Affinage

SOCS2

Suppressor of cytokine signaling 2 · UniProt O14508

Length
198 aa
Mass
22.2 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SOCS2 is the substrate-recognition subunit of a CRL5 (Cullin5–ElonginBC–Rbx2) E3 ubiquitin ligase that uses its SH2 domain to bind phosphotyrosine degrons on activated cytokine and growth-factor receptors and direct them for K48-linked ubiquitination and proteasomal degradation, thereby acting as a negative-feedback brake on growth-hormone and related signaling (PMID:25505247, PMID:21980433, PMID:28967904). The complex was biophysically reconstituted as a monomeric SOCS2–ElonginBC–Cullin5–Rbx2 assembly that engages substrate via phosphorylated receptor peptides, and the SOCS-box motif that recruits Elongin B/C is essential for all of its inhibitory and ligase activity (PMID:25505247, PMID:15690087, PMID:21980433). Structurally, the SH2 domain captures pTyr peptides from substrates such as GHR and EpoR in an extended conformation, with substrate-specific EF-loop conformations and an allosteric exosite that stabilizes the domain and tightens phosphopeptide binding (PMID:31182716, PMID:34857742). Its principal physiological role is degradation of the growth hormone receptor at phospho-Tyr487, limiting GH/STAT5b-driven somatic and mammary growth — loss of SOCS2 elevates GHR and prolongs STAT5 signaling in a STAT5b-dependent manner (PMID:21980433, PMID:28967904, PMID:12040024, PMID:16469767). SOCS2 extends this activity to additional receptors and non-receptor substrates, recognizing FLT3 and the cystine transporter SLC7A11 (promoting ferroptosis) for ubiquitin-dependent degradation, and targeting the kinase NDR1/STK38 and SOCS1/SOCS3 (PMID:23548639, PMID:35995846, PMID:28216640, PMID:16199887). Its own abundance is tuned transcriptionally — induced downstream of STAT5 and AhR — post-transcriptionally by METTL3/YTHDF2-mediated m6A decay of its mRNA, and post-translationally by the E3 ligase KIAA0317 (PMID:22090359, PMID:29171881, PMID:31578312). In immune cells SOCS2 acts as an anti-inflammatory regulator: it is induced by lipoxin A4/AhR signaling, restrains Th2 and iTreg responses and dendritic-cell inflammatory output, and limits NF-κB activation (PMID:16415877, PMID:21646394, PMID:23455506, PMID:28216640).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1998 Medium

    Established SOCS2 as a physical partner of an activated growth-factor receptor, the first clue that it docks onto receptor signaling complexes.

    Evidence Yeast two-hybrid plus reciprocal Co-IP/GST-pulldown against the IGF-IR cytoplasmic domain

    PMID:9727029

    Open questions at the time
    • Did not define the phosphotyrosine degron bound
    • No functional consequence of the interaction shown
    • Distinguished SOCS2 from SOCS1/SOCS3 only by binding, not mechanism
  2. 2002 High

    Resolved the paradox that SOCS2 enhances rather than suppresses growth and placed it as a GHR-binding negative regulator acting upstream of STAT5b.

    Evidence Transgenic and SOCS2/STAT5b double-knockout mouse genetics with GHR phosphopeptide binding mapping (pTyr595) and prolonged hepatocyte STAT5 phosphorylation

    PMID:12040024 PMID:12208853

    Open questions at the time
    • Mechanism of GHR downregulation (degradation vs signaling block) not yet defined
    • Biphasic dose-dependent growth phenotype unexplained
  3. 2005 Medium

    Showed the SOCS-box is indispensable for inhibitory function and that SOCS2 can act through E3-ligase-type degradation of other SOCS proteins, foreshadowing its ligase identity.

    Evidence SOCS2-/- mice with exogenous GH, structure/function mutagenesis of GHR tyrosines and the SOCS-box, and proteasome/elongin BC-dependent SOCS3 degradation assays

    PMID:15690087 PMID:16199887

    Open questions at the time
    • Direct demonstration of intrinsic ubiquitin ligase activity still lacking
    • Which substrates degraded in vivo unresolved
  4. 2006 High

    Expanded SOCS2 into immune and developmental physiology — anti-inflammatory control downstream of lipoxin A4/AhR and regulation of prolactin-driven mammary morphogenesis.

    Evidence SOCS2-/- mouse infection and DC stimulation models; Socs2/PrlR epistatic mouse crosses with pSTAT5 readouts; reports of non-GH JunB stabilization

    PMID:16415877 PMID:16419040 PMID:16469767

    Open questions at the time
    • Whether immune phenotypes reflect receptor degradation or signaling competition not separated
    • Direct substrates in immune cells not identified at this stage
  5. 2011 High

    Demonstrated direct intrinsic ubiquitin ligase activity, establishing SOCS2 as an E3 that ubiquitinates GHR for proteasomal degradation and assigning distinct GHR tyrosines to binding vs degradation.

    Evidence In vitro ubiquitin ligase assays, mutational mapping (Tyr487 for degradation), SOCS2-/- liver GHR levels, proteasome inhibition; parallel T-cell knockout studies of Th2 control

    PMID:21646394 PMID:21980433

    Open questions at the time
    • Full ligase complex composition and stoichiometry not yet defined
    • Substrate repertoire beyond GHR incomplete
  6. 2014 High

    Defined the molecular machine by reconstituting the full CRL5(SOCS2) complex and measuring its internal interaction affinities.

    Evidence In vitro reconstitution of SOCS2–ElonginBC–Cullin5–Rbx2, phospho-GHR peptide pulldown, SEC-MALS, native MS and ITC

    PMID:25505247

    Open questions at the time
    • Did not provide atomic structure of substrate engagement
    • Catalytic cycle and neddylation dependence not addressed
  7. 2017 High

    Provided structural and disease-relevant detail of substrate recognition, linking a GHR variant that disrupts SOCS2 binding to impaired receptor degradation and prolonged GH signaling.

    Evidence NMR comparison of GHR P495T, TIRF/surface receptor imaging, mutagenesis; proteomic identification of NDR1/STK38 as a K48-ubiquitinated substrate with SOCS2-/- colitis model

    PMID:28216640 PMID:28967904

    Open questions at the time
    • Whether GHR P495T causes a human growth phenotype not established here
    • Breadth of non-receptor substrate degron preferences unknown
  8. 2019 High

    Delivered atomic-resolution substrate recognition and revealed dual regulation of SOCS2 abundance by m6A mRNA decay and by a counteracting E3 ligase.

    Evidence Co-crystal structures of SOCS2-EloBC with GHR(pY595) and EpoR(pY426); METTL3/YTHDF2 m6A-seq/meRIP in HCC; KIAA0317 KO mice and inhibitor (BC-1365) in lung inflammation

    PMID:29171881 PMID:31182716 PMID:31578312

    Open questions at the time
    • Structural basis for substrate selectivity beyond pY pocket only partially explained by EF-loop
    • Crosstalk between transcriptional, m6A, and proteostatic control not integrated
  9. 2022 High

    Extended SOCS2 substrate scope to the cystine transporter SLC7A11, coupling its ligase activity to ferroptosis and radiosensitization in cancer.

    Evidence Co-IP, domain mutagenesis (SH2 N-terminal recognition; SOCS-BOX L162/C166 for elongin BC), K48 ubiquitination assays, ferroptosis readouts and xenografts

    PMID:35995846

    Open questions at the time
    • Generality of N-terminal (non-pTyr) substrate recognition unclear
    • In vivo contribution to tumor ferroptosis vs other pathways not isolated
  10. 2023 High

    Validated SOCS2 as a druggable target through structure-guided allosteric and covalent ligands that modulate phosphopeptide binding and block substrate recruitment.

    Evidence Crystal structure of an exosite-binding helical peptide enhancing binding; covalent Cys111 inhibitor MN551/prodrug MN714 with co-crystal, 19F NMR and cellular target engagement

    PMID:34857742 PMID:37816714

    Open questions at the time
    • Endogenous ligand or physiological role of the exosite unknown
    • Cellular and in vivo efficacy of covalent inhibitors not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the full substrate repertoire and degron rules of CRL5(SOCS2) are decoded in different tissues, and how its multilayer regulation is coordinated, remains open.
  • No unbiased proteome-wide degradation atlas across cell types
  • Integration of STAT5/AhR transcription, m6A decay, and KIAA0317 turnover into a quantitative regulatory model lacking
  • Whether reported non-degradative signaling roles (e.g., EGFR/Src in neurons) reflect a distinct mechanism unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-8953854 Metabolism of RNA 1
Partners
CUL5ELONGINBELONGINCFLT3GHRIGF1RSLC7A11STK38
Complex memberships
CRL5(SOCS2) (SOCS2–ElonginBC–Cullin5–Rbx2) E3 ubiquitin ligase

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SOCS2 (hSOCS-2) was identified as a binding partner of the activated insulin-like growth factor I receptor (IGF-IR) cytoplasmic domain via yeast two-hybrid screen and confirmed by GST-pulldown and co-immunoprecipitation in mammalian cells; interaction required kinase activity but not specific C-terminal tyrosines 950, 1250, 1251, or 1316. Yeast two-hybrid, GST-pulldown, reciprocal co-immunoprecipitation The Journal of biological chemistry Medium 9727029
1998 SOCS1 and SOCS3, but not SOCS2, inhibit IFN-mediated tyrosine phosphorylation and nuclear translocation of STAT1, and block IFN-induced antiviral and antiproliferative activities in stable cell lines. Stable cell line overexpression, Western blot for STAT1 phosphorylation, antiviral/antiproliferative assays The Journal of biological chemistry Medium 9857039
1997 SSI-2 (SOCS2) mRNA is induced by cytokine stimulation, and forced expression of SSI-2 in mouse myeloid leukemia M1 cells suppressed the apoptotic effect of LIF, similar to SSI-1. Northern blotting, forced expression/functional assay in M1 cells Biochemical and biophysical research communications Low 9266833
2002 SOCS2 overexpression in vivo (transgenic mice) results in enhanced growth rather than growth suppression, and SOCS2 protein binds endogenous GH receptors in multiple mouse organs; phosphopeptide binding studies identified phosphorylated tyrosine 595 on the GH receptor as the site of SOCS2 interaction. Transgenic mouse generation, co-immunoprecipitation with endogenous GHR, phosphopeptide binding assay The Journal of biological chemistry High 12208853
2002 The growth-enhancement phenotype of SOCS2-deficient mice is dependent on STAT5b; deletion of SOCS2 in mice also lacking STAT5b had little effect on growth, placing SOCS2 as a regulator upstream of STAT5b in the GH signaling pathway. Primary hepatocytes from SOCS2-/- mice show prolonged STAT5 phosphorylation in response to GH. Double-knockout mouse genetics (epistasis), primary hepatocyte GH signaling assay Molecular endocrinology (Baltimore, Md.) High 12040024
2005 SOCS2 negatively regulates GH signaling in vivo and in vitro; SOCS2-/- phenotype requires endogenous GH; SOCS2 binds two phosphorylated tyrosines on the GH receptor; mutagenesis showed both are essential for SOCS2 inhibitory function; the SOCS-box motif is essential for all inhibitory function. SOCS2-/- mice, exogenous GH treatment, structure/function mutagenesis, biochemical interaction studies The Journal of clinical investigation High 15690087
2005 SOCS2 promotes neurite outgrowth in CNS neurons and PC12 cells by binding to and constitutively phosphorylating the EGFR at Tyr845 (Src binding site), leading to inhibition of the neurite-inhibitory GTPase Rho and activation of Rac1; SOCS2-induced neurite outgrowth is blocked by EGFR inhibitors (PP3, AG490) or Src kinase inhibitor (PP2); overexpressed SHP-2 reduces constitutive EGFR phosphorylation and neurite outgrowth. Overexpression in neurons/PC12 cells, co-immunoprecipitation with EGFR, pharmacological inhibitors, GTPase activity assays The Journal of biological chemistry Medium 14764607
2005 SOCS2 can enhance IL-2- and IL-3-induced STAT phosphorylation and proliferation by promoting proteasome-dependent degradation of SOCS3 (and SOCS1); this requires an intact SOCS box and is enhanced by co-expression of elongin B/C, suggesting SOCS2 forms an E3 ligase complex that targets SOCS3 for degradation. Overexpression, proteasome inhibitor assays, co-expression with elongin B/C, Western blot for SOCS3 levels Molecular and cellular biology Medium 16199887
2006 Lipoxin A4 (LXA4) and aspirin-triggered lipoxin activate AhR and LXAR receptors in dendritic cells, triggering SOCS2 expression; SOCS2-deficient DCs are hyper-responsive to microbial stimuli and refractory to LXA4 inhibition (but not IL-10); in vivo, SOCS2-/- mice show uncontrolled cytokine production and elevated mortality upon infection. SOCS2-/- mouse model, DC stimulation assays, in vivo infection model Nature medicine High 16415877
2006 SOCS2 promotes prolactin-driven mammary alveolar morphogenesis; homozygous null mutation of Socs2 rescued the failure of lactation and reduced STAT5 phosphorylation in prolactin receptor heterozygous mice, demonstrating SOCS2 is a key negative regulator of the prolactin-signaling pathway in the mammary gland. Socs2-/- and PrlR+/- mouse genetics (epistasis), mammary gland transplantation, pSTAT5 measurement Molecular endocrinology (Baltimore, Md.) High 16469767
2006 SOCS2 interacts with the leptin receptor at Y1077 (with higher binding affinity than CIS) and not at Y985; SOCS2 can block CIS interaction with Y985 through direct binding of SOCS2 to the CIS SOCS box, with elongin B/C recruitment crucial for suppressing CIS activity. MAPPIT two-hybrid in intact cells, binding affinity analysis, co-expression assays Journal of cell science Medium 16684815
2007 Using MAPPIT, Y487 and Y595 were mapped as the major SOCS2 binding sites on the GH receptor (non-overlapping with STAT5 sites at Y534, Y566, Y627), ruling out SOCS2-mediated inhibition of STAT5 activation by competition for shared binding sites. MAPPIT mammalian two-hybrid, mutagenesis of GHR tyrosine residues Molecular endocrinology (Baltimore, Md.) Medium 17666591
2008 SOCS2 acts as an inhibitor of JAK2V617F-mediated signaling; SOCS2 knockdown induced constitutive STAT5 phosphorylation in JAK2V617F-expressing cells; cytokine independence in myeloproliferative disorder cell lines correlated with low SOCS2 expression, and CpG island hypermethylation of SOCS2 was identified in cytokine-independent cells. siRNA knockdown, STAT5 phosphorylation assay, CpG methylation analysis Leukemia Medium 18769447
2011 SOCS2 is part of a multimeric complex with intrinsic ubiquitin ligase activity; SOCS2 directly ubiquitinates the GH receptor (GHR) and regulates cellular GHR levels in a proteasome-dependent manner; the SOCS-box interaction with Elongin B/C controls SOCS2 protein turnover; Y487 on GHR (not Y595) accounts for SOCS2-mediated GHR degradation; increased GHR levels are observed in SOCS2-/- mouse livers. Ubiquitin ligase activity assay, mutational analysis, SOCS2-/- mouse liver fractionation, proteasome inhibitor experiments PloS one High 21980433
2011 SOCS2-/- CD4+ T cells show markedly enhanced Th2 differentiation; SOCS2-/- mice exhibit elevated IgE, eosinophilia, and type 2 responses after helminth antigen challenge; SOCS2-/- T cells show enhanced STAT6 and STAT5 phosphorylation but blunted STAT3 phosphorylation after T cell activation. SOCS2-/- mouse model, T cell differentiation assays, STAT phosphorylation Western blots, in vivo allergen/helminth challenge models The Journal of experimental medicine High 21646394
2011 STAT5A-mediated SOCS2 expression is required for JAK2/STAT3 inhibition following c-Src inhibitor treatment in head and neck squamous carcinoma; inhibition of STAT5A (not STAT5B) reduces SOCS2 expression; SOCS2 inhibits JAK2 activity and JAK2-STAT3 binding; SOCS2 overexpression prevents STAT3 reactivation. siRNA knockdown, kinase assays, Western blotting, overexpression studies, in vivo heterotransplant model Clinical cancer research Medium 22090359
2013 SOCS2 associates with activated FLT3 through phosphotyrosine residues Y589 and Y919, co-localizes with FLT3 at the cell membrane, increases FLT3 ubiquitination, accelerates receptor degradation via proteasomes, and negatively regulates FLT3 signaling by blocking Erk1/2 and STAT5 activation; SOCS2 expression decreases FLT3-ITD-mediated cell proliferation. Co-immunoprecipitation, co-localization microscopy, ubiquitination assay, proliferation/colony formation assays Molecular oncology Medium 23548639
2013 SOCS2 expression is induced by androgens through a mechanism requiring STAT5 and androgen receptor-dependent transcription in prostate cancer cells; SOCS2 inhibits GH activation of JAK2, Src, and STAT5, and inhibits cell invasion and proliferation in vitro; in vivo, SOCS2 limits proliferation and IGF-1 production in the prostate in response to GH. Androgen treatment + STAT5/AR knockdown, kinase activity assays, invasion/proliferation assays, in vivo mouse prostate model Carcinogenesis Medium 24031028
2013 SOCS2 is required for stable Foxp3 expression in inducible regulatory T cells (iTregs) in vitro and in vivo; SOCS2-deficient iTregs show elevated STAT6 phosphorylation upon IL-4 stimulation and secrete elevated IFN-γ and IL-13; SOCS2 maintains iTreg anti-inflammatory phenotype by downregulating IL-4 signaling. SOCS2-/- mouse, in vitro iTreg differentiation, in vivo OVA feeding model, cytokine measurement, STAT6 phosphorylation assay Journal of immunology (Baltimore, Md. : 1950) Medium 23455506
2014 SOCS2 biophysically reconstituted as part of the full-size CRL5(SOCS2) E3 ubiquitin ligase complex (SOCS2-ElonginBC-Cullin5-Rbx2); components pulled from human cell lysates using phosphorylated GHR peptide beads; complex is monomeric; affinities of protein-protein interactions within the complex measured by isothermal titration calorimetry. In vitro reconstitution, pulldown from cell lysates with phospho-GHR peptides, SEC-MALS, native MS, ITC The Journal of biological chemistry High 25505247
2016 Tolerogenic nanoparticle-mediated induction of DC tolerogenic phenotype and Treg differentiation is mediated by AhR-dependent induction of SOCS2, which results in inhibition of NF-κB activation and proinflammatory cytokine production. Nanoparticle treatment, SOCS2 KO DCs, NF-κB activity assay, Treg differentiation assay in vivo Science signaling Medium 27330188
2017 SOCS2 is the substrate recognition component of the E3 ubiquitin ligase responsible for ubiquitination and degradation of the GH receptor; a GHR variant P495T impairs SOCS2 binding (SOCS2 requires phosphorylated Tyr487 and Pro495/Thr494 residues for binding), resulting in decreased GHR internalization/degradation and prolonged GH signaling; NMR structural comparison confirmed the P495T substitution alters the SOCS2 binding site structure. TIRF microscopy, surface receptor expression measurement, mutagenesis, NMR spectroscopy, stable cell lines Oncogene High 28967904
2017 SOCS2 (Cullin5-SOCS2 E3 ligase) targets the serine-threonine kinase NDR1/STK38 for K48-linked ubiquitination and proteasomal degradation; SOCS2 interacts with NDR1; SOCS2 overexpression antagonizes NDR1-induced TNFα-stimulated NF-κB activity; depletion of NDR1 rescues the effect of SOCS2-deficiency on TNFα-induced NF-κB transactivation; SOCS2-/- mice show pro-inflammatory phenotype correlating with elevated NDR1 and nuclear p65. Mass spectrometry proteomics upon SOCS2 depletion, co-immunoprecipitation, ubiquitination assay (K48-linkage), NF-κB reporter assay, SOCS2-/- colitis model Scientific reports High 28216640
2018 METTL3-mediated N6-methyladenosine (m6A) modification of SOCS2 mRNA promotes SOCS2 mRNA degradation through the m6A reader protein YTHDF2; knockdown of METTL3 abolishes SOCS2 mRNA m6A modification and augments SOCS2 mRNA expression in HCC cells. m6A sequencing, meRIP-qPCR, METTL3 knockdown/CRISPR activation, YTHDF2 pathway analysis Hepatology (Baltimore, Md.) High 29171881
2019 Crystal structures of SOCS2-ElonginB-ElonginC in complex with phosphorylated peptides from GHR (pY595) and EpoR (pY426) solved at 1.98 Å and 2.69 Å; both peptides bind in extended conformation at the canonical SH2 pY binding site but capture different conformations of the EF loop via hydrophobic interactions; cancer-associated SNPs around the pY pocket weaken substrate-binding affinity. X-ray crystallography (co-crystal structures), biophysical binding affinity assays, cancer SNP mutagenesis Nature communications High 31182716
2019 KIAA0317 is an E3 ubiquitin ligase that degrades SOCS2 protein; KIAA0317-mediated SOCS2 degradation exacerbates inflammation in vitro; KIAA0317-knockout mice are resistant to LPS-induced pulmonary inflammation; a small molecule inhibitor of KIAA0317 (BC-1365) prevents SOCS2 degradation and attenuates LPS- and P. aeruginosa-induced lung inflammation in vivo. KIAA0317 KO mouse, siRNA knockdown, small molecule inhibitor, in vivo LPS/P. aeruginosa lung inflammation models JCI insight High 31578312
2021 An exosite on the SOCS2-SH2 domain (opposite side from the pTyr-binding site) binds a non-phosphorylated peptide (F3) as an α-helix, stabilizing the SH2 domain and slowing dissociation of phosphorylated ligands, enhancing phosphopeptide binding affinity and increasing SOCS2 inhibition of GH signaling. Crystal structure of SOCS2/F3, biophysical binding assays (SPR/ITC), GH signaling functional assay Nature communications High 34857742
2022 SOCS2 promotes ferroptosis and radiosensitization in HCC by recognizing the N-terminal domain of SLC7A11 via the SOCS2 SH2 domain, and the L162/C166 residues of the SOCS2-BOX bind elongin B/C to form a SOCS2/elonginB/C complex that recruits ubiquitin and promotes K48-linked polyubiquitination degradation of SLC7A11. Co-immunoprecipitation, ubiquitination assay (K48-linked), domain mutagenesis, ferroptosis assays (lipid peroxidation, Fe2+, GPX4), in vivo xenograft Cell death and differentiation High 35995846
2023 Structure-based design targeting the SOCS2-SH2 domain Cys111 yielded a covalent inhibitor (MN551) and prodrug (MN714); co-crystal structure confirms covalent modification at Cys111; covalent engagement at Cys111 competitively blocks recruitment of SOCS2 to its native substrate; prodrug MN714 is cell-permeable and demasks in cells (confirmed by 19F NMR and cellular target engagement assay). Structure-based drug design, co-crystal structure, 19F NMR spectroscopy, cellular target engagement assay Nature communications High 37816714
2006 SOCS2 overexpression in C2C12 cells inhibits spontaneous myotube formation and potentiates BMP-induced osteoblast differentiation by upregulating JunB protein through inhibition of JunB ubiquitin-proteasome degradation; SOCS2 reduces JunB ubiquitination in COS-7 cells; this effect does not require GH signaling. Stable transfection, proteasome inhibitor assay, ubiquitination assay, reporter gene assay Journal of cellular physiology Medium 16419040
2015 SOCS2 deficiency unleashes HSC proliferation in vitro, sustaining STAT5 phosphorylation in response to IL-3, thrombopoietin, and GM-CSF; in vivo, SOCS2 deficiency leads to unrestricted myelopoietic response to 5-FU and exhaustion of long-term HSC function across serial bone marrow transplantations. Socs2-/- mouse, in vitro HSC assays, STAT5 phosphorylation, serial bone marrow transplantation Cancer research Medium 25858143
2015 SOCS2 balances hepatocyte proliferation during liver regeneration by preventing increases in GHR via ubiquitination and suppressing GH pathway activity during the first wave of proliferation; at later times, SOCS2 enhances hepatocyte proliferation by modulating a decrease in serum IGF-1 that allows GH release. SOCS2-/- mouse partial hepatectomy model, GHR ubiquitination assay, serum IGF-1 measurement, BrdU proliferation assay The Journal of biological chemistry Medium 26703468
2009 SOCS2 expression is dramatically upregulated during human monocyte-derived DC maturation; silencing SOCS2 inhibits DC maturation (reduced CD83, CD40, CD86, HLA-DR) and decreases LPS-induced activation of MAP kinases (SAPK/JNK, p38, ERK), IRF3, and NF-κB translocation, implicating SOCS2 in both MyD88-dependent and -independent TLR4 signaling pathways. siRNA knockdown, flow cytometry for DC maturation markers, Western blot for MAPK/IRF3/NF-κB PloS one Medium 19779605
2019 In human macrophages stimulated with indoxyl sulfate (IS), IS-activated AhR associates with the p65 NF-κB subunit causing mutual inhibition and early suppression of TNF-α; later, SOCS2 (directly induced by IS-activated AhR) relieves NF-κB repression, and ultimately AhR induces TNF-α by binding AhR binding sites in the TNF-α gene. AhR/NF-κB co-association assay, SOCS2 siRNA knockdown, chromatin binding assay, time-course TNF-α production in human macrophages FASEB journal Medium 31284759

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology (Baltimore, Md.) 1076 29171881
1998 The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. The Journal of biological chemistry 327 9857039
2022 SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma. Cell death and differentiation 267 35995846
2006 Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent. Nature medicine 252 16415877
2005 SOCS2 negatively regulates growth hormone action in vitro and in vivo. The Journal of clinical investigation 194 15690087
2006 Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions. Cytokine & growth factor reviews 170 17070092
2016 Tolerogenic nanoparticles inhibit T cell-mediated autoimmunity through SOCS2. Science signaling 167 27330188
1998 Interaction of human suppressor of cytokine signaling (SOCS)-2 with the insulin-like growth factor-I receptor. The Journal of biological chemistry 166 9727029
1997 Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3. Biochemical and biophysical research communications 142 9266833
2002 Biological evidence that SOCS-2 can act either as an enhancer or suppressor of growth hormone signaling. The Journal of biological chemistry 138 12208853
2002 Growth enhancement in suppressor of cytokine signaling 2 (SOCS-2)-deficient mice is dependent on signal transducer and activator of transcription 5b (STAT5b). Molecular endocrinology (Baltimore, Md.) 131 12040024
2016 Androgen-induced Long Noncoding RNA (lncRNA) SOCS2-AS1 Promotes Cell Growth and Inhibits Apoptosis in Prostate Cancer Cells. The Journal of biological chemistry 127 27342777
2006 Socs2 and elf5 mediate prolactin-induced mammary gland development. Molecular endocrinology (Baltimore, Md.) 126 16469767
2005 SOCS2 can enhance interleukin-2 (IL-2) and IL-3 signaling by accelerating SOCS3 degradation. Molecular and cellular biology 122 16199887
1999 Growth hormone regulation of SOCS-2, SOCS-3, and CIS messenger ribonucleic acid expression in the rat. Endocrinology 118 10433229
1999 STAT5b mediates the GH-induced expression of SOCS-2 and SOCS-3 mRNA in the liver. Molecular and cellular endocrinology 100 10630411
2016 MicroRNA-194 Promotes Prostate Cancer Metastasis by Inhibiting SOCS2. Cancer research 96 28011622
2001 Lack of Socs2 expression causes the high-growth phenotype in mice. Genomics 93 11401434
2020 m6A methyltransferase METTL3 maintains colon cancer tumorigenicity by suppressing SOCS2 to promote cell proliferation. Oncology reports 92 32705223
2016 SOCS2: physiological and pathological functions. Frontiers in bioscience (Elite edition) 80 26709655
2023 Smoking-Induced M2-TAMs, via circEML4 in EVs, Promote the Progression of NSCLC through ALKBH5-Regulated m6A Modification of SOCS2 in NSCLC Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 74 37246269
2011 SOCS2 regulates T helper type 2 differentiation and the generation of type 2 allergic responses. The Journal of experimental medicine 71 21646394
2005 Role of salicylic acid and fatty acid desaturation pathways in ssi2-mediated signaling. Plant physiology 69 16306139
2020 LncRNA NEAT1/microRNA-129-5p/SOCS2 axis regulates liver fibrosis in alcoholic steatohepatitis. Journal of translational medicine 68 33228663
2004 SOCS2 induces neurite outgrowth by regulation of epidermal growth factor receptor activation. The Journal of biological chemistry 68 14764607
2012 SOCS2 deletion protects against hepatic steatosis but worsens insulin resistance in high-fat-diet-fed mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 67 22562833
2016 IL-8 induces miR-424-5p expression and modulates SOCS2/STAT5 signaling pathway in oral squamous cell carcinoma. Molecular oncology 66 27038552
2022 Engineered exosome-mediated delivery of circDIDO1 inhibits gastric cancer progression via regulation of MiR-1307-3p/SOCS2 Axis. Journal of translational medicine 64 35864511
2011 The SOCS2 ubiquitin ligase complex regulates growth hormone receptor levels. PloS one 62 21980433
2015 MiR-101 inhibits cell growth and tumorigenesis of Helicobacter pylori related gastric cancer by repression of SOCS2. Cancer biology & therapy 60 25561270
2019 MicroRNA-196a/-196b regulate the progression of hepatocellular carcinoma through modulating the JAK/STAT pathway via targeting SOCS2. Cell death & disease 59 30988277
2014 Identification of SOCS2 and SOCS6 as biomarkers in human colorectal cancer. British journal of cancer 59 25025962
2011 STAT5A-mediated SOCS2 expression regulates Jak2 and STAT3 activity following c-Src inhibition in head and neck squamous carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 58 22090359
2001 Insulin Induction of SOCS-2 and SOCS-3 mRNA expression in C2C12 Skeletal Muscle Cells Is Mediated by Stat5*. The Journal of biological chemistry 54 11279166
2014 Regulation of neurotrophin receptor (Trk) signaling: suppressor of cytokine signaling 2 (SOCS2) is a new player. Frontiers in molecular neuroscience 52 24860421
2013 Suppressor of cytokine signaling 2 (SOCS2) associates with FLT3 and negatively regulates downstream signaling. Molecular oncology 52 23548639
2006 A complex interaction pattern of CIS and SOCS2 with the leptin receptor. Journal of cell science 49 16684815
2015 SOCS2 Controls Proliferation and Stemness of Hematopoietic Cells under Stress Conditions and Its Deregulation Marks Unfavorable Acute Leukemias. Cancer research 48 25858143
2020 Ling-gui-zhu-gan decoction alleviates hepatic steatosis through SOCS2 modification by N6-methyladenosine. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 47 32559839
2019 Indoxyl sulfate-induced TNF-α is regulated by crosstalk between the aryl hydrocarbon receptor, NF-κB, and SOCS2 in human macrophages. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 47 31284759
2021 CircNOL10 suppresses breast cancer progression by sponging miR-767-5p to regulate SOCS2/JAK/STAT signaling. Journal of biomedical science 45 33397365
2020 CircHivep2 contributes to microglia activation and inflammation via miR-181a-5p/SOCS2 signalling in mice with kainic acid-induced epileptic seizures. Journal of cellular and molecular medicine 45 33002329
2001 Interleukin 9 induces expression of three cytokine signal inhibitors: cytokine-inducible SH2-containing protein, suppressor of cytokine signalling (SOCS)-2 and SOCS-3, but only SOCS-3 overexpression suppresses interleukin 9 signalling. The Biochemical journal 45 11115404
2013 Regulation of Foxp3+ inducible regulatory T cell stability by SOCS2. Journal of immunology (Baltimore, Md. : 1950) 44 23455506
2003 Restoration of defective cross talk in ssi2 mutants: role of salicylic acid, jasmonic acid, and fatty acids in SSI2-mediated signaling. Molecular plant-microbe interactions : MPMI 44 14601670
2020 MiR-3613-3p from carcinoma-associated fibroblasts exosomes promoted breast cancer cell proliferation and metastasis by regulating SOCS2 expression. IUBMB life 43 32344463
2021 SOCS2 Suppresses Inflammation and Apoptosis during NASH Progression through Limiting NF-κB Activation in Macrophages. International journal of biological sciences 42 34803490
2017 A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation. Oncogene 41 28967904
2013 t(8;9)(p22;p24)/PCM1-JAK2 activates SOCS2 and SOCS3 via STAT5. PloS one 41 23372669
2016 The suppressor of cytokine signaling 2 (SOCS2) inhibits tumor metastasis in hepatocellular carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 40 27465557
2012 TLR8 and NOD signaling synergistically induce the production of IL-1β and IL-23 in monocyte-derived DCs and enhance the expression of the feedback inhibitor SOCS2. Immunobiology 40 22795647
2010 PAD4-dependent antibiosis contributes to the ssi2-conferred hyper-resistance to the green peach aphid. Molecular plant-microbe interactions : MPMI 40 20367470
2014 SOCS2 correlates with malignancy and exerts growth-promoting effects in prostate cancer. Endocrine-related cancer 39 24280133
2014 β-Asarone (cis-2,4,5-trimethoxy-1-allyl phenyl), attenuates pro-inflammatory mediators by inhibiting NF-κB signaling and the JNK pathway in LPS activated BV-2 microglia cells. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 38 25066769
2013 SOCS2 mediates the cross talk between androgen and growth hormone signaling in prostate cancer. Carcinogenesis 38 24031028
2005 Suppressor of cytokine signalling 2 (SOCS-2) expression in breast carcinoma. Journal of clinical pathology 38 16189149
2008 SOCS2: inhibitor of JAK2V617F-mediated signal transduction. Leukemia 36 18769447
2019 SOCS2 Is Critical for the Balancing of Immune Response and Oxidate Stress Protecting Against Acetaminophen-Induced Acute Liver Injury. Frontiers in immunology 35 30723477
2017 The ubiquitin ligase Cullin5SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation. Scientific reports 35 28216640
2012 Inflammation and linear bone growth: the inhibitory role of SOCS2 on GH/IGF-1 signaling. Pediatric nephrology (Berlin, Germany) 35 22886280
2009 SOCS2 influences LPS induced human monocyte-derived dendritic cell maturation. PloS one 35 19779605
2005 Differential effects of SOCS2 on neuronal differentiation and morphology. Brain research 35 16360125
2021 The long-noncoding RNA SOCS2-AS1 suppresses endometrial cancer progression by regulating AURKA degradation. Cell death & disease 34 33824269
2023 Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2. Nature communications 33 37816714
2023 Analysis of epigenetic clocks links yoga, sleep, education, reduced meat intake, coffee, and a SOCS2 gene variant to slower epigenetic aging. GeroScience 32 38103096
2020 LncRNA SOCS2-AS1 inhibits progression and metastasis of colorectal cancer through stabilizing SOCS2 and sponging miR-1264. Aging 32 32437330
2007 Mammalian protein-protein interaction trap (MAPPIT) analysis of STAT5, CIS, and SOCS2 interactions with the growth hormone receptor. Molecular endocrinology (Baltimore, Md.) 32 17666591
2015 miRNA-101 inhibits ovarian cancer cells proliferation and invasion by down-regulating expression of SOCS-2. International journal of clinical and experimental medicine 31 26884939
2005 Role of SOCS2 in growth hormone actions. Trends in endocrinology and metabolism: TEM 31 15734145
2022 RPL38 knockdown inhibits the inflammation and apoptosis in chondrocytes through regulating METTL3-mediated SOCS2 m6A modification in osteoarthritis. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 30 35596790
2019 Structural insights into substrate recognition by the SOCS2 E3 ubiquitin ligase. Nature communications 30 31182716
2012 SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 29 22228213
2014 Biophysical studies on interactions and assembly of full-size E3 ubiquitin ligase: suppressor of cytokine signaling 2 (SOCS2)-elongin BC-cullin 5-ring box protein 2 (RBX2). The Journal of biological chemistry 28 25505247
2024 POU6F1 promotes ferroptosis by increasing lncRNA-CASC2 transcription to regulate SOCS2/SLC7A11 signaling in gastric cancer. Cell biology and toxicology 27 38267746
2020 LncRNA WDFY3-AS2 suppresses proliferation and invasion in oesophageal squamous cell carcinoma by regulating miR-2355-5p/SOCS2 axis. Journal of cellular and molecular medicine 26 32536038
2010 The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion. Diabetologia 26 20499047
2004 Reduced bone mineral density in SOCS-2-deficient mice. Pediatric research 26 15585682
2019 MiR-492 exerts tumor-promoting function in prostate cancer through repressing SOCS2 expression. European review for medical and pharmacological sciences 25 30779065
2019 SOCS2 modulates adipose tissue inflammation and expansion in mice. The Journal of nutritional biochemistry 25 31816561
2017 SOCS2 exacerbates myocardial injury induced by ischemia/reperfusion in diabetic mice and H9c2 cells through inhibiting the JAK-STAT-IGF-1 pathway. Life sciences 24 28867579
2016 Suppressor of cytokine signaling 2 (SOCS2) negatively regulates the expression of antimicrobial peptides by affecting the Stat transcriptional activity in shrimp Marsupenaeus japonicus. Fish & shellfish immunology 24 27492125
2009 Suppressor of cytokine signaling 2 (SOCS-2) homologue in disk abalone: cloning, sequence characterization and expression analysis. Fish & shellfish immunology 24 19340953
2022 Increased expression of miR-194-5p through the circPVRL3/miR-194-5p/SOCS2 axis promotes proliferation and metastasis in pancreatic ductal adenocarcinoma by activating the PI3K/AKT signaling pathway. Cancer cell international 23 36539807
2022 Hepatocellular carcinoma-derived exosomal miRNA-761 regulates the tumor microenvironment by targeting the SOCS2/JAK2/STAT3 pathway. World journal of emergency medicine 22 36119773
2015 SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration. The Journal of biological chemistry 22 26703468
2021 CircRNA circ_0006677 Inhibits the Progression and Glycolysis in Non-Small-Cell Lung Cancer by Sponging miR-578 and Regulating SOCS2 Expression. Frontiers in pharmacology 21 34054537
2021 Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands. Nature communications 20 34857742
2006 SOCS-2 interferes with myotube formation and potentiates osteoblast differentiation through upregulation of JunB in C2C12 cells. Journal of cellular physiology 20 16419040
2000 Synthesis and biological evaluation of integrin antagonists containing trans- and cis-2,5-disubstituted THF rings. Chemistry (Weinheim an der Bergstrasse, Germany) 20 10807178
2019 Role of SOCS2 in the Regulation of Immune Response and Development of the Experimental Autoimmune Encephalomyelitis. Mediators of inflammation 19 31949423
2008 Insulin regulates SOCS2 expression and the mitogenic effect of IGF-1 in mesangial cells. Kidney international 19 19008912
2022 SOCS2 protects against chemical-induced hepatocellular carcinoma progression by modulating inflammation and cell proliferation in the liver. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 18 36455458
2019 KIAA0317 regulates pulmonary inflammation through SOCS2 degradation. JCI insight 18 31578312
2024 Leveraging Therapeutic Proteins and Peptides from Lumbricus Earthworms: Targeting SOCS2 E3 Ligase for Cardiovascular Therapy through Molecular Dynamics Simulations. International journal of molecular sciences 17 39409145
2023 CTRP6 protects against ferroptosis to drive lung cancer progression and metastasis by destabilizing SOCS2 and augmenting the xCT/GPX4 pathway. Cancer letters 17 38084702
2022 Upregulation of miR-144-3p alleviates Doxorubicin-induced heart failure and cardiomyocytes apoptosis via SOCS2/PI3K/AKT axis. Chemical biology & drug design 17 35730258
2019 MiR-875 can regulate the proliferation and apoptosis of non-small cell lung cancer cells via targeting SOCS2. European review for medical and pharmacological sciences 17 31298374
2017 SOCS2 overexpression alleviates diabetic nephropathy in rats by inhibiting the TLR4/NF-κB pathway. Oncotarget 17 29207635
2021 Upregulation of circ-ASPH contributes to glioma cell proliferation and aggressiveness by targeting the miR-599/AR/SOCS2-AS1 signaling pathway. Oncology letters 16 33777211
2020 SOCS2 Inhibits Mitochondrial Fatty Acid Oxidation via Suppressing LepR/JAK2/AMPK Signaling Pathway in Mouse Adipocytes. Oxidative medicine and cellular longevity 16 32733634

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