inflammation. Journal of immunology (Baltimore, Md. : 1950) 386 22925925
2000 SOCS-3 is an insulin-induced negative regulator of insulin signaling. The Journal of biological chemistry 366 10821852
2001 Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. The Journal of clinical investigation 328 11748261
1999 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. Genes to cells : devoted to molecular & cellular mechanisms 325 10421843
2003 SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proceedings of the National Academy of Sciences of the United States of America 319 14617776
2003 SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses. Nature medicine 292 12847520
2000 CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. The Journal of biological chemistry 260 10882725
2013 SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nature structural & molecular biology 244 23454976
1999 Autoregulation of pituitary corticotroph SOCS-3 expression: characterization of the murine SOCS-3 promoter. Proceedings of the National Academy of Sciences of the United States of America 243 10359822
2009 SOCS1 and SOCS3 in the control of CNS immunity. Trends in immunology 237 19643666
2005 Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis. Nature medicine 220 16007096
2005 Activation of SOCS-3 by resistin. Molecular and cellular biology 209 15684405
2002 SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. The Journal of biological chemistry 184 12403768
2006 Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology 180 17241887
1999 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. Blood 180 10515892
2006 SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. The Journal of clinical investigation 175 16710471
2014 Inhibition of IL-6 family cytokines by SOCS3. Seminars in immunology 170 24418198
2018 Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3. The Journal of experimental medicine 152 29626115
2008 Expression and functional significance of SOCS-1 and SOCS-3 in astrocytes. Journal of immunology (Baltimore, Md. : 1950) 112 18713987
2018 The roles of SOCS3 and STAT3 in bacterial infection and inflammatory diseases. Scandinavian journal of immunology 111 30341772
2001 STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma. Blood 103 11159537
2015 SOCS3 and its role in associated diseases. Human immunology 96 26429311
2018 SOCS3 as a future target to treat metabolic disorders. Hormones (Athens, Greece) 86 30414080
2007 Reciprocal regulation of SOCS 1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme. Clinical cancer research : an official journal of the American Association for Cancer Research 86 17438093
1999 Inhibitory roles for SHP-1 and SOCS-3 following pituitary proopiomelanocortin induction by leukemia inhibitory factor. The Journal of clinical investigation 81 10545526
2003 Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3. American journal of physiology. Gastrointestinal and liver physiology 78 12519742
2002 Ageing increases SOCS-3 expression in rat hypothalamus: effects of food restriction. Biochemical and biophysical research communications 74 12163036
2000 Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor. Biochemical and biophysical research communications 74 11071852
1998 CIS3 and JAB have different regulatory roles in interleukin-6 mediated differentiation and STAT3 activation in M1 leukemia cells. Oncogene 74 9811457
2020 The JAK1/STAT3/SOCS3 axis in bone development, physiology, and pathology. Experimental & molecular medicine 73 32788655
2016 SOCS3 revisited: a broad regulator of disease, now ready for therapeutic use? Cellular and molecular life sciences : CMLS 72 27137184
2007 Methylation of SOCS-3 and SOCS-1 in the carcinogenesis of Barrett's adenocarcinoma. Gut 72 17376806
2007 Deficient SOCS3 expression in CD4+CD25+FoxP3+ regulatory T cells and SOCS3-mediated suppression of Treg function. European journal of immunology 71 17621372
2005 Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNalpha. Leukemia 71 15618960
2014 SOCS3 and STAT3, major controllers of the outcome of infection with Mycobacterium tuberculosis. Seminars in immunology 69 25458989
2003 A role of suppressor of cytokine signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated interleukin 2 production. The Journal of experimental medicine 65 12591901
1998 Cytokine-inducible SH2 protein (CIS3) and JAK2 binding protein (JAB) abolish prolactin receptor-mediated STAT5 signaling. FEBS letters 65 9883901
2020 Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit. BMC cardiovascular disorders 64 32169038
2015 MicroRNA-185 targets SOCS3 to inhibit beta-cell dysfunction in diabetes. PloS one 62 25658748
2008 The role of SOCS-3 protein in leptin resistance and obesity. Acta medica Indonesiana 56 18560028
2004 Analysis of SOCS-3 promoter responses to interferon gamma. The Journal of biological chemistry 55 14742442
2007 SOCS3 protein developmentally regulates the chemokine receptor CXCR4-FAK signaling pathway during B lymphopoiesis. Immunity 50 18031698
2020 Resident alveolar macrophage-derived vesicular SOCS3 dampens allergic airway inflammation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 48 32030817
2015 FXR induces SOCS3 and suppresses hepatocellular carcinoma. Oncotarget 48 26416445
2013 SOCS3 promotor hypermethylation and STAT3-NF-κB interaction downregulate SOCS3 expression in human coronary artery smooth muscle cells. American journal of physiology. Heart and circulatory physiology 48 23335796
2019 Lidocaine Potentiates SOCS3 to Attenuate Inflammation in Microglia and Suppress Neuropathic Pain. Cellular and molecular neurobiology 47 31209627
2005 Regulation of pancreatic beta-cell mass and proliferation by SOCS-3. Journal of molecular endocrinology 46 16216905
2019 Radiotherapy resistance acquisition in Glioblastoma. Role of SOCS1 and SOCS3. PloS one 45 30811476
2017 Role of Leptin and SOCS3 in Inhibiting the Type I Interferon Response During Obesity. Inflammation 44 27704310
2006 Elevated expression and genetic association links the SOCS3 gene to atopic dermatitis. American journal of human genetics 44 16685656
2006 Suppressor of cytokine signaling 3 (SOCS3) in Th2 cells evokes Th2 cytokines, IgE, and eosinophilia. Current allergy and asthma reports 42 16476192
2005 SOCS-3 induces myoblast differentiation. The Journal of biological chemistry 42 15653674
2015 SOCS3 Drives Proteasomal Degradation of TBK1 and Negatively Regulates Antiviral Innate Immunity. Molecular and cellular biology 40 25939384
2014 Gene silencing of SOCS3 by siRNA intranasal delivery inhibits asthma phenotype in mice. PloS one 40 24637581
2017 IL-10 and socs3 Are Predictive Biomarkers of Dengue Hemorrhagic Fever. Mediators of inflammation 39 28827898
2016 SOCS-3 Regulates Alveolar Bone Loss in Experimental Periodontitis. Journal of dental research 38 27126447
2008 Molecular basis of oncostatin M-induced SOCS-3 expression in astrocytes. Glia 38 18571793
2010 Deficient SOCS3 and SHP-1 expression in psoriatic T cells. The Journal of investigative dermatology 37 20130595
2010 SOCS-3 antagonises the proliferative and migratory effects of fibroblast growth factor-2 in prostate cancer by inhibition of p44/p42 MAPK signalling. Endocrine-related cancer 36 20335309
2010 SOCS3 regulates graft-versus-host disease. Blood 36 20435883
2015 Methylation and microRNA-mediated epigenetic regulation of SOCS3. Molecular biology reports 35 25682267
2019 Hepatocyte growth control by SOCS1 and SOCS3. Cytokine 34 31154249
2018 Down-expression of P2RX2, KCNQ5, ERBB3 and SOCS3 through DNA hypermethylation in elderly women with presbycusis. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 34 29325454
2018 Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection. Journal of the American Heart Association 34 29343476
2014 Expression of suppressor of cytokine signaling-3 (SOCS3) and its role in neuronal death after complete spinal cord injury. Experimental neurology 34 24959867
2010 Enforced SOCS1 and SOCS3 expression attenuates Lck-mediated cellular transformation. International journal of oncology 34 20372794
2008 Decreased expression of SOCS-3 mRNA in breast cancer with lymph node metastasis. Oncology reports 34 18097573
2013 Critical and independent role for SOCS3 in either myeloid or T cells in resistance to Mycobacterium tuberculosis. PLoS pathogens 33 23853585
2012 A requirement for SOCS-1 and SOCS-3 phosphorylation in Bcr-Abl-induced tumorigenesis. Neoplasia (New York, N.Y.) 33 22787435
2005 Estrogen receptor-alpha regulates SOCS-3 expression in human breast cancer cells. Biochemical and biophysical research communications 33 16055089
2001 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. Circulation research 33 11304496
2021 Endothelial SOCS3 maintains homeostasis and promotes survival in endotoxemic mice. JCI insight 32 34138760
2020 DNMT1 deregulation of SOCS3 axis drives cardiac fibroblast activation in diabetic cardiac fibrosis. Journal of cellular physiology 32 32989761
2020 Endogenous hydrogen sulfide improves vascular remodeling through PPARδ/SOCS3 signaling. Journal of advanced research 32 33318871
2011 Zoledronic acid inhibits macrophage SOCS3 expression and enhances cytokine production. Journal of cellular biochemistry 31 21751240
2013 Gene methylation and silencing of SOCS3 in mantle cell lymphoma. British journal of haematology 30 23432547
2003 Sepsis-induced SOCS-3 expression is immunologically restricted to phagocytes. Journal of leukocyte biology 29 12960286
2020 MiR-30a-5p promotes cholangiocarcinoma cell proliferation through targeting SOCS3. Journal of Cancer 28 32284757
2012 SOCS3 promotes interleukin-17 expression of human T cells. Blood 27 23033269
2012 Neuron-intrinsic inhibitors of axon regeneration: PTEN and SOCS3. International review of neurobiology 27 23206599
2012 SOCS3: A novel therapeutic target for cardioprotection. JAK-STAT 27 24058778
2019 HNF1α Controls Liver Lipid Metabolism and Insulin Resistance via Negatively Regulating the SOCS-3-STAT3 Signaling Pathway. Journal of diabetes research 25 31223625
2016 miR-203 and miR-221 regulate SOCS1 and SOCS3 in essential thrombocythemia. Blood cancer journal 25 26990535
2006 SOCS3 is required to temporally fine-tune photoreceptor cell differentiation. Developmental biology 25 17198696
2024 SOCS3 regulates pathological retinal angiogenesis through modulating SPP1 expression in microglia and macrophages. Molecular therapy : the journal of the American Society of Gene Therapy 24 38504518
2021 SOCS3 Promotes ALV-J Virus Replication via Inhibiting JAK2/STAT3 Phosphorylation During Infection. Frontiers in cellular and infection microbiology 24 34568100
2019 Suppressor of Cytokine Signaling 3 (SOCS3) Degrades p65 and Regulate HIV-1 Replication. Frontiers in microbiology 23 30766526
2020 Chimeric Peptidomimetics of SOCS 3 Able to Interact with JAK2 as Anti-inflammatory Compounds. ACS medicinal chemistry letters 22 32435361
2018 PPARγ alleviated hepatocyte steatosis through reducing SOCS3 by inhibiting JAK2/STAT3 pathway. Biochemical and biophysical research communications 22 29550470
2013 Multiple roles of SOCS proteins: differential expression of SOCS1 and SOCS3 in atherosclerosis. International journal of molecular medicine 22 23545584
2005 SOCS3/CIS3 negative regulation of STAT3 in HGF-induced keratinocyte migration. Biochemical and biophysical research communications 22 15629435
2023 PTK6 inhibits autophagy to promote uveal melanoma tumorigenesis by binding to SOCS3 and regulating mTOR phosphorylation. Cell death & disease 21 36690663
2014 Frequent SOCS3 and 3OST2 promoter methylation and their epigenetic regulation in endometrial carcinoma. American journal of cancer research 21 25628929
2005 Expression of STAT3 and SOCS3 in pancreatic acinar cells. The Journal of surgical research 20 15893771

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