{"gene":"SOCS7","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2007,"finding":"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.","method":"siRNA knockdown, rescue experiments with cytoplasmic vs. nuclear-targeted NCK constructs, co-immunoprecipitation, live imaging, domain mapping, cell-cycle assays, p53 phosphorylation assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP for domain-specific interactions, functional rescue experiments with nuclear/cytoplasmic NCK constructs, epistasis to ATM/ATR-p53 pathway, multiple orthogonal methods in a single rigorous study","pmids":["17803907"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Yeast two-hybrid screen, deletion mutant mapping, co-immunoprecipitation, confocal fluorescence microscopy (SOCS7-GFP fusion)","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus confirmatory co-IP, single lab, two orthogonal methods","pmids":["15242778"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Co-immunoprecipitation of SOCS7 with INSR and IRS1; Socs7 knockout mice; insulin tolerance test; glucose tolerance test; IRS protein-level quantification","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP establishing protein interactions, corroborated by in vivo knockout phenotype with defined molecular readouts (IRS levels, insulin signaling), multiple orthogonal methods","pmids":["16127460"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Gene targeting (Socs7−/− mice), histology, in situ hybridization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with defined CNS phenotype, but molecular mechanism not resolved beyond expression data; single lab","pmids":["15494444"],"is_preprint":false},{"year":2009,"finding":"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.","method":"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","journal":"Clinical immunology (Orlando, Fla.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout cells with defined functional readouts, ELISA and qPCR, single lab","pmids":["19427817"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Socs6/Socs7 double-knockout mice; ex vivo co-immunoprecipitation/binding assays with DAB1; DAB1 phosphorylation quantification; DAB1 mutation to diminish SH2 binding; cortical histology","journal":"Cerebral cortex (New York, N.Y. : 1991)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ex vivo binding with domain-mutant validation, in vivo double-KO epistasis, single lab","pmids":["26503265"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination site mapping plus in vivo KO phenotype; single lab with multiple orthogonal methods","pmids":["32978373"],"is_preprint":false},{"year":2010,"finding":"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.","method":"qRT-PCR and immunoblotting in Huh-7 cells treated with IFN-α, rosiglitazone, or GW9262; comparison of SOCS1/3/7 responses","journal":"The Journal of general virology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological modulation without direct PPAR-γ binding or promoter experiments; single lab, single cell model","pmids":["20357037"],"is_preprint":false},{"year":2013,"finding":"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.","method":"siRNA knockdown of SOCS7; luciferase reporter assay for miR-145 targeting; STAT3 nuclear translocation imaging; IFN-β mRNA quantification; cell growth assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validation plus functional knockdown phenotype, single lab, two orthogonal methods","pmids":["23392170"],"is_preprint":false},{"year":2017,"finding":"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.","method":"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","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct transcriptional regulation, functional knockdown with defined signaling readout, in vitro and in vivo corroboration, single lab","pmids":["28240316"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter for promoter regulation, functional overexpression with defined pathway readouts, in vitro and in vivo; single lab","pmids":["35706000"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Proteomics analysis, co-immunoprecipitation of SOCS7 with HuR, ubiquitination assays, gain/loss-of-function in cell viability and in vivo tumor growth assays","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay plus in vivo tumor model, single lab, multiple orthogonal methods","pmids":["35624501"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Protein-based degrader fusion screen across cell lines; flow cytometry/Western blot for target depletion; KRAS degrader functional assay (proliferation in pancreatic cancer cells)","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional E3 ligase activity demonstrated in multiple cell lines with a defined substrate, single lab, two orthogonal readouts","pmids":["38746666"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus functional rescue experiment, in vitro and in vivo corroboration, single lab","pmids":["35201663"],"is_preprint":false},{"year":2025,"finding":"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.","method":"CRISPR/Cas9 Socs7 knockout mice; histology and IHC; CASA sperm analysis; TUNEL apoptosis assay","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vivo knockout with comprehensive phenotyping; negative result but methodologically rigorous; single lab","pmids":["40226015"],"is_preprint":false}],"current_model":"SOCS7 is a multi-functional SOCS-box E3 ubiquitin ligase adaptor that negatively regulates multiple signaling pathways: it shuttles the adaptor NCK into the nucleus (via nuclear import/export signals) to mediate DNA-damage-induced cell-cycle arrest and p53 Ser15 phosphorylation downstream of ATM/ATR in a septin-dependent manner; it suppresses insulin signaling by associating with the insulin receptor and IRS1 to promote IRS protein degradation; it terminates reelin signaling by binding phosphorylated DAB1 via its SH2 domain and targeting it for degradation; it blocks NF-κB activity by inhibiting the IKK complex (with its own levels controlled by PTPN14-mediated K11/K48 ubiquitination); it mediates ubiquitination of HuR to suppress FOXM1-driven oncogenesis; and it interacts with the actin cytoskeleton through vinexin, with its expression transcriptionally controlled by PPAR-γ and the p53/miR-199a-3p and TGF-β1/EGR1 axes."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2004,"claim":"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","pmids":["15242778"],"confidence":"Medium","gaps":["No functional consequence of the vinexin interaction defined","Whether cytoskeletal localization relates to SOCS7 E3 activity unknown"]},{"year":2004,"claim":"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","pmids":["15494444"],"confidence":"Medium","gaps":["Molecular mechanism of hydrocephalus not resolved","No substrate linked to the CNS phenotype at this stage"]},{"year":2005,"claim":"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","pmids":["16127460"],"confidence":"High","gaps":["Direct ubiquitination of IRS by SOCS7 not formally shown here","Tissue-specific contributions not dissected"]},{"year":2007,"claim":"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","pmids":["17803907"],"confidence":"High","gaps":["How DNA damage triggers SOCS7-dependent NCK import not defined","Relationship between this shuttle role and SOCS7 E3 activity unclear"]},{"year":2009,"claim":"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","pmids":["19427817"],"confidence":"Medium","gaps":["Direct substrate in the mast cell pathway not identified","Receptor-proximal mechanism unresolved"]},{"year":2017,"claim":"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","pmids":["26503265"],"confidence":"Medium","gaps":["Relative SOCS6 vs SOCS7 contribution not separated","Whether DAB1 ubiquitination is direct not fully resolved"]},{"year":2020,"claim":"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","pmids":["32978373"],"confidence":"Medium","gaps":["E3 ligase ubiquitinating SOCS7 not identified","Direct SOCS7 target within the IKK complex not defined"]},{"year":2022,"claim":"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","pmids":["35624501"],"confidence":"Medium","gaps":["Ubiquitin linkage type on HuR not specified","Generality across tumor types untested"]},{"year":2022,"claim":"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","pmids":["35706000","35201663"],"confidence":"Medium","gaps":["Direct SOCS7 substrate in PI3K/AKT and MEK/ERK pathways not identified","Mechanism mostly inferred from overexpression"]},{"year":2024,"claim":"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","pmids":["38746666"],"confidence":"Medium","gaps":["Endogenous substrate recognition determinants not mapped here","In vivo efficacy of degraders untested"]},{"year":2025,"claim":"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","pmids":["40226015"],"confidence":"Medium","gaps":["Possible redundancy with other SOCS proteins in testis not tested","Function of high testicular expression unexplained"]},{"year":null,"claim":"How SOCS7 selects its physiological substrate repertoire and how its degradation, nuclear-shuttling, and cytoskeletal functions are coordinated remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[12,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,5,11,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[12]}],"complexes":[],"partners":["NCK","INSR","IRS1","DAB1","PTPN14","ELAVL1","VINEXIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14512","full_name":"Suppressor of cytokine signaling 7","aliases":["Nck, Ash and phospholipase C gamma-binding protein","Nck-associated protein 4","NAP-4"],"length_aa":581,"mass_kda":63.0,"function":"Substrate-recognition component of a cullin-5-RING E3 ubiquitin-protein ligase complex (ECS complex, also named CRL5 complex), which mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as DAB1 and IRS1 (PubMed:16127460). Specifically recognizes and binds phosphorylated proteins via its SH2 domain, promoting their ubiquitination (By similarity). The ECS(SOCS7) complex acts as a key regulator of reelin signaling by mediating ubiquitination and degradation of phosphorylated DAB1 in the cortical plate of the developing cerebral cortex, thereby regulating neuron positioning during cortex development (By similarity). Functions in insulin signaling and glucose homeostasis through IRS1 ubiquitination and subsequent proteasomal degradation (PubMed:16127460). Also inhibits prolactin, growth hormone and leptin signaling by preventing STAT3 and STAT5 activation, sequestering them in the cytoplasm and reducing their binding to DNA (PubMed:15677474)","subcellular_location":"Cytoplasm; Nucleus; Cell membrane","url":"https://www.uniprot.org/uniprotkb/O14512/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SOCS7","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SOCS7","total_profiled":1310},"omim":[{"mim_id":"616337","title":"SUPPRESSOR OF CYTOKINE SIGNALING 4; SOCS4","url":"https://www.omim.org/entry/616337"},{"mim_id":"613422","title":"POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 2; KCTD2","url":"https://www.omim.org/entry/613422"},{"mim_id":"608788","title":"SUPPRESSOR OF CYTOKINE SIGNALING 7; SOCS7","url":"https://www.omim.org/entry/608788"},{"mim_id":"603597","title":"SUPPRESSOR OF CYTOKINE SIGNALING 1; SOCS1","url":"https://www.omim.org/entry/603597"},{"mim_id":"603151","title":"SEPTIN 7; SEPTIN7","url":"https://www.omim.org/entry/603151"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":42.7},{"tissue":"testis","ntpm":69.2}],"url":"https://www.proteinatlas.org/search/SOCS7"},"hgnc":{"alias_symbol":["NAP4","NCKAP4"],"prev_symbol":[]},"alphafold":{"accession":"O14512","domains":[{"cath_id":"3.30.505.10","chopping":"386-513","consensus_level":"medium","plddt":83.7606,"start":386,"end":513},{"cath_id":"-","chopping":"515-581","consensus_level":"medium","plddt":83.7266,"start":515,"end":581}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14512","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14512-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14512-F1-predicted_aligned_error_v6.png","plddt_mean":54.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SOCS7","jax_strain_url":"https://www.jax.org/strain/search?query=SOCS7"},"sequence":{"accession":"O14512","fasta_url":"https://rest.uniprot.org/uniprotkb/O14512.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14512/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14512"}},"corpus_meta":[{"pmid":"17803907","id":"PMC_17803907","title":"Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7.","date":"2007","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17803907","citation_count":181,"is_preprint":false},{"pmid":"28240316","id":"PMC_28240316","title":"p53 induces miR199a-3p to suppress SOCS7 for STAT3 activation and renal fibrosis in UUO.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28240316","citation_count":89,"is_preprint":false},{"pmid":"16127460","id":"PMC_16127460","title":"Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of Langerhans.","date":"2005","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/16127460","citation_count":80,"is_preprint":false},{"pmid":"20357037","id":"PMC_20357037","title":"Hepatitis C virus core protein genotype 3a increases SOCS-7 expression through PPAR-{gamma} in Huh-7 cells.","date":"2010","source":"The Journal of general 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International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/19929568","citation_count":12,"is_preprint":false},{"pmid":"34345210","id":"PMC_34345210","title":"Long noncoding RNA UCA1 regulates HCV replication and antiviral response via miR-145-5p/SOCS7/IFN pathway.","date":"2021","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34345210","citation_count":10,"is_preprint":false},{"pmid":"22397880","id":"PMC_22397880","title":"Common variants in SOCS7 gene predict obesity, disturbances in lipid metabolism and insulin resistance.","date":"2012","source":"Nutrition, metabolism, and cardiovascular diseases : NMCD","url":"https://pubmed.ncbi.nlm.nih.gov/22397880","citation_count":10,"is_preprint":false},{"pmid":"30884777","id":"PMC_30884777","title":"Molecular Cloning and Expression Analysis of Three Suppressors of Cytokine Signaling Genes (SOCS5, SOCS6, SOCS7) in the Mealworm Beetle Tenebrio molitor.","date":"2019","source":"Insects","url":"https://pubmed.ncbi.nlm.nih.gov/30884777","citation_count":10,"is_preprint":false},{"pmid":"24046004","id":"PMC_24046004","title":"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).","date":"2013","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/24046004","citation_count":10,"is_preprint":false},{"pmid":"31905601","id":"PMC_31905601","title":"Differential Transcription of SOCS5 and SOCS7 in Multiple Sclerosis Patients Treated with Interferon Beta or Glatiramer Acetate.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31905601","citation_count":9,"is_preprint":false},{"pmid":"35624501","id":"PMC_35624501","title":"SOCS7/HuR/FOXM1 signaling axis inhibited high-grade serous ovarian carcinoma progression.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35624501","citation_count":7,"is_preprint":false},{"pmid":"38746666","id":"PMC_38746666","title":"Discovery of SOCS7 as a versatile E3 ligase for protein-based degraders.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38746666","citation_count":6,"is_preprint":false},{"pmid":"36169255","id":"PMC_36169255","title":"Lack of association between SOCS3 and SOCS7 polymorphisms and psoriasis.","date":"2022","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/36169255","citation_count":5,"is_preprint":false},{"pmid":"40155732","id":"PMC_40155732","title":"MiR-203 improved renal cell injury in diabetic nephropathy by targeting SOCS6/SOCS7 and inhibiting JAK/STAT pathway activation.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40155732","citation_count":5,"is_preprint":false},{"pmid":"23767996","id":"PMC_23767996","title":"Polymorphisms in the SOCS7 gene and glucose homeostasis traits.","date":"2013","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/23767996","citation_count":4,"is_preprint":false},{"pmid":"35201663","id":"PMC_35201663","title":"miR-221 promotes keratinocyte proliferation and migration by targeting SOCS7 and is regulated by YB-1.","date":"2022","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35201663","citation_count":2,"is_preprint":false},{"pmid":"40226015","id":"PMC_40226015","title":"Testis-enriched Socs7 is not essential for spermatogenesis and male fertility in mice.","date":"2025","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/40226015","citation_count":2,"is_preprint":false},{"pmid":"36769102","id":"PMC_36769102","title":"SOCS7-Derived BC-Box Motif Peptide Mediated Cholinergic Differentiation of Human Adipose-Derived Mesenchymal Stem Cells.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36769102","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15392,"output_tokens":4214,"usd":0.054693,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12152,"output_tokens":3829,"usd":0.078243,"stage2_stop_reason":"end_turn"},"total_usd":0.132936,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, rescue experiments with cytoplasmic vs. nuclear-targeted NCK constructs, co-immunoprecipitation, live imaging, domain mapping, cell-cycle assays, p53 phosphorylation assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP for domain-specific interactions, functional rescue experiments with nuclear/cytoplasmic NCK constructs, epistasis to ATM/ATR-p53 pathway, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"17803907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, deletion mutant mapping, co-immunoprecipitation, confocal fluorescence microscopy (SOCS7-GFP fusion)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus confirmatory co-IP, single lab, two orthogonal methods\",\n      \"pmids\": [\"15242778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of SOCS7 with INSR and IRS1; Socs7 knockout mice; insulin tolerance test; glucose tolerance test; IRS protein-level quantification\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP establishing protein interactions, corroborated by in vivo knockout phenotype with defined molecular readouts (IRS levels, insulin signaling), multiple orthogonal methods\",\n      \"pmids\": [\"16127460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Gene targeting (Socs7−/− mice), histology, in situ hybridization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with defined CNS phenotype, but molecular mechanism not resolved beyond expression data; single lab\",\n      \"pmids\": [\"15494444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Clinical immunology (Orlando, Fla.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout cells with defined functional readouts, ELISA and qPCR, single lab\",\n      \"pmids\": [\"19427817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Socs6/Socs7 double-knockout mice; ex vivo co-immunoprecipitation/binding assays with DAB1; DAB1 phosphorylation quantification; DAB1 mutation to diminish SH2 binding; cortical histology\",\n      \"journal\": \"Cerebral cortex (New York, N.Y. : 1991)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo binding with domain-mutant validation, in vivo double-KO epistasis, single lab\",\n      \"pmids\": [\"26503265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination site mapping plus in vivo KO phenotype; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32978373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"qRT-PCR and immunoblotting in Huh-7 cells treated with IFN-α, rosiglitazone, or GW9262; comparison of SOCS1/3/7 responses\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological modulation without direct PPAR-γ binding or promoter experiments; single lab, single cell model\",\n      \"pmids\": [\"20357037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of SOCS7; luciferase reporter assay for miR-145 targeting; STAT3 nuclear translocation imaging; IFN-β mRNA quantification; cell growth assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validation plus functional knockdown phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"23392170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct transcriptional regulation, functional knockdown with defined signaling readout, in vitro and in vivo corroboration, single lab\",\n      \"pmids\": [\"28240316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter for promoter regulation, functional overexpression with defined pathway readouts, in vitro and in vivo; single lab\",\n      \"pmids\": [\"35706000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomics analysis, co-immunoprecipitation of SOCS7 with HuR, ubiquitination assays, gain/loss-of-function in cell viability and in vivo tumor growth assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay plus in vivo tumor model, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35624501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Protein-based degrader fusion screen across cell lines; flow cytometry/Western blot for target depletion; KRAS degrader functional assay (proliferation in pancreatic cancer cells)\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional E3 ligase activity demonstrated in multiple cell lines with a defined substrate, single lab, two orthogonal readouts\",\n      \"pmids\": [\"38746666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus functional rescue experiment, in vitro and in vivo corroboration, single lab\",\n      \"pmids\": [\"35201663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR/Cas9 Socs7 knockout mice; histology and IHC; CASA sperm analysis; TUNEL apoptosis assay\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo knockout with comprehensive phenotyping; negative result but methodologically rigorous; single lab\",\n      \"pmids\": [\"40226015\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SOCS7 is a multi-functional SOCS-box E3 ubiquitin ligase adaptor that negatively regulates multiple signaling pathways: it shuttles the adaptor NCK into the nucleus (via nuclear import/export signals) to mediate DNA-damage-induced cell-cycle arrest and p53 Ser15 phosphorylation downstream of ATM/ATR in a septin-dependent manner; it suppresses insulin signaling by associating with the insulin receptor and IRS1 to promote IRS protein degradation; it terminates reelin signaling by binding phosphorylated DAB1 via its SH2 domain and targeting it for degradation; it blocks NF-κB activity by inhibiting the IKK complex (with its own levels controlled by PTPN14-mediated K11/K48 ubiquitination); it mediates ubiquitination of HuR to suppress FOXM1-driven oncogenesis; and it interacts with the actin cytoskeleton through vinexin, with its expression transcriptionally controlled by PPAR-γ and the p53/miR-199a-3p and TGF-β1/EGR1 axes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#2, #5, #12]. 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 [#12]. Endogenous substrate-directed roles include suppression of insulin signaling via association with the insulin receptor and IRS1 and consequent loss of IRS proteins [#2], termination of reelin signaling by binding phosphorylated DAB1 through its SH2 domain to promote DAB1 degradation [#5], and ubiquitination of the RNA-binding protein HuR to reduce HuR-stabilized FOXM1 and limit ovarian tumor growth [#11]. 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 [#0]. SOCS7 also restrains inflammatory and cytokine signaling, inhibiting IKK/NF-\\u03baB activity—with its own levels set by PTPN14-mediated K11/K48 ubiquitination [#6]—and damping mast cell hyperactivation [#4]. SOCS7 expression is itself tightly controlled, repressed by multiple miRNAs (miR-145, miR-199a-3p, miR-221) and by a TGF-\\u03b21/EGR1 promoter axis, downstream of which SOCS7 limits STAT3 activation and PI3K/AKT and MEK/ERK-driven cell migration [#8, #9, #10, #13]. In vivo, SOCS7 loss causes hydrocephalus [#3] but is dispensable for spermatogenesis [#14].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the first physical link between SOCS7 and the cytoskeleton, indicating SOCS7 is not solely a cytokine-signaling adaptor but also localizes with actin.\",\n      \"evidence\": \"Yeast two-hybrid screen with deletion mapping and confocal imaging of SOCS7-GFP identifying vinexin binding via a proline-rich region\",\n      \"pmids\": [\"15242778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of the vinexin interaction defined\", \"Whether cytoskeletal localization relates to SOCS7 E3 activity unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated an essential in vivo role for SOCS7 in the CNS, raising the question of which signaling substrates underlie the phenotype.\",\n      \"evidence\": \"Socs7 gene-targeted mice with histology and in situ hybridization revealing hydrocephalus and high brain expression\",\n      \"pmids\": [\"15494444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of hydrocephalus not resolved\", \"No substrate linked to the CNS phenotype at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined SOCS7 as a negative regulator of insulin signaling, providing its first concrete receptor pathway and substrate axis.\",\n      \"evidence\": \"Co-IP of SOCS7 with INSR and IRS1 plus Socs7 knockout mice showing elevated IRS levels and enhanced insulin action\",\n      \"pmids\": [\"16127460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitination of IRS by SOCS7 not formally shown here\", \"Tissue-specific contributions not dissected\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed a non-degradative function: SOCS7 as a nuclear shuttle coupling cytoskeletal and DNA-damage responses through NCK and septins.\",\n      \"evidence\": \"siRNA knockdown, nuclear/cytoplasmic NCK rescue constructs, reciprocal co-IP, live imaging, and p53 Ser15 phosphorylation assays in the ATM/ATR pathway\",\n      \"pmids\": [\"17803907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DNA damage triggers SOCS7-dependent NCK import not defined\", \"Relationship between this shuttle role and SOCS7 E3 activity unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended SOCS7's negative-regulatory role to innate/allergic immunity, identifying mast cell cytokine and TSLP signaling as a controlled output.\",\n      \"evidence\": \"Socs7-/- bone marrow-derived mast cells with IgE/Fc\\u03b5RI stimulation, cytokine ELISA, and qRT-PCR\",\n      \"pmids\": [\"19427817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate in the mast cell pathway not identified\", \"Receptor-proximal mechanism unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified DAB1 as a direct SH2-domain substrate, mechanistically tying SOCS7 to reelin signaling and cortical layering.\",\n      \"evidence\": \"Socs6/Socs7 double-knockout mice, ex vivo DAB1 binding assays with SH2-disrupting DAB1 mutants, and cortical histology\",\n      \"pmids\": [\"26503265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative SOCS6 vs SOCS7 contribution not separated\", \"Whether DAB1 ubiquitination is direct not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed SOCS7 in the NF-\\u03baB pathway and identified PTPN14 as the regulator controlling SOCS7 stability via K11/K48 ubiquitination.\",\n      \"evidence\": \"Co-IP of PTPN14 with SOCS7, ubiquitin linkage mapping, PTPN14 knockout ALF model, and IKK/NF-\\u03baB activity assays\",\n      \"pmids\": [\"32978373\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase ubiquitinating SOCS7 not identified\", \"Direct SOCS7 target within the IKK complex not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated a tumor-suppressive degradation axis by which SOCS7 ubiquitinates HuR to reduce FOXM1.\",\n      \"evidence\": \"Proteomics, co-IP of SOCS7 with HuR, ubiquitination assays, and gain/loss-of-function in ovarian cancer cells and tumor xenografts\",\n      \"pmids\": [\"35624501\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage type on HuR not specified\", \"Generality across tumor types untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established SOCS7 as a downstream effector of miRNA and TGF-\\u03b21/EGR1 control that limits keratinocyte proliferation and migration via PI3K/AKT and MEK/ERK.\",\n      \"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\",\n      \"pmids\": [\"35706000\", \"35201663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SOCS7 substrate in PI3K/AKT and MEK/ERK pathways not identified\", \"Mechanism mostly inferred from overexpression\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Directly proved SOCS7 is a functional E3 ubiquitin ligase capable of degrading recruited targets, validating its mechanistic core and therapeutic potential.\",\n      \"evidence\": \"Intracellular-antibody SOCS7 degrader fusions across cell lines with target depletion readouts and a KRAS degrader proliferation assay\",\n      \"pmids\": [\"38746666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous substrate recognition determinants not mapped here\", \"In vivo efficacy of degraders untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Clarified the boundaries of SOCS7 physiological requirement by showing it is dispensable for male fertility despite high testicular expression.\",\n      \"evidence\": \"CRISPR/Cas9 Socs7 knockout mice with histology, CASA sperm analysis, and TUNEL assays\",\n      \"pmids\": [\"40226015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Possible redundancy with other SOCS proteins in testis not tested\", \"Function of high testicular expression unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SOCS7 selects its physiological substrate repertoire and how its degradation, nuclear-shuttling, and cytoskeletal functions are coordinated remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [12, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 5, 11, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NCK\", \"INSR\", \"IRS1\", \"DAB1\", \"PTPN14\", \"ELAVL1\", \"vinexin\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}