{"gene":"SOCS5","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2002,"finding":"SOCS5 protein is preferentially expressed in Th1 cells and interacts directly with the cytoplasmic region of the IL-4Rα chain in a phosphorylation-independent manner, resulting in inhibition of IL-4-mediated STAT6 activation and suppression of Th2 differentiation; transgenic mice constitutively expressing SOCS5 showed significantly reduced IL-4-mediated Th2 development.","method":"Co-immunoprecipitation, transgenic mouse model, flow cytometry, cytokine signaling assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus in vivo transgenic model with defined cellular phenotype, replicated functionally","pmids":["12242343"],"is_preprint":false},{"year":2005,"finding":"SOCS5 associates with the EGF receptor complex in an EGF-independent manner and inhibits EGF mitogenic signaling; this inhibition requires the SOCS5 SOCS box, suggesting it acts through SOCS box-recruited E3 ubiquitin ligase activity to promote proteasomal degradation of the EGF-R.","method":"Co-immunoprecipitation, engineered cell line constitutively expressing EGF-R and SOCS5 or SOCS5 deletion mutants, mitogenic response assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus domain-deletion mutagenesis with functional readout in defined cell line","pmids":["15695332"],"is_preprint":false},{"year":2013,"finding":"SOCS5 contains a conserved JAK Interaction Region (JIR) in its N-terminus that directly binds JAK kinase domains; co-expression of SOCS5 specifically reduces JAK1 and JAK2 (but not JAK3 or TYK2) autophosphorylation and directly inhibits JAK1 kinase activity via a mechanism distinct from SOCS1/SOCS3. Additionally, the SOCS5 SH2 domain binds phosphoTyr317 of Shc-1 with high affinity, suggesting SOCS5 negatively regulates EGF/growth factor-driven Shc-1 signaling.","method":"In vitro kinase assays, co-immunoprecipitation, domain mutagenesis, peptide binding/SH2 domain interaction studies","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro kinase inhibition assay plus mutagenesis and binding studies with multiple orthogonal methods","pmids":["23990909"],"is_preprint":false},{"year":2015,"finding":"The JAK Interaction Region (JIR) within the intrinsically disordered N-terminus of SOCS5 adopts preformed structural elements including an α-helix (residues 224-233), a turn, and an extended structure as determined by NMR; a phosphorylation site (Ser211) within the JIR modulates JAK binding.","method":"NMR spectroscopy (chemical shift analysis, relaxation measurements, NOE analysis), site-directed mutagenesis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structure determination with mutagenesis-based functional validation","pmids":["26173083"],"is_preprint":false},{"year":2017,"finding":"SOCS5 restricts influenza A virus replication in airway epithelium through regulation of EGFR signaling; Socs5-deficient mice exhibit heightened disease severity with increased viral titres, and restoration of SOCS5 levels restricts influenza virus infection.","method":"Socs5 knockout mouse model, viral titre measurement, weight loss phenotyping, primary epithelial cell assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined viral/cellular phenotype, multiple readouts in vivo and in vitro","pmids":["28195529"],"is_preprint":false},{"year":2014,"finding":"MeCP2 promotes expression of miR-124, which suppresses translation of SOCS5 mRNA; loss of MeCP2 leads to SOCS5 accumulation, which in turn inhibits STAT1 and STAT3 activation and impairs Th1 and Th17 differentiation.","method":"MeCP2 knockdown, miR-124 functional assays, Western blot for SOCS5/STAT phosphorylation, Th1/Th17 differentiation assays in vitro and in vivo","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — epistatic pathway placement with multiple orthogonal methods and in vivo validation","pmids":["24619648"],"is_preprint":false},{"year":2016,"finding":"In chronic lymphocytic leukemia, STAT3-dependent upregulation of SOCS5 in monocytes decouples IL-4R signaling from STAT6 activation, impairing dendritic cell differentiation and reducing expression of HLA-DR, costimulatory molecules, and pro-inflammatory cytokines; IL-10 treatment of healthy donor monocytes mimics this effect via STAT3-dependent SOCS5 induction.","method":"Western blot, flow cytometry, cytokine secretion assays, IL-10 treatment experiments, patient-derived monocytes","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway placement in primary patient cells with multiple functional readouts, single lab","pmids":["27317770"],"is_preprint":false},{"year":2019,"finding":"SOCS5 overexpression promotes HCC cell migration and invasion by inactivating PI3K/Akt/mTOR-mediated autophagy; SOCS5 knockdown suppresses HCC metastasis in vitro and in vivo by activating this autophagy pathway.","method":"SOCS5 knockdown/overexpression, PI3K/Akt/mTOR pathway Western blot, autophagy assays, migration/invasion assays, in vivo metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — loss- and gain-of-function with pathway readouts in vitro and in vivo, single lab","pmids":["31406106"],"is_preprint":false},{"year":2019,"finding":"SOCS5 expression is epigenetically silenced in T-ALL by DNMT3A-mediated DNA methylation and MeCP2-mediated histone deacetylation; SOCS5 silencing activates JAK-STAT signaling and negatively regulates IL-7 and IL-4 receptors, accelerating leukemia engraftment and progression in a xenograft model.","method":"DNA methylation analysis, chromatin studies, SOCS5 knockdown/reconstitution, JAK-STAT signaling assays, human T-ALL xenograft mouse model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — epigenetic mechanism identified with multiple methods plus in vivo xenograft model, single lab","pmids":["30974024"],"is_preprint":false},{"year":2024,"finding":"The SOCS5 SH2 domain, specifically amino acids Y413 and D443, directly binds the RRM domain of RBMX; the SOCS5-RBMX complex co-stimulates the SREBP1 promoter to induce de novo lipogenesis and promote HCC metastasis. Mutations at Y413 and D443 abolish this interaction and reverse lipogenesis.","method":"Co-immunoprecipitation, GST pulldown, proteomics, metabolomics, promoter assays, site-directed mutagenesis, in vivo and in vitro experiments","journal":"NPJ precision oncology","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP, GST pulldown, mutagenesis of specific binding residues, and multiple orthogonal methods including proteomics and metabolomics","pmids":["38429411"],"is_preprint":false},{"year":2000,"finding":"SOCS5 (CIS6) was cloned as a member of the CIS/SOCS family with a conserved central SH2 domain and SOCS box, and was assigned to human chromosomal bands 2p21 and 3p22; it is expressed in heart, muscle, spleen, thymus, and myeloma cell lines.","method":"cDNA cloning, Northern blot analysis, in situ hybridization","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 3 — cloning and expression characterization, foundational identification of gene structure","pmids":["10773671"],"is_preprint":false},{"year":2004,"finding":"SOCS5-deficient (Socs5-/-) mice are viable, healthy, and fertile with no abnormalities in lymphocyte compartments; SOCS5 is expressed in primary B and T cells but is dispensable for lymphocyte production, antigen/cytokine-induced proliferation, and Th1/Th2 differentiation under the conditions tested.","method":"Targeted gene disruption (knockout mouse), Mendelian ratio analysis, lymphocyte phenotyping, Th1/Th2 differentiation assays, Leishmania major infection model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with comprehensive immune phenotyping across multiple assays and infection model","pmids":["15199163"],"is_preprint":false},{"year":2018,"finding":"miR-18a and miR-25 target SOCS5 in HCC; SOCS5 loss activates mTOR signaling by reducing TSC1 levels, promoting tumor growth, establishing a SOCS5/miR-18a/miR-25/TSC1/mTOR tumor-suppressive axis in liver cancer.","method":"miRNA target validation (luciferase reporter assay), SOCS5 overexpression/knockdown, mTOR/TSC1 pathway Western blot, HCC cell proliferation assays","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — luciferase validation plus pathway mechanistic studies, single lab","pmids":["30191950"],"is_preprint":false},{"year":2022,"finding":"SOCS5 enhances transcription of Bcl-2, promoting Bcl-2-recruited autophagy and mediating temozolomide resistance in glioblastoma cells; SOCS5 knockdown inhibits TMZ chemoresistance by reducing Bcl-2-mediated autophagy.","method":"SOCS5 knockdown/overexpression, Bcl-2 transcription assays, autophagy assays, drug resistance functional assays","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2-3 — mechanistic pathway (SOCS5→Bcl-2→autophagy) with loss-of-function rescue experiments, single lab","pmids":["35730472"],"is_preprint":false},{"year":2022,"finding":"SOCS5 knockdown inhibits HIF-1α protein expression and resists hypoxia-induced mitochondrial damage in HCC cells; the mechanism involves inhibition of the PI3K/Akt/mTOR/HIF-1α signaling axis, suppressing hypoxia-driven invasion and migration.","method":"SOCS5 knockdown, CoCl2 hypoxia model, immunofluorescence, electron microscopy, rescue experiments with LY294002 and rapamycin, in vivo subcutaneous and lung metastasis models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods with pharmacological rescue and in vivo validation, single lab","pmids":["36319626"],"is_preprint":false},{"year":2023,"finding":"POU2F1 acts as an upstream transcriptional activator of SOCS5, and the POU2F1-SOCS5-CDKN1A axis drives diabetic retinopathy by promoting DNA damage and cellular senescence; SOCS5 knockdown reduces vascular leakage, apoptosis, and senescence in DR models.","method":"In vitro (HG-induced HRMECs) and in vivo (STZ-induced DR mice) models, SOCS5 knockdown, CDKN1A expression analysis, POU2F1 transcription factor studies","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function in both in vitro and in vivo DR models with identification of upstream transcriptional regulator and downstream effector","pmids":["41922309"],"is_preprint":false}],"current_model":"SOCS5 is an intracellular suppressor of cytokine and growth factor signaling that operates through at least two distinct mechanisms: (1) its N-terminal JAK Interaction Region (JIR) directly binds and inhibits JAK1/JAK2 kinase activity to suppress JAK-STAT signaling, and (2) its SH2 domain binds phosphotyrosine motifs on receptors (IL-4Rα, EGFR complex) and adaptor proteins (Shc-1/pY317), while its SOCS box recruits E3 ubiquitin ligase activity to promote proteasomal degradation of the EGFR; additionally, the SOCS5 SH2 domain interacts with RBMX to co-stimulate SREBP1-driven lipogenesis, and SOCS5 can promote Bcl-2 transcription and HIF-1α expression to regulate autophagy and hypoxic responses."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of SOCS5 as a new CIS/SOCS family member with a conserved SH2 domain and SOCS box established it as a candidate cytokine signaling regulator.","evidence":"cDNA cloning, Northern blot, and chromosomal mapping in human tissues and cell lines","pmids":["10773671"],"confidence":"Medium","gaps":["No signaling function demonstrated","No binding partners identified","No loss-of-function data"]},{"year":2002,"claim":"The first functional role was established: SOCS5 binds IL-4Rα and suppresses IL-4/STAT6 signaling, positioning it as a regulator of Th1/Th2 balance.","evidence":"Co-immunoprecipitation and transgenic mouse overexpression model with Th2 differentiation assays","pmids":["12242343"],"confidence":"High","gaps":["Mechanism of IL-4Rα binding unclear (phosphorylation-independent)","Endogenous requirement not tested via loss-of-function"]},{"year":2004,"claim":"Genetic knockout unexpectedly revealed that SOCS5 is dispensable for lymphocyte development and Th1/Th2 differentiation under standard conditions, suggesting functional redundancy in immune cells.","evidence":"Socs5-/- mice with comprehensive immune phenotyping, Th differentiation assays, and Leishmania major infection","pmids":["15199163"],"confidence":"High","gaps":["Redundant SOCS family members not identified","Non-immune phenotypes not examined","Stress or disease-specific requirements not tested"]},{"year":2005,"claim":"SOCS5 was shown to associate with and inhibit EGFR signaling in a SOCS box-dependent manner, establishing a second major signaling axis and linking SOCS5 to receptor tyrosine kinase regulation via ubiquitin-proteasome degradation.","evidence":"Co-immunoprecipitation and SOCS box deletion mutagenesis with mitogenic response assays in engineered cell lines","pmids":["15695332"],"confidence":"High","gaps":["Direct ubiquitination of EGFR not demonstrated","E3 ligase complex identity not resolved","EGF-independent binding mechanism unclear"]},{"year":2013,"claim":"The N-terminal JIR was identified as a novel domain that directly binds and inhibits JAK1/JAK2 kinase activity via a mechanism distinct from SOCS1/3, and the SH2 domain was shown to bind Shc-1 pY317, unifying JAK and growth factor suppressive activities.","evidence":"In vitro kinase assays, domain mutagenesis, peptide binding studies","pmids":["23990909"],"confidence":"High","gaps":["Selectivity mechanism for JAK1/2 over JAK3/TYK2 not resolved","In vivo contribution of JIR versus SH2 domain not dissected"]},{"year":2014,"claim":"SOCS5 was placed downstream of MeCP2/miR-124 regulation, revealing that SOCS5 accumulation inhibits STAT1 and STAT3 activation and impairs Th1/Th17 differentiation — broadening its role beyond Th2 suppression.","evidence":"MeCP2 knockdown, miR-124 functional assays, STAT phosphorylation Western blots, in vivo T cell differentiation","pmids":["24619648"],"confidence":"High","gaps":["Whether SOCS5 directly inhibits STAT1/3 or acts via JAK not resolved","Relative contribution of miR-124 versus other miRNAs unclear"]},{"year":2015,"claim":"NMR structural analysis of the JIR revealed preformed α-helical and extended structural elements within the otherwise disordered N-terminus, and identified Ser211 phosphorylation as a modulator of JAK binding, providing the first structural basis for SOCS5-JAK interaction.","evidence":"NMR spectroscopy (chemical shifts, relaxation, NOE) with site-directed mutagenesis","pmids":["26173083"],"confidence":"High","gaps":["Full structure of JIR-JAK complex not solved","Kinase responsible for Ser211 phosphorylation unknown","Functional consequence of Ser211 phosphorylation in cells not shown"]},{"year":2016,"claim":"In CLL, STAT3-driven SOCS5 induction in monocytes was shown to decouple IL-4R/STAT6 signaling and impair dendritic cell differentiation, demonstrating a disease-relevant immunosuppressive circuit.","evidence":"Patient-derived monocytes, IL-10 treatment, Western blot, flow cytometry, cytokine secretion assays","pmids":["27317770"],"confidence":"Medium","gaps":["Single lab finding in CLL","Causal role of SOCS5 not confirmed by genetic manipulation in patient cells"]},{"year":2017,"claim":"SOCS5 was shown to restrict influenza A virus replication through EGFR signaling regulation in airway epithelium, establishing an in vivo non-immune function for SOCS5 with pathophysiological relevance.","evidence":"Socs5-/- mice with viral titre measurement, weight loss phenotyping, primary epithelial cell assays","pmids":["28195529"],"confidence":"High","gaps":["Precise EGFR-dependent mechanism in epithelial antiviral defense not fully delineated","Whether SOCS5 acts cell-autonomously versus via paracrine signals not resolved"]},{"year":2018,"claim":"SOCS5 was positioned in an miR-18a/miR-25–SOCS5–TSC1–mTOR tumor-suppressive axis in HCC, linking SOCS5 loss to mTOR activation via reduced TSC1 levels.","evidence":"miRNA target validation by luciferase assay, SOCS5 overexpression/knockdown, mTOR/TSC1 pathway analysis","pmids":["30191950"],"confidence":"Medium","gaps":["Mechanism by which SOCS5 maintains TSC1 levels not defined","Single lab, not independently confirmed"]},{"year":2019,"claim":"SOCS5 was shown to regulate PI3K/Akt/mTOR-dependent autophagy and promote HCC metastasis, and separately, epigenetic silencing of SOCS5 in T-ALL was found to activate JAK-STAT signaling and accelerate leukemia, establishing SOCS5 as a context-dependent oncogene and tumor suppressor.","evidence":"SOCS5 knockdown/overexpression with autophagy/migration assays and in vivo models (HCC); DNA methylation/chromatin studies with xenograft models (T-ALL)","pmids":["31406106","30974024"],"confidence":"Medium","gaps":["Context-dependent oncogenic versus tumor-suppressive roles not mechanistically reconciled","Direct SOCS5 substrate in mTOR pathway unidentified"]},{"year":2022,"claim":"SOCS5 was found to promote Bcl-2 transcription driving autophagy-mediated temozolomide resistance in glioblastoma, and separately to sustain HIF-1α via PI3K/Akt/mTOR to drive hypoxic invasion in HCC, revealing SOCS5 as a regulator of stress-adaptive transcriptional programs.","evidence":"Knockdown/overexpression with Bcl-2 transcription and autophagy assays (GBM); CoCl2 hypoxia model, pharmacological rescue, in vivo metastasis models (HCC)","pmids":["35730472","36319626"],"confidence":"Medium","gaps":["Mechanism by which SOCS5 activates Bcl-2 transcription unknown","Whether SOCS5 acts directly on PI3K/Akt or via intermediate signaling not resolved","Findings from single labs"]},{"year":2024,"claim":"The SH2 domain of SOCS5 was shown to directly bind RBMX via specific residues (Y413, D443), and this complex co-activates SREBP1-driven de novo lipogenesis in HCC, revealing a novel non-canonical function of SOCS5 in metabolic gene regulation.","evidence":"Co-IP, GST pulldown, site-directed mutagenesis, proteomics, metabolomics, promoter assays, in vivo experiments","pmids":["38429411"],"confidence":"High","gaps":["Whether RBMX interaction is relevant outside HCC unknown","How the SOCS5-RBMX complex activates SREBP1 transcription mechanistically not defined"]},{"year":null,"claim":"It remains unresolved how SOCS5 toggles between tumor-suppressive (T-ALL, immune contexts) and oncogenic (HCC, GBM) functions, whether the JIR and SH2 domain mediate separable signaling outputs in vivo, and what structural basis governs the full SOCS5-JAK or SOCS5-RBMX complexes.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length SOCS5 structure available","JIR-JAK complex structure not solved","Context-dependent tumor-suppressive versus oncogenic switching mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9,13]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,4,5,6,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5,6,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,12,14]}],"complexes":[],"partners":["JAK1","JAK2","IL4R","EGFR","SHC1","RBMX"],"other_free_text":[]},"mechanistic_narrative":"SOCS5 is a multifunctional negative regulator of cytokine and growth factor signaling that modulates JAK-STAT, EGFR, and PI3K/Akt/mTOR pathways across immune and epithelial cell contexts. Its N-terminal JAK Interaction Region (JIR), which contains preformed structural elements within an otherwise disordered domain, directly binds and inhibits JAK1 and JAK2 kinase activity, while its SH2 domain engages phosphotyrosine motifs on adaptors such as Shc-1 (pY317), and its SOCS box recruits E3 ubiquitin ligase machinery to promote proteasomal degradation of the EGFR [PMID:23990909, PMID:15695332, PMID:26173083]. SOCS5 inhibits IL-4Rα-STAT6 signaling to suppress Th2 differentiation [PMID:12242343], restricts influenza A virus replication via EGFR pathway regulation in airway epithelium [PMID:28195529], and its SH2 domain interacts with the RNA-binding protein RBMX to co-activate SREBP1-driven de novo lipogenesis in hepatocellular carcinoma [PMID:38429411]. Epigenetic silencing of SOCS5 in T-ALL activates JAK-STAT signaling and accelerates leukemia progression, while in HCC, SOCS5 modulates PI3K/Akt/mTOR-dependent autophagy and HIF-1α-mediated hypoxic responses [PMID:30974024, PMID:31406106, PMID:36319626]."},"prefetch_data":{"uniprot":{"accession":"O75159","full_name":"Suppressor of cytokine signaling 5","aliases":["Cytokine-inducible SH2 protein 6","CIS-6","Cytokine-inducible SH2-containing protein 5"],"length_aa":536,"mass_kda":61.2,"function":"SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. May be a substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Inhibits for instance EGF signaling by mediating the degradation of the EGF receptor/EGFR. Involved in the regulation of T-helper cell differentiation by inhibiting of the IL4 signaling pathway which promotes differentiation into the Th2 phenotype. Can also partially inhibit IL6 and LIF signaling","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O75159/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SOCS5","classification":"Not Classified","n_dependent_lines":93,"n_total_lines":1208,"dependency_fraction":0.07698675496688742},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SOCS5","total_profiled":1310},"omim":[{"mim_id":"616337","title":"SUPPRESSOR OF CYTOKINE SIGNALING 4; SOCS4","url":"https://www.omim.org/entry/616337"},{"mim_id":"607094","title":"SUPPRESSOR OF CYTOKINE SIGNALING 5; SOCS5","url":"https://www.omim.org/entry/607094"},{"mim_id":"131550","title":"EPIDERMAL GROWTH FACTOR RECEPTOR; EGFR","url":"https://www.omim.org/entry/131550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SOCS5"},"hgnc":{"alias_symbol":["KIAA0671","SOCS-5","CIS6","CISH6","Cish5"],"prev_symbol":[]},"alphafold":{"accession":"O75159","domains":[{"cath_id":"-","chopping":"275-288_357-371_481-530","consensus_level":"medium","plddt":82.9501,"start":275,"end":530},{"cath_id":"3.30.505.10","chopping":"381-477","consensus_level":"medium","plddt":93.7957,"start":381,"end":477}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75159","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75159-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75159-F1-predicted_aligned_error_v6.png","plddt_mean":61.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SOCS5","jax_strain_url":"https://www.jax.org/strain/search?query=SOCS5"},"sequence":{"accession":"O75159","fasta_url":"https://rest.uniprot.org/uniprotkb/O75159.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75159/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75159"}},"corpus_meta":[{"pmid":"12242343","id":"PMC_12242343","title":"Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12242343","citation_count":171,"is_preprint":false},{"pmid":"31406106","id":"PMC_31406106","title":"SOCS5 inhibition induces autophagy to impair metastasis in hepatocellular carcinoma cells via the PI3K/Akt/mTOR pathway.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31406106","citation_count":110,"is_preprint":false},{"pmid":"16210657","id":"PMC_16210657","title":"The control of allergic conjunctivitis by suppressor of cytokine signaling (SOCS)3 and SOCS5 in a murine model.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 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model, flow cytometry, cytokine signaling assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus in vivo transgenic model with defined cellular phenotype, replicated functionally\",\n      \"pmids\": [\"12242343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SOCS5 associates with the EGF receptor complex in an EGF-independent manner and inhibits EGF mitogenic signaling; this inhibition requires the SOCS5 SOCS box, suggesting it acts through SOCS box-recruited E3 ubiquitin ligase activity to promote proteasomal degradation of the EGF-R.\",\n      \"method\": \"Co-immunoprecipitation, engineered cell line constitutively expressing EGF-R and SOCS5 or SOCS5 deletion mutants, mitogenic response assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus domain-deletion mutagenesis with functional readout in defined cell line\",\n      \"pmids\": [\"15695332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SOCS5 contains a conserved JAK Interaction Region (JIR) in its N-terminus that directly binds JAK kinase domains; co-expression of SOCS5 specifically reduces JAK1 and JAK2 (but not JAK3 or TYK2) autophosphorylation and directly inhibits JAK1 kinase activity via a mechanism distinct from SOCS1/SOCS3. Additionally, the SOCS5 SH2 domain binds phosphoTyr317 of Shc-1 with high affinity, suggesting SOCS5 negatively regulates EGF/growth factor-driven Shc-1 signaling.\",\n      \"method\": \"In vitro kinase assays, co-immunoprecipitation, domain mutagenesis, peptide binding/SH2 domain interaction studies\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro kinase inhibition assay plus mutagenesis and binding studies with multiple orthogonal methods\",\n      \"pmids\": [\"23990909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The JAK Interaction Region (JIR) within the intrinsically disordered N-terminus of SOCS5 adopts preformed structural elements including an α-helix (residues 224-233), a turn, and an extended structure as determined by NMR; a phosphorylation site (Ser211) within the JIR modulates JAK binding.\",\n      \"method\": \"NMR spectroscopy (chemical shift analysis, relaxation measurements, NOE analysis), site-directed mutagenesis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure determination with mutagenesis-based functional validation\",\n      \"pmids\": [\"26173083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SOCS5 restricts influenza A virus replication in airway epithelium through regulation of EGFR signaling; Socs5-deficient mice exhibit heightened disease severity with increased viral titres, and restoration of SOCS5 levels restricts influenza virus infection.\",\n      \"method\": \"Socs5 knockout mouse model, viral titre measurement, weight loss phenotyping, primary epithelial cell assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined viral/cellular phenotype, multiple readouts in vivo and in vitro\",\n      \"pmids\": [\"28195529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MeCP2 promotes expression of miR-124, which suppresses translation of SOCS5 mRNA; loss of MeCP2 leads to SOCS5 accumulation, which in turn inhibits STAT1 and STAT3 activation and impairs Th1 and Th17 differentiation.\",\n      \"method\": \"MeCP2 knockdown, miR-124 functional assays, Western blot for SOCS5/STAT phosphorylation, Th1/Th17 differentiation assays in vitro and in vivo\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistatic pathway placement with multiple orthogonal methods and in vivo validation\",\n      \"pmids\": [\"24619648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In chronic lymphocytic leukemia, STAT3-dependent upregulation of SOCS5 in monocytes decouples IL-4R signaling from STAT6 activation, impairing dendritic cell differentiation and reducing expression of HLA-DR, costimulatory molecules, and pro-inflammatory cytokines; IL-10 treatment of healthy donor monocytes mimics this effect via STAT3-dependent SOCS5 induction.\",\n      \"method\": \"Western blot, flow cytometry, cytokine secretion assays, IL-10 treatment experiments, patient-derived monocytes\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement in primary patient cells with multiple functional readouts, single lab\",\n      \"pmids\": [\"27317770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SOCS5 overexpression promotes HCC cell migration and invasion by inactivating PI3K/Akt/mTOR-mediated autophagy; SOCS5 knockdown suppresses HCC metastasis in vitro and in vivo by activating this autophagy pathway.\",\n      \"method\": \"SOCS5 knockdown/overexpression, PI3K/Akt/mTOR pathway Western blot, autophagy assays, migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss- and gain-of-function with pathway readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"31406106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SOCS5 expression is epigenetically silenced in T-ALL by DNMT3A-mediated DNA methylation and MeCP2-mediated histone deacetylation; SOCS5 silencing activates JAK-STAT signaling and negatively regulates IL-7 and IL-4 receptors, accelerating leukemia engraftment and progression in a xenograft model.\",\n      \"method\": \"DNA methylation analysis, chromatin studies, SOCS5 knockdown/reconstitution, JAK-STAT signaling assays, human T-ALL xenograft mouse model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epigenetic mechanism identified with multiple methods plus in vivo xenograft model, single lab\",\n      \"pmids\": [\"30974024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The SOCS5 SH2 domain, specifically amino acids Y413 and D443, directly binds the RRM domain of RBMX; the SOCS5-RBMX complex co-stimulates the SREBP1 promoter to induce de novo lipogenesis and promote HCC metastasis. Mutations at Y413 and D443 abolish this interaction and reverse lipogenesis.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, proteomics, metabolomics, promoter assays, site-directed mutagenesis, in vivo and in vitro experiments\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP, GST pulldown, mutagenesis of specific binding residues, and multiple orthogonal methods including proteomics and metabolomics\",\n      \"pmids\": [\"38429411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SOCS5 (CIS6) was cloned as a member of the CIS/SOCS family with a conserved central SH2 domain and SOCS box, and was assigned to human chromosomal bands 2p21 and 3p22; it is expressed in heart, muscle, spleen, thymus, and myeloma cell lines.\",\n      \"method\": \"cDNA cloning, Northern blot analysis, in situ hybridization\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — cloning and expression characterization, foundational identification of gene structure\",\n      \"pmids\": [\"10773671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SOCS5-deficient (Socs5-/-) mice are viable, healthy, and fertile with no abnormalities in lymphocyte compartments; SOCS5 is expressed in primary B and T cells but is dispensable for lymphocyte production, antigen/cytokine-induced proliferation, and Th1/Th2 differentiation under the conditions tested.\",\n      \"method\": \"Targeted gene disruption (knockout mouse), Mendelian ratio analysis, lymphocyte phenotyping, Th1/Th2 differentiation assays, Leishmania major infection model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with comprehensive immune phenotyping across multiple assays and infection model\",\n      \"pmids\": [\"15199163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-18a and miR-25 target SOCS5 in HCC; SOCS5 loss activates mTOR signaling by reducing TSC1 levels, promoting tumor growth, establishing a SOCS5/miR-18a/miR-25/TSC1/mTOR tumor-suppressive axis in liver cancer.\",\n      \"method\": \"miRNA target validation (luciferase reporter assay), SOCS5 overexpression/knockdown, mTOR/TSC1 pathway Western blot, HCC cell proliferation assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — luciferase validation plus pathway mechanistic studies, single lab\",\n      \"pmids\": [\"30191950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SOCS5 enhances transcription of Bcl-2, promoting Bcl-2-recruited autophagy and mediating temozolomide resistance in glioblastoma cells; SOCS5 knockdown inhibits TMZ chemoresistance by reducing Bcl-2-mediated autophagy.\",\n      \"method\": \"SOCS5 knockdown/overexpression, Bcl-2 transcription assays, autophagy assays, drug resistance functional assays\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic pathway (SOCS5→Bcl-2→autophagy) with loss-of-function rescue experiments, single lab\",\n      \"pmids\": [\"35730472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SOCS5 knockdown inhibits HIF-1α protein expression and resists hypoxia-induced mitochondrial damage in HCC cells; the mechanism involves inhibition of the PI3K/Akt/mTOR/HIF-1α signaling axis, suppressing hypoxia-driven invasion and migration.\",\n      \"method\": \"SOCS5 knockdown, CoCl2 hypoxia model, immunofluorescence, electron microscopy, rescue experiments with LY294002 and rapamycin, in vivo subcutaneous and lung metastasis models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with pharmacological rescue and in vivo validation, single lab\",\n      \"pmids\": [\"36319626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"POU2F1 acts as an upstream transcriptional activator of SOCS5, and the POU2F1-SOCS5-CDKN1A axis drives diabetic retinopathy by promoting DNA damage and cellular senescence; SOCS5 knockdown reduces vascular leakage, apoptosis, and senescence in DR models.\",\n      \"method\": \"In vitro (HG-induced HRMECs) and in vivo (STZ-induced DR mice) models, SOCS5 knockdown, CDKN1A expression analysis, POU2F1 transcription factor studies\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in both in vitro and in vivo DR models with identification of upstream transcriptional regulator and downstream effector\",\n      \"pmids\": [\"41922309\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SOCS5 is an intracellular suppressor of cytokine and growth factor signaling that operates through at least two distinct mechanisms: (1) its N-terminal JAK Interaction Region (JIR) directly binds and inhibits JAK1/JAK2 kinase activity to suppress JAK-STAT signaling, and (2) its SH2 domain binds phosphotyrosine motifs on receptors (IL-4Rα, EGFR complex) and adaptor proteins (Shc-1/pY317), while its SOCS box recruits E3 ubiquitin ligase activity to promote proteasomal degradation of the EGFR; additionally, the SOCS5 SH2 domain interacts with RBMX to co-stimulate SREBP1-driven lipogenesis, and SOCS5 can promote Bcl-2 transcription and HIF-1α expression to regulate autophagy and hypoxic responses.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SOCS5 is a multifunctional negative regulator of cytokine and growth factor signaling that modulates JAK-STAT, EGFR, and PI3K/Akt/mTOR pathways across immune and epithelial cell contexts. Its N-terminal JAK Interaction Region (JIR), which contains preformed structural elements within an otherwise disordered domain, directly binds and inhibits JAK1 and JAK2 kinase activity, while its SH2 domain engages phosphotyrosine motifs on adaptors such as Shc-1 (pY317), and its SOCS box recruits E3 ubiquitin ligase machinery to promote proteasomal degradation of the EGFR [PMID:23990909, PMID:15695332, PMID:26173083]. SOCS5 inhibits IL-4Rα-STAT6 signaling to suppress Th2 differentiation [PMID:12242343], restricts influenza A virus replication via EGFR pathway regulation in airway epithelium [PMID:28195529], and its SH2 domain interacts with the RNA-binding protein RBMX to co-activate SREBP1-driven de novo lipogenesis in hepatocellular carcinoma [PMID:38429411]. Epigenetic silencing of SOCS5 in T-ALL activates JAK-STAT signaling and accelerates leukemia progression, while in HCC, SOCS5 modulates PI3K/Akt/mTOR-dependent autophagy and HIF-1α-mediated hypoxic responses [PMID:30974024, PMID:31406106, PMID:36319626].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of SOCS5 as a new CIS/SOCS family member with a conserved SH2 domain and SOCS box established it as a candidate cytokine signaling regulator.\",\n      \"evidence\": \"cDNA cloning, Northern blot, and chromosomal mapping in human tissues and cell lines\",\n      \"pmids\": [\"10773671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No signaling function demonstrated\", \"No binding partners identified\", \"No loss-of-function data\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The first functional role was established: SOCS5 binds IL-4Rα and suppresses IL-4/STAT6 signaling, positioning it as a regulator of Th1/Th2 balance.\",\n      \"evidence\": \"Co-immunoprecipitation and transgenic mouse overexpression model with Th2 differentiation assays\",\n      \"pmids\": [\"12242343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of IL-4Rα binding unclear (phosphorylation-independent)\", \"Endogenous requirement not tested via loss-of-function\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic knockout unexpectedly revealed that SOCS5 is dispensable for lymphocyte development and Th1/Th2 differentiation under standard conditions, suggesting functional redundancy in immune cells.\",\n      \"evidence\": \"Socs5-/- mice with comprehensive immune phenotyping, Th differentiation assays, and Leishmania major infection\",\n      \"pmids\": [\"15199163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundant SOCS family members not identified\", \"Non-immune phenotypes not examined\", \"Stress or disease-specific requirements not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"SOCS5 was shown to associate with and inhibit EGFR signaling in a SOCS box-dependent manner, establishing a second major signaling axis and linking SOCS5 to receptor tyrosine kinase regulation via ubiquitin-proteasome degradation.\",\n      \"evidence\": \"Co-immunoprecipitation and SOCS box deletion mutagenesis with mitogenic response assays in engineered cell lines\",\n      \"pmids\": [\"15695332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitination of EGFR not demonstrated\", \"E3 ligase complex identity not resolved\", \"EGF-independent binding mechanism unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The N-terminal JIR was identified as a novel domain that directly binds and inhibits JAK1/JAK2 kinase activity via a mechanism distinct from SOCS1/3, and the SH2 domain was shown to bind Shc-1 pY317, unifying JAK and growth factor suppressive activities.\",\n      \"evidence\": \"In vitro kinase assays, domain mutagenesis, peptide binding studies\",\n      \"pmids\": [\"23990909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity mechanism for JAK1/2 over JAK3/TYK2 not resolved\", \"In vivo contribution of JIR versus SH2 domain not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"SOCS5 was placed downstream of MeCP2/miR-124 regulation, revealing that SOCS5 accumulation inhibits STAT1 and STAT3 activation and impairs Th1/Th17 differentiation — broadening its role beyond Th2 suppression.\",\n      \"evidence\": \"MeCP2 knockdown, miR-124 functional assays, STAT phosphorylation Western blots, in vivo T cell differentiation\",\n      \"pmids\": [\"24619648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SOCS5 directly inhibits STAT1/3 or acts via JAK not resolved\", \"Relative contribution of miR-124 versus other miRNAs unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"NMR structural analysis of the JIR revealed preformed α-helical and extended structural elements within the otherwise disordered N-terminus, and identified Ser211 phosphorylation as a modulator of JAK binding, providing the first structural basis for SOCS5-JAK interaction.\",\n      \"evidence\": \"NMR spectroscopy (chemical shifts, relaxation, NOE) with site-directed mutagenesis\",\n      \"pmids\": [\"26173083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full structure of JIR-JAK complex not solved\", \"Kinase responsible for Ser211 phosphorylation unknown\", \"Functional consequence of Ser211 phosphorylation in cells not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"In CLL, STAT3-driven SOCS5 induction in monocytes was shown to decouple IL-4R/STAT6 signaling and impair dendritic cell differentiation, demonstrating a disease-relevant immunosuppressive circuit.\",\n      \"evidence\": \"Patient-derived monocytes, IL-10 treatment, Western blot, flow cytometry, cytokine secretion assays\",\n      \"pmids\": [\"27317770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab finding in CLL\", \"Causal role of SOCS5 not confirmed by genetic manipulation in patient cells\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"SOCS5 was shown to restrict influenza A virus replication through EGFR signaling regulation in airway epithelium, establishing an in vivo non-immune function for SOCS5 with pathophysiological relevance.\",\n      \"evidence\": \"Socs5-/- mice with viral titre measurement, weight loss phenotyping, primary epithelial cell assays\",\n      \"pmids\": [\"28195529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise EGFR-dependent mechanism in epithelial antiviral defense not fully delineated\", \"Whether SOCS5 acts cell-autonomously versus via paracrine signals not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"SOCS5 was positioned in an miR-18a/miR-25–SOCS5–TSC1–mTOR tumor-suppressive axis in HCC, linking SOCS5 loss to mTOR activation via reduced TSC1 levels.\",\n      \"evidence\": \"miRNA target validation by luciferase assay, SOCS5 overexpression/knockdown, mTOR/TSC1 pathway analysis\",\n      \"pmids\": [\"30191950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SOCS5 maintains TSC1 levels not defined\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SOCS5 was shown to regulate PI3K/Akt/mTOR-dependent autophagy and promote HCC metastasis, and separately, epigenetic silencing of SOCS5 in T-ALL was found to activate JAK-STAT signaling and accelerate leukemia, establishing SOCS5 as a context-dependent oncogene and tumor suppressor.\",\n      \"evidence\": \"SOCS5 knockdown/overexpression with autophagy/migration assays and in vivo models (HCC); DNA methylation/chromatin studies with xenograft models (T-ALL)\",\n      \"pmids\": [\"31406106\", \"30974024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent oncogenic versus tumor-suppressive roles not mechanistically reconciled\", \"Direct SOCS5 substrate in mTOR pathway unidentified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"SOCS5 was found to promote Bcl-2 transcription driving autophagy-mediated temozolomide resistance in glioblastoma, and separately to sustain HIF-1α via PI3K/Akt/mTOR to drive hypoxic invasion in HCC, revealing SOCS5 as a regulator of stress-adaptive transcriptional programs.\",\n      \"evidence\": \"Knockdown/overexpression with Bcl-2 transcription and autophagy assays (GBM); CoCl2 hypoxia model, pharmacological rescue, in vivo metastasis models (HCC)\",\n      \"pmids\": [\"35730472\", \"36319626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SOCS5 activates Bcl-2 transcription unknown\", \"Whether SOCS5 acts directly on PI3K/Akt or via intermediate signaling not resolved\", \"Findings from single labs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The SH2 domain of SOCS5 was shown to directly bind RBMX via specific residues (Y413, D443), and this complex co-activates SREBP1-driven de novo lipogenesis in HCC, revealing a novel non-canonical function of SOCS5 in metabolic gene regulation.\",\n      \"evidence\": \"Co-IP, GST pulldown, site-directed mutagenesis, proteomics, metabolomics, promoter assays, in vivo experiments\",\n      \"pmids\": [\"38429411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RBMX interaction is relevant outside HCC unknown\", \"How the SOCS5-RBMX complex activates SREBP1 transcription mechanistically not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how SOCS5 toggles between tumor-suppressive (T-ALL, immune contexts) and oncogenic (HCC, GBM) functions, whether the JIR and SH2 domain mediate separable signaling outputs in vivo, and what structural basis governs the full SOCS5-JAK or SOCS5-RBMX complexes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length SOCS5 structure available\", \"JIR-JAK complex structure not solved\", \"Context-dependent tumor-suppressive versus oncogenic switching mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5, 6, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 12, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"JAK1\",\n      \"JAK2\",\n      \"IL4R\",\n      \"EGFR\",\n      \"SHC1\",\n      \"RBMX\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}