{"gene":"CISH","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1999,"finding":"CIS (CISH) inhibits GH signaling to STAT5b by binding to tyrosine-phosphorylated membrane-distal residues of the GH receptor (GHR) cytoplasmic domain, acting via a mechanism distinct from SOCS-1 (direct JAK2 inhibition) and SOCS-3 (membrane-proximal GHR tyrosines). In vitro binding assays using GST-GHR fusion proteins showed CIS and SOCS-2 bound fusions containing as few as 80 COOH-terminal GHR residues, provided they were tyrosine-phosphorylated.","method":"GST pulldown/in vitro binding assay with tyrosine-phosphorylated GHR fusion proteins; transient transfection in COS cells measuring STAT5b phosphorylation and transcriptional activity","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding assay with mutagenesis, single lab, single study","pmids":["10585430"],"is_preprint":false},{"year":2010,"finding":"CISH variants at the promoter region (e.g., -292 SNP) reduce CISH expression by 25–40% in peripheral blood mononuclear cells following IL-2 stimulation, indicating that CISH controls interleukin-2-mediated immune signaling. Carriers of variant CISH alleles showed a muted CISH induction response to IL-2.","method":"Case-control genetic association study; functional assay measuring CISH expression in PBMCs from carriers of variant vs. wild-type alleles following IL-2 stimulation","journal":"The New England journal of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large multi-population case-control with functional validation of reduced CISH expression in primary human cells, single lab for functional component","pmids":["20484391"],"is_preprint":false},{"year":2011,"finding":"CISH is induced during dendritic cell (DC) development and acts as a negative feedback regulator of STAT5 activation at the later stage of DC progenitor proliferation, facilitating DC differentiation. CISH knockdown enhanced DC yield via cell-cycle activation and reduced apoptosis, but also reduced MHC class I expression, co-stimulatory molecules, pro-inflammatory cytokines, and impaired CTL activation.","method":"CISH knockdown by siRNA in mouse bone marrow-derived DCs; flow cytometry, proliferation assays, cytokine measurement, in vivo tumor immunotherapy models","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function knockdown with multiple cellular readouts, single lab","pmids":["22002016"],"is_preprint":false},{"year":2018,"finding":"CISH is induced by IL-13 via STAT6 phosphorylation in human lung fibroblasts and negatively regulates IL-13-induced CCL26 (eotaxin-3) production. Loss-of-function (siRNA) increased CCL26; gain-of-function (overexpression) decreased CCL26 expression.","method":"siRNA knockdown and plasmid overexpression of CISH in human lung fibroblasts; ELISA and quantitative RT-PCR for CCL26; Western blotting for STAT6 phosphorylation","journal":"Allergology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal loss- and gain-of-function with defined molecular readout, single lab","pmids":["30197185"],"is_preprint":false},{"year":2022,"finding":"CISH negatively regulates natural cytotoxicity receptor (NCR) signaling in NK cells in addition to IL-15 signaling. In conditional Cish-knockout NK cells, NCR stimulation triggered increased CISH protein expression and CISH deletion lowered activation thresholds, increased antitumor cytotoxicity, reduced TIGIT expression (limiting NK exhaustion), and improved resistance to tumor metastasis and primary breast cancer growth. These effects were confirmed in human NK cells using CRISPRi-dCas9 targeting of CISH.","method":"Conditional NK cell-specific Cish-knockout mouse model; in vitro NK cytotoxicity and signaling assays; in vivo tumor metastasis (B16F10, EO771) and orthotopic breast cancer models; CRISPRi-dCas9 targeting in human NK-92 and primary NK cells; global gene expression profiling","journal":"Journal for immunotherapy of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model with multiple orthogonal in vitro and in vivo readouts, replicated in human NK cells with orthogonal CRISPRi approach","pmids":["35589278"],"is_preprint":false},{"year":2023,"finding":"CISH targets ATP6V1A (an essential subunit of the vacuolar ATPase V-ATPase proton pump) for proteasomal degradation, thereby impairing lysosomal function in activated T cells from older adults. Impaired lysosomal activity leads to intracellular accumulation of multivesicular bodies and amphisomes, and subsequent export of mitochondrial DNA (mtDNA) into the extracellular environment, contributing to inflammaging. CISH silencing in aged T cells restored lysosomal activity and reduced amphisomal mtDNA release.","method":"CISH silencing in primary human T cells from older adults; Western blotting for ATP6V1A; lysosomal activity assays; multivesicular body/amphisome quantification by imaging; extracellular mtDNA measurement; antigen-specific in vivo CISH-deficient CD4+ T cell responses","journal":"Nature aging","confidence":"High","confidence_rationale":"Tier 2 / Strong — identification of specific substrate (ATP6V1A) with functional consequence (lysosomal impairment, mtDNA release) validated in primary human cells and in vivo, multiple orthogonal methods","pmids":["37118554"],"is_preprint":false},{"year":2020,"finding":"CISH protein negatively regulates STAT3 activity in oral squamous cell carcinoma cells and is a direct target of miR-944. Luciferase reporter assays confirmed miR-944 directly targets CISH mRNA. Restoration of CISH abolished miR-944-induced STAT3 phosphorylation, pro-inflammatory cytokine secretion, and cell migration/invasion, demonstrating that miR-944's oncogenic activity is CISH-dependent.","method":"Luciferase reporter assay for miR-944 targeting of CISH; gain- and loss-of-function (siRNA, overexpression); Western blotting for STAT3 phosphorylation; transwell migration/invasion; ELISA for cytokines","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by reporter assay plus reciprocal gain/loss-of-function with defined molecular readout (STAT3 phosphorylation), single lab","pmids":["32961483"],"is_preprint":false}],"current_model":"CISH (CIS/CIS-1/SOCS) is an inducible SH2 domain-containing protein that negatively regulates cytokine signaling by binding phosphotyrosine residues on cytokine receptors (e.g., membrane-distal GHR tyrosines) to block STAT access and signaling; it acts as a negative feedback inhibitor of STAT5 downstream of IL-2 and other cytokines, controls NK cell natural cytotoxicity receptor (NCR) signaling to limit NK cell exhaustion, and promotes proteasomal degradation of ATP6V1A (a V-ATPase subunit) to impair lysosomal function in aging T cells, leading to mitochondrial DNA release and inflammaging."},"narrative":{"mechanistic_narrative":"CISH (CIS-1) is a cytokine-inducible SH2-domain protein that functions as a negative-feedback inhibitor across multiple cytokine signaling pathways, dampening STAT activation downstream of receptor engagement [PMID:10585430, PMID:20484391]. Mechanistically, it binds tyrosine-phosphorylated membrane-distal residues of the growth hormone receptor cytoplasmic domain to block STAT5b signaling, a mode distinct from the JAK-directed or membrane-proximal actions of other SOCS family members [PMID:10585430]. The same feedback logic operates across diverse cytokine inputs: CISH is induced by IL-2 to limit IL-2-mediated immune responses [PMID:20484391], by IL-13 via STAT6 to restrain CCL26/eotaxin-3 production in lung fibroblasts [PMID:30197185], and constrains STAT3 activity in oral squamous carcinoma cells, where its loss (driven by miR-944) promotes inflammatory cytokine secretion and invasion [PMID:32961483]. In immune-cell physiology, CISH sets activation thresholds: it negatively regulates both IL-15 and natural cytotoxicity receptor (NCR) signaling in NK cells, and its deletion lowers activation thresholds, reduces TIGIT-associated exhaustion, and enhances antitumor cytotoxicity [PMID:35589278], while during dendritic-cell development it brakes STAT5-driven progenitor proliferation to permit differentiation [PMID:22002016]. Beyond cytokine feedback, CISH also acts as a substrate-targeting adaptor for proteasomal degradation: in activated T cells from older adults it targets the V-ATPase subunit ATP6V1A for degradation, impairing lysosomal function and driving export of mitochondrial DNA that contributes to inflammaging [PMID:37118554].","teleology":[{"year":1999,"claim":"Established the molecular mechanism by which CISH inhibits cytokine signaling, distinguishing it from other SOCS proteins by showing it engages phosphorylated receptor tyrosines rather than the kinase directly.","evidence":"GST pulldown with tyrosine-phosphorylated GHR fusion proteins and STAT5b reporter assays in COS cells","pmids":["10585430"],"confidence":"Medium","gaps":["Single in vitro binding study; no structural model of the SH2-phosphotyrosine interaction","Whether CIS recruits a degradation machinery to GHR not addressed here"]},{"year":2010,"claim":"Connected CISH function to IL-2-driven immune signaling in humans by showing promoter variants blunt IL-2-induced CISH expression, implicating it as a tunable feedback node in primary cells.","evidence":"Case-control genetic association with functional measurement of CISH induction in PBMCs from variant vs wild-type carriers after IL-2 stimulation","pmids":["20484391"],"confidence":"Medium","gaps":["Downstream signaling consequences of reduced CISH not mechanistically dissected","Does not identify which receptor tyrosines CISH engages in the IL-2 context"]},{"year":2011,"claim":"Defined a developmental role for CISH as a STAT5 brake during dendritic-cell maturation, showing the feedback inhibitor also shapes immune-cell differentiation rather than only acute signaling.","evidence":"siRNA knockdown in mouse bone marrow-derived DCs with proliferation, cytokine, surface-marker readouts and in vivo tumor immunotherapy models","pmids":["22002016"],"confidence":"Medium","gaps":["Knockdown only; not validated in conditional knockout","Direct receptor target in DC progenitors not identified"]},{"year":2018,"claim":"Extended the STAT-feedback model to IL-13/STAT6 signaling, showing CISH restrains an allergic-inflammation chemokine output in a non-immune stromal cell type.","evidence":"Reciprocal siRNA knockdown and overexpression in human lung fibroblasts with CCL26 readout and STAT6 phospho-blotting","pmids":["30197185"],"confidence":"Medium","gaps":["Mechanism of CISH action on the IL-13 receptor not mapped","Single cell type, single lab"]},{"year":2020,"claim":"Showed CISH is a tumor-suppressive STAT3 brake whose loss via miR-944 drives oncogenic signaling, generalizing its feedback role to STAT3 and to cancer biology.","evidence":"Luciferase reporter target validation plus reciprocal gain/loss-of-function with STAT3 phospho-blotting and invasion assays in oral squamous carcinoma cells","pmids":["32961483"],"confidence":"Medium","gaps":["Direct biochemical link between CISH and STAT3 not resolved","In vitro cell-line evidence only"]},{"year":2022,"claim":"Identified CISH as a regulator of NCR signaling beyond IL-15 in NK cells and validated it as an immunotherapy target by showing deletion enhances cytotoxicity and limits exhaustion.","evidence":"NK-specific conditional Cish-knockout mouse with in vitro signaling/cytotoxicity assays, in vivo tumor models, and orthogonal CRISPRi in human NK cells","pmids":["35589278"],"confidence":"High","gaps":["Precise NCR receptor phosphotyrosines bound by CISH not mapped","Mechanism linking CISH loss to reduced TIGIT not defined"]},{"year":2023,"claim":"Revealed a non-canonical CISH function as a substrate-targeting adaptor driving ATP6V1A degradation, linking CISH to lysosomal failure and mtDNA-driven inflammaging in aged T cells.","evidence":"CISH silencing in primary human T cells from older adults with ATP6V1A blotting, lysosomal/amphisome imaging, extracellular mtDNA measurement, and in vivo CD4+ T cell responses","pmids":["37118554"],"confidence":"High","gaps":["E3 ligase/proteasomal machinery CISH recruits to ATP6V1A not identified","Whether SH2 phosphotyrosine binding mediates ATP6V1A targeting unknown"]},{"year":null,"claim":"How CISH selects between its phosphotyrosine-receptor feedback role and its substrate-degradation adaptor role, and the structural basis and ubiquitin machinery underlying ATP6V1A targeting, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CISH bound to any receptor or substrate in the corpus","Identity of the ubiquitin ligase partner not established","Determinants of substrate vs receptor selectivity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3,4,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5]}],"complexes":[],"partners":["GHR","ATP6V1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NSE2","full_name":"Cytokine-inducible SH2-containing protein","aliases":["CIS-1","Protein G18","Suppressor of cytokine signaling","SOCS"],"length_aa":258,"mass_kda":28.7,"function":"SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. CIS is involved in the negative regulation of cytokines that signal through the JAK-STAT5 pathway such as erythropoietin, prolactin and interleukin 3 (IL3) receptor. Inhibits STAT5 trans-activation by suppressing its tyrosine phosphorylation. 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 (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9NSE2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CISH","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CISH","total_profiled":1310},"omim":[{"mim_id":"620532","title":"HYPER-IgE SYNDROME 6, AUTOSOMAL DOMINANT, WITH RECURRENT INFECTIONS; HIES6","url":"https://www.omim.org/entry/620532"},{"mim_id":"614383","title":"BACTEREMIA, SUSCEPTIBILITY TO, 2; BACTS2","url":"https://www.omim.org/entry/614383"},{"mim_id":"612472","title":"METHYLTRANSFERASE 3, N6-ADENOSINE-METHYLTRANSFERASE COMPLEX CATALYTIC SUBUNIT; METTL3","url":"https://www.omim.org/entry/612472"},{"mim_id":"611162","title":"MALARIA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/611162"},{"mim_id":"607948","title":"MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/607948"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":59.2}],"url":"https://www.proteinatlas.org/search/CISH"},"hgnc":{"alias_symbol":["CIS","G18","CIS-1","SOCS"],"prev_symbol":[]},"alphafold":{"accession":"Q9NSE2","domains":[{"cath_id":"3.30.505.10","chopping":"61-170_205-217","consensus_level":"medium","plddt":87.6965,"start":61,"end":217},{"cath_id":"1.10.750.20","chopping":"221-258","consensus_level":"medium","plddt":91.5392,"start":221,"end":258}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NSE2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NSE2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NSE2-F1-predicted_aligned_error_v6.png","plddt_mean":72.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CISH","jax_strain_url":"https://www.jax.org/strain/search?query=CISH"},"sequence":{"accession":"Q9NSE2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NSE2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NSE2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NSE2"}},"corpus_meta":[{"pmid":"17525754","id":"PMC_17525754","title":"SOCS proteins, cytokine signalling and immune regulation.","date":"2007","source":"Nature reviews. 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STAT5b by binding to tyrosine-phosphorylated membrane-distal residues of the GH receptor (GHR) cytoplasmic domain, acting via a mechanism distinct from SOCS-1 (direct JAK2 inhibition) and SOCS-3 (membrane-proximal GHR tyrosines). In vitro binding assays using GST-GHR fusion proteins showed CIS and SOCS-2 bound fusions containing as few as 80 COOH-terminal GHR residues, provided they were tyrosine-phosphorylated.\",\n      \"method\": \"GST pulldown/in vitro binding assay with tyrosine-phosphorylated GHR fusion proteins; transient transfection in COS cells measuring STAT5b phosphorylation and transcriptional activity\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding assay with mutagenesis, single lab, single study\",\n      \"pmids\": [\"10585430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CISH variants at the promoter region (e.g., -292 SNP) reduce CISH expression by 25–40% in peripheral blood mononuclear cells following IL-2 stimulation, indicating that CISH controls interleukin-2-mediated immune signaling. Carriers of variant CISH alleles showed a muted CISH induction response to IL-2.\",\n      \"method\": \"Case-control genetic association study; functional assay measuring CISH expression in PBMCs from carriers of variant vs. wild-type alleles following IL-2 stimulation\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large multi-population case-control with functional validation of reduced CISH expression in primary human cells, single lab for functional component\",\n      \"pmids\": [\"20484391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CISH is induced during dendritic cell (DC) development and acts as a negative feedback regulator of STAT5 activation at the later stage of DC progenitor proliferation, facilitating DC differentiation. CISH knockdown enhanced DC yield via cell-cycle activation and reduced apoptosis, but also reduced MHC class I expression, co-stimulatory molecules, pro-inflammatory cytokines, and impaired CTL activation.\",\n      \"method\": \"CISH knockdown by siRNA in mouse bone marrow-derived DCs; flow cytometry, proliferation assays, cytokine measurement, in vivo tumor immunotherapy models\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function knockdown with multiple cellular readouts, single lab\",\n      \"pmids\": [\"22002016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CISH is induced by IL-13 via STAT6 phosphorylation in human lung fibroblasts and negatively regulates IL-13-induced CCL26 (eotaxin-3) production. Loss-of-function (siRNA) increased CCL26; gain-of-function (overexpression) decreased CCL26 expression.\",\n      \"method\": \"siRNA knockdown and plasmid overexpression of CISH in human lung fibroblasts; ELISA and quantitative RT-PCR for CCL26; Western blotting for STAT6 phosphorylation\",\n      \"journal\": \"Allergology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal loss- and gain-of-function with defined molecular readout, single lab\",\n      \"pmids\": [\"30197185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CISH negatively regulates natural cytotoxicity receptor (NCR) signaling in NK cells in addition to IL-15 signaling. In conditional Cish-knockout NK cells, NCR stimulation triggered increased CISH protein expression and CISH deletion lowered activation thresholds, increased antitumor cytotoxicity, reduced TIGIT expression (limiting NK exhaustion), and improved resistance to tumor metastasis and primary breast cancer growth. These effects were confirmed in human NK cells using CRISPRi-dCas9 targeting of CISH.\",\n      \"method\": \"Conditional NK cell-specific Cish-knockout mouse model; in vitro NK cytotoxicity and signaling assays; in vivo tumor metastasis (B16F10, EO771) and orthotopic breast cancer models; CRISPRi-dCas9 targeting in human NK-92 and primary NK cells; global gene expression profiling\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model with multiple orthogonal in vitro and in vivo readouts, replicated in human NK cells with orthogonal CRISPRi approach\",\n      \"pmids\": [\"35589278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CISH targets ATP6V1A (an essential subunit of the vacuolar ATPase V-ATPase proton pump) for proteasomal degradation, thereby impairing lysosomal function in activated T cells from older adults. Impaired lysosomal activity leads to intracellular accumulation of multivesicular bodies and amphisomes, and subsequent export of mitochondrial DNA (mtDNA) into the extracellular environment, contributing to inflammaging. CISH silencing in aged T cells restored lysosomal activity and reduced amphisomal mtDNA release.\",\n      \"method\": \"CISH silencing in primary human T cells from older adults; Western blotting for ATP6V1A; lysosomal activity assays; multivesicular body/amphisome quantification by imaging; extracellular mtDNA measurement; antigen-specific in vivo CISH-deficient CD4+ T cell responses\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identification of specific substrate (ATP6V1A) with functional consequence (lysosomal impairment, mtDNA release) validated in primary human cells and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"37118554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CISH protein negatively regulates STAT3 activity in oral squamous cell carcinoma cells and is a direct target of miR-944. Luciferase reporter assays confirmed miR-944 directly targets CISH mRNA. Restoration of CISH abolished miR-944-induced STAT3 phosphorylation, pro-inflammatory cytokine secretion, and cell migration/invasion, demonstrating that miR-944's oncogenic activity is CISH-dependent.\",\n      \"method\": \"Luciferase reporter assay for miR-944 targeting of CISH; gain- and loss-of-function (siRNA, overexpression); Western blotting for STAT3 phosphorylation; transwell migration/invasion; ELISA for cytokines\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by reporter assay plus reciprocal gain/loss-of-function with defined molecular readout (STAT3 phosphorylation), single lab\",\n      \"pmids\": [\"32961483\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CISH (CIS/CIS-1/SOCS) is an inducible SH2 domain-containing protein that negatively regulates cytokine signaling by binding phosphotyrosine residues on cytokine receptors (e.g., membrane-distal GHR tyrosines) to block STAT access and signaling; it acts as a negative feedback inhibitor of STAT5 downstream of IL-2 and other cytokines, controls NK cell natural cytotoxicity receptor (NCR) signaling to limit NK cell exhaustion, and promotes proteasomal degradation of ATP6V1A (a V-ATPase subunit) to impair lysosomal function in aging T cells, leading to mitochondrial DNA release and inflammaging.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CISH (CIS-1) is a cytokine-inducible SH2-domain protein that functions as a negative-feedback inhibitor across multiple cytokine signaling pathways, dampening STAT activation downstream of receptor engagement [#0, #1]. Mechanistically, it binds tyrosine-phosphorylated membrane-distal residues of the growth hormone receptor cytoplasmic domain to block STAT5b signaling, a mode distinct from the JAK-directed or membrane-proximal actions of other SOCS family members [#0]. The same feedback logic operates across diverse cytokine inputs: CISH is induced by IL-2 to limit IL-2-mediated immune responses [#1], by IL-13 via STAT6 to restrain CCL26/eotaxin-3 production in lung fibroblasts [#3], and constrains STAT3 activity in oral squamous carcinoma cells, where its loss (driven by miR-944) promotes inflammatory cytokine secretion and invasion [#6]. In immune-cell physiology, CISH sets activation thresholds: it negatively regulates both IL-15 and natural cytotoxicity receptor (NCR) signaling in NK cells, and its deletion lowers activation thresholds, reduces TIGIT-associated exhaustion, and enhances antitumor cytotoxicity [#4], while during dendritic-cell development it brakes STAT5-driven progenitor proliferation to permit differentiation [#2]. Beyond cytokine feedback, CISH also acts as a substrate-targeting adaptor for proteasomal degradation: in activated T cells from older adults it targets the V-ATPase subunit ATP6V1A for degradation, impairing lysosomal function and driving export of mitochondrial DNA that contributes to inflammaging [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the molecular mechanism by which CISH inhibits cytokine signaling, distinguishing it from other SOCS proteins by showing it engages phosphorylated receptor tyrosines rather than the kinase directly.\",\n      \"evidence\": \"GST pulldown with tyrosine-phosphorylated GHR fusion proteins and STAT5b reporter assays in COS cells\",\n      \"pmids\": [\"10585430\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single in vitro binding study; no structural model of the SH2-phosphotyrosine interaction\", \"Whether CIS recruits a degradation machinery to GHR not addressed here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected CISH function to IL-2-driven immune signaling in humans by showing promoter variants blunt IL-2-induced CISH expression, implicating it as a tunable feedback node in primary cells.\",\n      \"evidence\": \"Case-control genetic association with functional measurement of CISH induction in PBMCs from variant vs wild-type carriers after IL-2 stimulation\",\n      \"pmids\": [\"20484391\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Downstream signaling consequences of reduced CISH not mechanistically dissected\", \"Does not identify which receptor tyrosines CISH engages in the IL-2 context\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined a developmental role for CISH as a STAT5 brake during dendritic-cell maturation, showing the feedback inhibitor also shapes immune-cell differentiation rather than only acute signaling.\",\n      \"evidence\": \"siRNA knockdown in mouse bone marrow-derived DCs with proliferation, cytokine, surface-marker readouts and in vivo tumor immunotherapy models\",\n      \"pmids\": [\"22002016\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Knockdown only; not validated in conditional knockout\", \"Direct receptor target in DC progenitors not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the STAT-feedback model to IL-13/STAT6 signaling, showing CISH restrains an allergic-inflammation chemokine output in a non-immune stromal cell type.\",\n      \"evidence\": \"Reciprocal siRNA knockdown and overexpression in human lung fibroblasts with CCL26 readout and STAT6 phospho-blotting\",\n      \"pmids\": [\"30197185\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of CISH action on the IL-13 receptor not mapped\", \"Single cell type, single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed CISH is a tumor-suppressive STAT3 brake whose loss via miR-944 drives oncogenic signaling, generalizing its feedback role to STAT3 and to cancer biology.\",\n      \"evidence\": \"Luciferase reporter target validation plus reciprocal gain/loss-of-function with STAT3 phospho-blotting and invasion assays in oral squamous carcinoma cells\",\n      \"pmids\": [\"32961483\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct biochemical link between CISH and STAT3 not resolved\", \"In vitro cell-line evidence only\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified CISH as a regulator of NCR signaling beyond IL-15 in NK cells and validated it as an immunotherapy target by showing deletion enhances cytotoxicity and limits exhaustion.\",\n      \"evidence\": \"NK-specific conditional Cish-knockout mouse with in vitro signaling/cytotoxicity assays, in vivo tumor models, and orthogonal CRISPRi in human NK cells\",\n      \"pmids\": [\"35589278\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Precise NCR receptor phosphotyrosines bound by CISH not mapped\", \"Mechanism linking CISH loss to reduced TIGIT not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-canonical CISH function as a substrate-targeting adaptor driving ATP6V1A degradation, linking CISH to lysosomal failure and mtDNA-driven inflammaging in aged T cells.\",\n      \"evidence\": \"CISH silencing in primary human T cells from older adults with ATP6V1A blotting, lysosomal/amphisome imaging, extracellular mtDNA measurement, and in vivo CD4+ T cell responses\",\n      \"pmids\": [\"37118554\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"E3 ligase/proteasomal machinery CISH recruits to ATP6V1A not identified\", \"Whether SH2 phosphotyrosine binding mediates ATP6V1A targeting unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CISH selects between its phosphotyrosine-receptor feedback role and its substrate-degradation adaptor role, and the structural basis and ubiquitin machinery underlying ATP6V1A targeting, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of CISH bound to any receptor or substrate in the corpus\", \"Identity of the ubiquitin ligase partner not established\", \"Determinants of substrate vs receptor selectivity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3, 4, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GHR\", \"ATP6V1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}