Affinage

SOCS7

Suppressor of cytokine signaling 7 · UniProt O14512

Length
581 aa
Mass
63.0 kDa
Annotated
2026-06-10
26 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SOCS7 is a SOCS-box E3 ubiquitin ligase adaptor that acts as a negative regulator of multiple receptor and stress signaling pathways, principally through SH2-domain-dependent substrate recognition and targeted proteasomal degradation (PMID:16127460, PMID:26503265, PMID:38746666). Its catalytic competence as an E3 ligase is demonstrated directly: when fused to an intracellular antibody, SOCS7 drives proteasomal degradation of a tethered target irrespective of subcellular localization, and a SOCS7-KRAS degrader suppresses mutant-KRAS pancreatic cancer proliferation (PMID:38746666). Endogenous substrate-directed roles include suppression of insulin signaling via association with the insulin receptor and IRS1 and consequent loss of IRS proteins (PMID:16127460), termination of reelin signaling by binding phosphorylated DAB1 through its SH2 domain to promote DAB1 degradation (PMID:26503265), and ubiquitination of the RNA-binding protein HuR to reduce HuR-stabilized FOXM1 and limit ovarian tumor growth (PMID:35624501). Beyond degradation, SOCS7 carries the adaptor NCK into the nucleus via its own import/export signals while engaging septins through a distinct domain; nuclear NCK accumulation disassembles actin stress fibers, arrests the cell cycle, and is required for p53 Ser15 phosphorylation downstream of ATM/ATR in the DNA damage response (PMID:17803907). SOCS7 also restrains inflammatory and cytokine signaling, inhibiting IKK/NF-κB activity—with its own levels set by PTPN14-mediated K11/K48 ubiquitination (PMID:32978373)—and damping mast cell hyperactivation (PMID:19427817). SOCS7 expression is itself tightly controlled, repressed by multiple miRNAs (miR-145, miR-199a-3p, miR-221) and by a TGF-β1/EGR1 promoter axis, downstream of which SOCS7 limits STAT3 activation and PI3K/AKT and MEK/ERK-driven cell migration (PMID:23392170, PMID:28240316, PMID:35706000, PMID:35201663). In vivo, SOCS7 loss causes hydrocephalus (PMID:15494444) but is dispensable for spermatogenesis (PMID:40226015).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2004 Medium

    Established the first physical link between SOCS7 and the cytoskeleton, indicating SOCS7 is not solely a cytokine-signaling adaptor but also localizes with actin.

    Evidence Yeast two-hybrid screen with deletion mapping and confocal imaging of SOCS7-GFP identifying vinexin binding via a proline-rich region

    PMID:15242778

    Open questions at the time
    • No functional consequence of the vinexin interaction defined
    • Whether cytoskeletal localization relates to SOCS7 E3 activity unknown
  2. 2004 Medium

    Demonstrated an essential in vivo role for SOCS7 in the CNS, raising the question of which signaling substrates underlie the phenotype.

    Evidence Socs7 gene-targeted mice with histology and in situ hybridization revealing hydrocephalus and high brain expression

    PMID:15494444

    Open questions at the time
    • Molecular mechanism of hydrocephalus not resolved
    • No substrate linked to the CNS phenotype at this stage
  3. 2005 High

    Defined SOCS7 as a negative regulator of insulin signaling, providing its first concrete receptor pathway and substrate axis.

    Evidence Co-IP of SOCS7 with INSR and IRS1 plus Socs7 knockout mice showing elevated IRS levels and enhanced insulin action

    PMID:16127460

    Open questions at the time
    • Direct ubiquitination of IRS by SOCS7 not formally shown here
    • Tissue-specific contributions not dissected
  4. 2007 High

    Revealed a non-degradative function: SOCS7 as a nuclear shuttle coupling cytoskeletal and DNA-damage responses through NCK and septins.

    Evidence siRNA knockdown, nuclear/cytoplasmic NCK rescue constructs, reciprocal co-IP, live imaging, and p53 Ser15 phosphorylation assays in the ATM/ATR pathway

    PMID:17803907

    Open questions at the time
    • How DNA damage triggers SOCS7-dependent NCK import not defined
    • Relationship between this shuttle role and SOCS7 E3 activity unclear
  5. 2009 Medium

    Extended SOCS7's negative-regulatory role to innate/allergic immunity, identifying mast cell cytokine and TSLP signaling as a controlled output.

    Evidence Socs7-/- bone marrow-derived mast cells with IgE/FcεRI stimulation, cytokine ELISA, and qRT-PCR

    PMID:19427817

    Open questions at the time
    • Direct substrate in the mast cell pathway not identified
    • Receptor-proximal mechanism unresolved
  6. 2017 Medium

    Identified DAB1 as a direct SH2-domain substrate, mechanistically tying SOCS7 to reelin signaling and cortical layering.

    Evidence Socs6/Socs7 double-knockout mice, ex vivo DAB1 binding assays with SH2-disrupting DAB1 mutants, and cortical histology

    PMID:26503265

    Open questions at the time
    • Relative SOCS6 vs SOCS7 contribution not separated
    • Whether DAB1 ubiquitination is direct not fully resolved
  7. 2020 Medium

    Placed SOCS7 in the NF-κB pathway and identified PTPN14 as the regulator controlling SOCS7 stability via K11/K48 ubiquitination.

    Evidence Co-IP of PTPN14 with SOCS7, ubiquitin linkage mapping, PTPN14 knockout ALF model, and IKK/NF-κB activity assays

    PMID:32978373

    Open questions at the time
    • E3 ligase ubiquitinating SOCS7 not identified
    • Direct SOCS7 target within the IKK complex not defined
  8. 2022 Medium

    Demonstrated a tumor-suppressive degradation axis by which SOCS7 ubiquitinates HuR to reduce FOXM1.

    Evidence Proteomics, co-IP of SOCS7 with HuR, ubiquitination assays, and gain/loss-of-function in ovarian cancer cells and tumor xenografts

    PMID:35624501

    Open questions at the time
    • Ubiquitin linkage type on HuR not specified
    • Generality across tumor types untested
  9. 2022 Medium

    Established SOCS7 as a downstream effector of miRNA and TGF-β1/EGR1 control that limits keratinocyte proliferation and migration via PI3K/AKT and MEK/ERK.

    Evidence ChIP and luciferase assays for EGR1 at the SOCS7 promoter, miR-221 3'UTR luciferase reporter, SOCS7 overexpression rescue, and in vivo wound-healing models

    PMID:35201663 PMID:35706000

    Open questions at the time
    • Direct SOCS7 substrate in PI3K/AKT and MEK/ERK pathways not identified
    • Mechanism mostly inferred from overexpression
  10. 2024 Medium

    Directly proved SOCS7 is a functional E3 ubiquitin ligase capable of degrading recruited targets, validating its mechanistic core and therapeutic potential.

    Evidence Intracellular-antibody SOCS7 degrader fusions across cell lines with target depletion readouts and a KRAS degrader proliferation assay

    PMID:38746666

    Open questions at the time
    • Endogenous substrate recognition determinants not mapped here
    • In vivo efficacy of degraders untested
  11. 2025 Medium

    Clarified the boundaries of SOCS7 physiological requirement by showing it is dispensable for male fertility despite high testicular expression.

    Evidence CRISPR/Cas9 Socs7 knockout mice with histology, CASA sperm analysis, and TUNEL assays

    PMID:40226015

    Open questions at the time
    • Possible redundancy with other SOCS proteins in testis not tested
    • Function of high testicular expression unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SOCS7 selects its physiological substrate repertoire and how its degradation, nuclear-shuttling, and cytoskeletal functions are coordinated remain unresolved.
  • No structural basis for SH2/SOCS-box substrate selection
  • Integration of E3 activity with NCK/septin nuclear shuttling unknown
  • Lack of unifying model linking the diverse pathway outputs

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 2 GO:0098772 molecular function regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
GO:0140096 catalytic activity, acting on a protein 1
Partners
DAB1ELAVL1INSRIRS1NCKPTPN14VINEXIN

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 SOCS7 acts as a nuclear shuttle for the adaptor protein NCK: SOCS7 possesses nuclear import/export signals and carries NCK into the nucleus. SOCS7 interacts with septins through one domain and with NCK through a distinct domain. Nuclear accumulation of NCK (driven by SOCS7) causes actin stress fiber disintegration, loss of cell polarity, and cell-cycle arrest. The septin-SOCS7-NCK axis is required for p53 Ser15 phosphorylation downstream of ATM/ATR in the DNA damage response. siRNA knockdown, rescue experiments with cytoplasmic vs. nuclear-targeted NCK constructs, co-immunoprecipitation, live imaging, domain mapping, cell-cycle assays, p53 phosphorylation assays Cell High 17803907
2004 SOCS7 interacts with the cytoskeletal protein vinexin through a central proline-rich region N-terminal to its SH2 domain (likely via vinexin's SH3 domain binding a poly-proline region of SOCS7). A portion of SOCS7 co-localizes with vinexin and actin at the cytoskeleton. Yeast two-hybrid screen, deletion mutant mapping, co-immunoprecipitation, confocal fluorescence microscopy (SOCS7-GFP fusion) Experimental cell research Medium 15242778
2005 SOCS7 associates with the insulin receptor (INSR) and IRS1, and negatively regulates insulin signaling: SOCS7-deficient mice show increased IRS protein levels, enhanced insulin action, prolonged hypoglycemia, and enlarged pancreatic islets, establishing SOCS7 as a negative regulator of insulin signaling upstream of IRS proteins. Co-immunoprecipitation of SOCS7 with INSR and IRS1; Socs7 knockout mice; insulin tolerance test; glucose tolerance test; IRS protein-level quantification The Journal of clinical investigation High 16127460
2004 Loss of SOCS7 in mice causes hydrocephalus with ventricular dilation, cortical thinning, and disorganization of the subcommissural organ; in situ hybridization shows prominent SOCS7 expression in the brain, consistent with a direct functional role there. Gene targeting (Socs7−/− mice), histology, in situ hybridization Proceedings of the National Academy of Sciences of the United States of America Medium 15494444
2009 SOCS7 deficiency in mast cells leads to hyperactivation following IgE-mediated stimuli, elevated pro-inflammatory cytokine production (IL-13, IL-6, TNF-α), increased IL-7Rα transcript, and increased TSLP production after FcεRI aggregation, placing SOCS7 as a negative regulator of mast cell cytokine signaling and TSLP pathway. Socs7−/− bone marrow-derived mast cell cultures; IgE-mediated stimulation; ELISA for cytokines; qRT-PCR for IL-7Rα and TSLP; serum immunoglobulin measurement; skin histology Clinical immunology (Orlando, Fla.) Medium 19427817
2017 SOCS7 (together with SOCS6) terminates reelin signaling by binding the phosphorylated reelin adaptor DAB1 via their SH2 domains and promoting its degradation; combined SOCS6/SOCS7 loss causes constitutive DAB1 accumulation and cortical layer inversion recapitulating the reeler phenotype. Socs6/Socs7 double-knockout mice; ex vivo co-immunoprecipitation/binding assays with DAB1; DAB1 phosphorylation quantification; DAB1 mutation to diminish SH2 binding; cortical histology Cerebral cortex (New York, N.Y. : 1991) Medium 26503265
2020 PTPN14 interacts with SOCS7 and promotes its ubiquitin-mediated proteasomal degradation at K11 and K48 linkages, reducing SOCS7 protein levels. SOCS7 in turn inhibits the NF-κB pathway by blocking IKK complex activity, thereby reducing downstream inflammatory cytokine expression in acute liver failure. Co-immunoprecipitation of PTPN14 with SOCS7; ubiquitination assay identifying K11/K48 linkages; PTPN14 knockout mice (LPS/D-GalN ALF model); NF-κB/IKK activity assays; inflammatory cytokine measurement Cell death & disease Medium 32978373
2010 In cells expressing HCV genotype 3a core protein, SOCS7 expression is upregulated independently of STAT3 activation and is instead modulated by PPAR-γ activity, as shown by PPAR-γ agonist (rosiglitazone) and antagonist (GW9262) treatments altering SOCS7 mRNA levels. qRT-PCR and immunoblotting in Huh-7 cells treated with IFN-α, rosiglitazone, or GW9262; comparison of SOCS1/3/7 responses The Journal of general virology Low 20357037
2013 SOCS7 silencing in bladder cancer cells promotes nuclear translocation of STAT3 and enhances IFN-β induction in response to the TLR3 ligand poly(I:C); miR-145 directly targets the SOCS7 3′UTR (validated by luciferase reporter assay) and decreases SOCS7 expression, recapitulating the STAT3 nuclear translocation and IFN-β induction phenotype. siRNA knockdown of SOCS7; luciferase reporter assay for miR-145 targeting; STAT3 nuclear translocation imaging; IFN-β mRNA quantification; cell growth assays Cell death & disease Medium 23392170
2017 p53 transcriptionally activates miR-199a-3p (ChIP demonstrated p53 binding to the miR-199a-3p promoter), which directly targets SOCS7; SOCS7 silencing promotes STAT3 activation, and restoration of SOCS7 expression suppresses TGF-β1-induced fibrotic gene expression (collagen I, vimentin), establishing a p53/miR-199a-3p/SOCS7/STAT3 axis in renal fibrosis. ChIP for p53 at miR-199a-3p promoter; miR-199a-3p overexpression/inhibition; SOCS7 siRNA knockdown; STAT3 phosphorylation assays; luciferase reporter for miR-199a-3p/SOCS7 targeting (inferred); Western blot for fibrotic markers in HK-2 cells and UUO mouse model Scientific reports Medium 28240316
2022 TGF-β1 negatively regulates SOCS7 transcription through EGR1, which binds EGR1/SP1 overlapping sites in the SOCS7 promoter (validated by ChIP and luciferase assay). SOCS7 overexpression suppresses TGF-β1-induced keratinocyte migration by inhibiting the PI3K/AKT and MEK/ERK pathways. ChIP for EGR1 at SOCS7 promoter; luciferase reporter assay; SOCS7 overexpression; scratch/Transwell migration assays; Western blot for PI3K/AKT and MEK/ERK signaling; in vivo mouse wound-healing model Cell communication and signaling : CCS Medium 35706000
2022 SOCS7 mediates ubiquitination of the RNA-binding protein HuR, promoting its degradation; this in turn reduces FOXM1 mRNA (which HuR stabilizes), suppressing ovarian cancer cell viability and tumor growth. Proteomics analysis, co-immunoprecipitation of SOCS7 with HuR, ubiquitination assays, gain/loss-of-function in cell viability and in vivo tumor growth assays Journal of experimental & clinical cancer research : CR Medium 35624501
2024 SOCS7 functions as an active E3 ubiquitin ligase: when fused to an intracellular antibody targeting a tagged protein of interest, SOCS7 drives proteasomal degradation of that target regardless of subcellular localization. A SOCS7-based degrader directed against KRAS inhibits mutant KRAS pancreatic cancer cell proliferation. Protein-based degrader fusion screen across cell lines; flow cytometry/Western blot for target depletion; KRAS degrader functional assay (proliferation in pancreatic cancer cells) iScience Medium 38746666
2022 miR-221 directly targets the SOCS7 3′UTR in keratinocytes; SOCS7 overexpression reverses the pro-proliferative and pro-migratory effects of miR-221 in HaCaT cells, placing SOCS7 as a downstream effector that limits keratinocyte proliferation and migration. Luciferase reporter assay (miR-221/SOCS7 3′UTR); miR-221 mimic/inhibitor overexpression; SOCS7 overexpression rescue; in vivo mouse wound model; qRT-PCR and fluorescence in situ hybridization Journal of cellular and molecular medicine Medium 35201663
2025 Socs7 knockout in mice (CRISPR/Cas9) does not impair spermatogenesis, sperm quality, testicular morphology, or male fertility, establishing that SOCS7 is dispensable for male germ cell function despite high testicular expression. CRISPR/Cas9 Socs7 knockout mice; histology and IHC; CASA sperm analysis; TUNEL apoptosis assay American journal of translational research Medium 40226015

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7. Cell 181 17803907
2017 p53 induces miR199a-3p to suppress SOCS7 for STAT3 activation and renal fibrosis in UUO. Scientific reports 89 28240316
2005 Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of Langerhans. The Journal of clinical investigation 80 16127460
2010 Hepatitis C virus core protein genotype 3a increases SOCS-7 expression through PPAR-{gamma} in Huh-7 cells. The Journal of general virology 62 20357037
2013 socs7, a target gene of microRNA-145, regulates interferon-β induction through STAT3 nuclear translocation in bladder cancer cells. Cell death & disease 61 23392170
2004 Development of hydrocephalus in mice lacking SOCS7. Proceedings of the National Academy of Sciences of the United States of America 50 15494444
2004 The suppressor of cytokine signaling (SOCS)-7 interacts with the actin cytoskeleton through vinexin. Experimental cell research 28 15242778
2009 Loss of SOCS7 in mice results in severe cutaneous disease and increased mast cell activation. Clinical immunology (Orlando, Fla.) 24 19427817
2020 PTPN14 aggravates inflammation through promoting proteasomal degradation of SOCS7 in acute liver failure. Cell death & disease 20 32978373
2017 Cortical Layer Inversion and Deregulation of Reelin Signaling in the Absence of SOCS6 and SOCS7. Cerebral cortex (New York, N.Y. : 1991) 16 26503265
2022 Transforming growth factor-β1 negatively regulates SOCS7 via EGR1 during wound healing. Cell communication and signaling : CCS 14 35706000
2021 DZNep, an inhibitor of the histone methyltransferase EZH2, suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 pathway. PeerJ 13 34040893
2009 Defective interleukin-4/Stat6 activity correlates with increased constitutive expression of negative regulators SOCS-3, SOCS-7, and CISH in colon cancer cells. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 12 19929568
2021 Long noncoding RNA UCA1 regulates HCV replication and antiviral response via miR-145-5p/SOCS7/IFN pathway. International journal of biological sciences 10 34345210
2019 Molecular Cloning and Expression Analysis of Three Suppressors of Cytokine Signaling Genes (SOCS5, SOCS6, SOCS7) in the Mealworm Beetle Tenebrio molitor. Insects 10 30884777
2013 Observations on the effects of Suppressor of Cytokine Signaling 7 (SOCS7) knockdown in breast cancer cells: their in vitro response to Insulin Like Growth Factor I (IGF-I). Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 10 24046004
2012 Common variants in SOCS7 gene predict obesity, disturbances in lipid metabolism and insulin resistance. Nutrition, metabolism, and cardiovascular diseases : NMCD 10 22397880
2019 Differential Transcription of SOCS5 and SOCS7 in Multiple Sclerosis Patients Treated with Interferon Beta or Glatiramer Acetate. International journal of molecular sciences 9 31905601
2022 SOCS7/HuR/FOXM1 signaling axis inhibited high-grade serous ovarian carcinoma progression. Journal of experimental & clinical cancer research : CR 7 35624501
2024 Discovery of SOCS7 as a versatile E3 ligase for protein-based degraders. iScience 6 38746666
2025 MiR-203 improved renal cell injury in diabetic nephropathy by targeting SOCS6/SOCS7 and inhibiting JAK/STAT pathway activation. Scientific reports 5 40155732
2022 Lack of association between SOCS3 and SOCS7 polymorphisms and psoriasis. Immunity, inflammation and disease 5 36169255
2013 Polymorphisms in the SOCS7 gene and glucose homeostasis traits. BMC research notes 4 23767996
2025 Testis-enriched Socs7 is not essential for spermatogenesis and male fertility in mice. American journal of translational research 2 40226015
2023 SOCS7-Derived BC-Box Motif Peptide Mediated Cholinergic Differentiation of Human Adipose-Derived Mesenchymal Stem Cells. International journal of molecular sciences 2 36769102
2022 miR-221 promotes keratinocyte proliferation and migration by targeting SOCS7 and is regulated by YB-1. Journal of cellular and molecular medicine 2 35201663

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