{"gene":"IL6ST","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1992,"finding":"gp130 (IL6ST) was identified as the signal-transducing receptor (150-kDa binding protein) for oncostatin M (OSM); anti-gp130 monoclonal antibodies blocked OSM binding and biological activity, and COS-7 cells transfected with full-length gp130 cDNA showed increased OSM binding.","method":"Chemical cross-linking, immunoprecipitation with anti-gp130 mAbs, transfection of COS-7 cells with gp130 cDNA, growth inhibition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (cross-linking, IP, transfection, functional assay) in a single study","pmids":["1324910"],"is_preprint":false},{"year":1993,"finding":"The CNTF receptor complex comprises CNTFRα, LIFRβ, and gp130; CNTF and LIF signaling depends on heterodimerization of gp130 with LIFRβ (unlike IL-6 which requires gp130 homodimerization), and ligand-induced association of these receptor components results in tyrosine phosphorylation of receptor subunits.","method":"Receptor complex reconstitution, ligand-binding assays, tyrosine phosphorylation assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution of tripartite receptor complex with functional validation, highly cited foundational study","pmids":["8390097"],"is_preprint":false},{"year":1994,"finding":"gp130 is a shared signal-transducing subunit for IL-11, alongside IL-6, LIF, OSM, and CNTF; an anti-gp130 blocking mAb inhibited IL-11-triggered cell proliferation, and IL-11 stimulation induced gp130 phosphorylation.","method":"Blocking mAb inhibition of proliferation assay, receptor phosphorylation assay","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional and biochemical evidence; replicated across multiple cytokines in the family","pmids":["8020567"],"is_preprint":false},{"year":1994,"finding":"gp130 activates a Ras-independent signal transduction pathway via Jak tyrosine kinase family members and STAT proteins; additionally, ligand-induced homo- or heterodimerization of gp130 is required to activate Jak kinases.","method":"Biochemical signaling assays, pathway analysis in hematopoietic cells","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 — pathway characterization, reviewed with functional data, but primarily a review synthesizing experimental findings","pmids":["8075593"],"is_preprint":false},{"year":1995,"finding":"Btk and Tec tyrosine kinases are constitutively associated with gp130 and are activated upon IL-6 plus soluble IL-6Rα stimulation; Btk activation was specific to gp130 signaling (not IL-3 or G-CSF) in pro-B cells.","method":"Co-immunoprecipitation, kinase activation assays in pro-B cell line","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with functional kinase activation assays demonstrating specificity","pmids":["7530500"],"is_preprint":false},{"year":1995,"finding":"SHP2 (Syp) associates with gp130 and JAK2 in response to IL-11 stimulation; the C-terminal SH2 domain of SHP2 mediates the interaction and a YXXV phosphopeptide from gp130 competed with this association.","method":"GST pulldown, reciprocal co-immunoprecipitation, phosphopeptide competition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and GST pulldown with peptide competition, multiple orthogonal methods","pmids":["7559603"],"is_preprint":false},{"year":1998,"finding":"gp130 activates the JAK/STAT pathway (JAK1, JAK2, Tyk2; STAT1, STAT3), the SHP2/Ras-MAPK pathway, and PI3K pathways; activated STATs dimerize, translocate to the nucleus, and bind enhancer elements to activate transcription; SOCS proteins, tyrosine phosphatases, and PIAS act as feedback inhibitors of gp130 signaling.","method":"Biochemical signaling assays, review of multiple experimental studies","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 — synthesis of extensive experimental literature with >1700 citations; multiple orthogonal methods across many labs","pmids":["9716487"],"is_preprint":false},{"year":1998,"finding":"The STAT3-dependent signaling pathway downstream of gp130 promotes cardiac myocyte hypertrophy; dominant-negative STAT3 attenuated LIF-induced hypertrophic responses (c-fos and ANF mRNA, protein synthesis), while wild-type STAT3 augmented them, without affecting MAPK activity.","method":"Adenovirus-mediated transfection of WT and DN STAT3 in cardiac myocytes, [3H]leucine incorporation, mRNA analysis","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1-2 — gain- and loss-of-function with adenoviral dominant-negative construct, multiple functional readouts","pmids":["9711940"],"is_preprint":false},{"year":2001,"finding":"The crystal structure (2.4 Å) of viral IL-6 bound to the extracellular domain of human gp130 revealed that two ligand-receptor complexes are cross-linked into a tetramer through direct interactions between the immunoglobulin domain of gp130 (D1/IGD) and site III of viral IL-6, which is necessary for receptor activation.","method":"X-ray crystallography at 2.4 Å resolution","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with functional validation of site III interactions","pmids":["11251120"],"is_preprint":false},{"year":2001,"finding":"Reconstitution of soluble IL-6/IL-6Rα/gp130 complexes showed that the cytokine-binding homology region (CHR, D2D3) of gp130 forms a trimeric 'recognition' complex with IL-6 and IL-6Rα, while addition of the Ig-like domain (D1/IGD) shifts the complex to a hexameric 'activation' complex; the gp130 IGD is recruited by site III of the cytokine.","method":"In vitro reconstitution of soluble receptor complexes, size-exclusion chromatography, protein engineering (hyperactive single-chain hyper-IL-6)","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with defined stoichiometry, resolved mechanism of stepwise complex assembly","pmids":["11412113"],"is_preprint":false},{"year":2003,"finding":"SOCS3 specifically regulates gp130/IL-6 signaling (not IL-10 signaling); Socs3-deficient macrophages showed prolonged STAT3 phosphorylation after IL-6 stimulation and an expanded transcriptional response dominated by STAT1-mediated IFN-regulated genes, demonstrating that SOCS3 controls the quality (STAT1/STAT3 balance) of the gp130 response.","method":"Socs3-deficient mouse macrophages (genetic knockout), phospho-STAT3 and phospho-STAT1 immunoblotting, transcriptomic analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined molecular mechanism and multiple readouts, replicated across cytokines","pmids":["12754506"],"is_preprint":false},{"year":2003,"finding":"Hepatocyte-specific deletion of gp130 completely blocked gp130-dependent STAT3 activation and acute phase response gene expression; LPS challenge in gp130-deficient hepatocytes caused acute liver injury with increased hepatocyte apoptosis, elevated TNF-α, and reduced NF-κB activation, demonstrating gp130's hepatocellular protective role.","method":"Cre-loxP conditional knockout (hepatocyte-specific), IL-6/OSM/LPS challenge, STAT3 phosphorylation and gene expression assays, apoptosis analysis","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with tissue-specific deletion, multiple molecular and phenotypic readouts","pmids":["12891556"],"is_preprint":false},{"year":2005,"finding":"PP2A dephosphorylates gp130 at Ser-782; inhibition of PP2A by okadaic acid promoted Ser-782 phosphorylation and subsequent proteasomal degradation of gp130, thereby suppressing IL-6-induced STAT3 activation. PP1 inhibition had no such effect.","method":"In vitro phosphatase assay with purified PP2A, okadaic acid treatment of HepG2 cells, proteasome inhibitor MG115, immunoblotting","journal":"Molecular and cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro phosphatase assay combined with pharmacological inhibitors and proteasome blockade, multiple orthogonal methods","pmids":["15786731"],"is_preprint":false},{"year":2005,"finding":"Soluble gp130 (sgp130) does not inhibit IL-27 signaling, indicating that IL-27 does not bind gp130 with high affinity despite signaling through a receptor complex containing gp130 and WSX-1.","method":"Recombinant sgp130-Fc inhibition assay of IL-27-induced signaling","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assay but single lab, single method","pmids":["15607729"],"is_preprint":false},{"year":2005,"finding":"Madindoline A (MadA) binds specifically and noncovalently to the extracellular domain of gp130 (KD ~288 μM by SPR), inhibiting gp130 homodimerization and IL-6-dependent STAT3 tyrosine phosphorylation; the HFI moiety alone is insufficient for binding.","method":"Affinity precipitation with matrix-bound MadA, surface plasmon resonance (SPR) binding assay, STAT3 phosphorylation in HepG2 cells","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — SPR binding assay with affinity precipitation and functional cell assay, multiple orthogonal methods","pmids":["16086584"],"is_preprint":false},{"year":2004,"finding":"Signals through gp130 upregulate Wnt5a via STAT3, leading to N-cadherin upregulation and promotion of cadherin-dependent cell adhesion in cardiomyocytes; dominant-negative STAT3 blocked LIF-induced Wnt5a induction, and antisense Wnt5a cDNA inhibited LIF-induced cell adhesion.","method":"LIF stimulation of cultured cardiomyocytes, dominant-negative STAT3 transfection, antisense Wnt5a cDNA, Western blot and mRNA analysis","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with DN-STAT3 and antisense, multiple readouts establishing pathway position","pmids":["15327998"],"is_preprint":false},{"year":2007,"finding":"IL-6/gp130/STAT3 signaling drives vascular smooth muscle cell (VSMC) migration and neointima formation; IL-6 induced gp130 tyrosine phosphorylation, STAT3 recruitment/activation, and cyclin D1 expression; adenovirus-mediated dominant-negative gp130 or STAT3 blocked balloon injury-induced STAT3 phosphorylation, cyclin D1 induction, SMC migration, and neointima formation in rat carotid artery.","method":"In vitro IL-6 stimulation of VSMCs, adenoviral dominant-negative constructs, balloon injury rat model, STAT3 phosphorylation/cyclin D1 immunoblotting, siRNA","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — in vivo and in vitro loss-of-function with multiple molecular and phenotypic readouts","pmids":["17322172"],"is_preprint":false},{"year":2008,"finding":"Structure-guided mutagenesis of the extracellular domain of sgp130 identified amino acid residues that increase binding affinity to the IL-6/sIL-6R complex; triple mutant T102Y/Q113F/N114L showed additive improvement; NMR analysis of the membrane-proximal domain informed a more stable sgp130Fc variant that selectively inhibits IL-6 trans-signaling.","method":"Structure-guided mutagenesis, NMR spectroscopy of membrane-proximal domain, cell proliferation inhibition assay, acute phase gene expression in mouse model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structure plus mutagenesis plus functional in vitro and in vivo assays","pmids":["18650419"],"is_preprint":false},{"year":2008,"finding":"GP130-STAT3 signaling functions cell-autonomously in bronchiolar epithelial cells to promote cell migration required for airway repair; conditional deletion of Gp130 or Stat3 in pulmonary epithelium prevented restoration of epithelial cell shape and numbers after naphthalene injury; dominant-negative STAT3 inhibited epithelial cell migration in vitro.","method":"Conditional (epithelium-specific) Cre-loxP knockout of Gp130 and Stat3 in mice, naphthalene injury model, dominant-negative STAT3 in vitro migration assay","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — parallel conditional KOs (Gp130 and Stat3) with phenotypic rescue and in vitro mechanistic assay","pmids":["18467707"],"is_preprint":false},{"year":2008,"finding":"Astrocyte gp130 expression is required for astrocyte survival during Toxoplasma encephalitis; GFAP-Cre-driven gp130 deletion caused loss of astrocytes in inflammatory lesions, impaired parasite containment, and increased apoptosis of non-infected astrocytes stimulated with TNF, despite intact IFN-γ-induced antiparasitic activity.","method":"Astrocyte-specific conditional gp130 KO (GFAP-Cre gp130fl/fl), T. gondii infection model, in vitro parasite growth assay, apoptosis analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with cell-autonomous functional consequence and in vitro mechanistic validation","pmids":["18684959"],"is_preprint":false},{"year":2008,"finding":"Hepatocyte gp130-dependent STAT3 activation (not Ras/MAPK) is required for acute phase gene expression and hepatocyte protection during liver regeneration; gp130-ΔRas mice showed enhanced SOCS3 and delayed proliferation; SOCS3 induction by gp130/STAT3 times DNA synthesis during regeneration.","method":"Hepatocyte-specific signaling-module knock-in mice (gp130-ΔSTAT and gp130-ΔRas), partial hepatectomy model, LPS challenge, SOCS3 analysis, co-stimulation with IL-6 and HGF","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — parallel signaling-module knock-in mice isolating STAT vs. Ras pathways with multiple readouts","pmids":["18216023"],"is_preprint":false},{"year":2010,"finding":"IL-27p28 acts as a natural antagonist of gp130-mediated signaling independently of EBI3; it antagonized cytokine signaling through gp130 (blocking IL-6-mediated IL-17 and IL-10 production) and IL-27p28-transgenic mice had defective germinal center formation and antibody production.","method":"IL-27p28 transgenic mouse model, cytokine stimulation assays, antibody production measurement","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — transgenic mouse model with functional in vivo phenotype and in vitro signaling assays","pmids":["21057510"],"is_preprint":false},{"year":2011,"finding":"Soluble gp130 (sgp130) can inhibit classic IL-6 signaling when the molar ratio of sIL-6R to IL-6 is in excess, by trapping free IL-6 in IL-6·sIL-6R·sgp130 complexes; in vivo, sgp130Fc blocked IL-6 signaling in the colon but not liver/lung, indicating the colon as a major site of IL-6 trans-signaling.","method":"In vitro signaling assays with recombinant proteins at defined molar ratios, in vivo mouse model with sgp130Fc administration","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — mechanistic in vitro reconstitution of inhibition mechanism combined with in vivo organ-specific validation","pmids":["21990364"],"is_preprint":false},{"year":2014,"finding":"Alternative intronic polyadenylation in intron 10 of the gp130 (IL6ST) transcript generates a novel mRNA encoding sgp130-E10, a 70-80 kDa soluble gp130 isoform that binds the IL-6/sIL-6R complex but not IL-6 alone, and specifically inhibits IL-6 trans-signaling.","method":"RNA sequencing and RT-PCR, expression in human PBMCs, recombinant protein production as Fc-fusion, IL-6/sIL-6R binding assay, trans-signaling inhibition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — identification of novel mRNA isoform with biochemical and functional characterization","pmids":["24973212"],"is_preprint":false},{"year":2016,"finding":"Intracellular IL-23p19 associates with the cytokine receptor subunit gp130 and stimulates gp130-dependent STAT3 activation in endothelial cells, promoting ICAM-1/VCAM-1 upregulation and leukocyte transendothelial migration.","method":"Co-immunoprecipitation of IL-23p19 with gp130, immunohistochemistry of patient tissue, STAT3 phosphorylation assays, leukocyte adhesion assays","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP plus functional cell assay in single study; clinical patient tissue corroboration","pmids":["26980441"],"is_preprint":false},{"year":2018,"finding":"Soluble gp130 inhibits IL-6 and IL-11 cluster signaling (where membrane-bound cytokine:receptor complexes on transmitter cells activate gp130 on receiver cells), but does not inhibit intracellular autocrine classic or trans-signaling.","method":"Cell-cell co-culture cluster signaling assay with natural and synthetic membrane-bound IL-6:IL-6R complexes, sgp130 and anti-gp130 antibody blockade","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — mechanistically defined assay distinguishing three modes of gp130 signaling, multiple cytokines tested","pmids":["30279168"],"is_preprint":false},{"year":2018,"finding":"Breast cancer-derived exosomes contain gp130 protein; exosomal gp130 triggers IL-6 secretion from macrophages and activates gp130/STAT3 signaling (including STAT3 phosphorylation), altering macrophage polarization toward a tumor-associated phenotype; these effects were blocked by a gp130 inhibitor or by preventing exosome uptake.","method":"Exosome characterization, macrophage stimulation with cancer-derived exosomes, gp130 inhibitor treatment, STAT3 phosphorylation assay, exosome uptake blockade","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 3 — single study with pharmacological inhibition and multiple functional readouts but mechanism of exosomal gp130 action not fully resolved","pmids":["29867925"],"is_preprint":false},{"year":2020,"finding":"Dominant-negative truncating mutations in IL6ST (encoding GP130) lacking the recycling motif and all four STAT3-recruiting tyrosine residues accumulate at the cell surface and act in a dominant-negative manner, impairing cellular responses to IL-6, IL-11, LIF, and OSM in heterozygous patient leukocytes and fibroblasts, causing autosomal dominant hyper-IgE syndrome.","method":"Patient genetic analysis, overexpression of mutant GP130 constructs, signaling assays in patient-derived heterozygous leukocytes and fibroblasts","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — patient-derived cells with defined molecular mechanism, multiple cytokines tested, multiple independent kindreds","pmids":["32207811"],"is_preprint":false},{"year":2020,"finding":"Complete loss-of-function variants in IL6ST (nonsense and splice variants) abolish signaling by all GP130-dependent cytokines (IL-6, IL-11, IL-27, OSM, LIF); lentiviral reconstitution of GP130 reversed the signaling defect in patient-derived cells, demonstrating that GP130 is the essential common transducer for the entire IL-6 cytokine family.","method":"Patient genetic analysis (exome/genome sequencing), signaling assays in patient-derived cells, lentiviral GP130 reconstitution","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic reconstitution in patient-derived cells across all cytokines tested","pmids":["31914175"],"is_preprint":false},{"year":2020,"finding":"OSM (from macrophages) signals through its receptor complex including gp130 in cardiomyocytes to promote cardiomyocyte proliferation via Src-mediated Yap Y357 phosphorylation independently of the Hippo pathway; gp130 activation is sufficient to promote cardiomyocyte proliferation and heart regeneration; Yap deletion blocked gp130-induced heart regeneration.","method":"Seven genetic mouse lines (conditional KO/KI), RNA sequencing, co-immunoprecipitation, imaging flow cytometry, cardiac injury models, AAV gene therapy","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic models with epistasis analysis, Co-IP, and functional rescue in vivo","pmids":["32600062"],"is_preprint":false},{"year":2020,"finding":"A homozygous IL6ST variant (p.R281Q) causes selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, or CNTF signaling; molecular dynamics simulations suggest the variant increases flexibility of GP130 extracellular membrane-proximal domains, destabilizing hexameric cytokine-receptor complexes while the trimeric LIF-GP130-LIFR complex is spared due to an additional membrane-proximal interaction.","method":"Patient genetic analysis, transfected cell signaling assays, primary patient-derived cells, genome-edited mouse model, molecular dynamics simulations and structural modeling","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 1-2 — human patient variant validated in multiple systems with structural modeling and mouse model","pmids":["32566365"],"is_preprint":false},{"year":2021,"finding":"The gp130/JAK2/STAT3 pathway mediates sepsis-induced skeletal muscle atrophy (ICUAW); IL6ST knockdown in myotubes diminished IL-6-induced STAT3 phosphorylation and myotube atrophy; muscle-specific Il6st knockout mice had attenuated CLP-induced STAT3 phosphorylation, reduced MuRF1 protein, and less muscle weight loss.","method":"Myocyte-specific Il6st conditional KO mice, CLP sepsis model, C2C12 myotube IL6ST knockdown, JAK2/STAT3 inhibitors, RNAseq","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO with pharmacological validation, multiple molecular and phenotypic readouts","pmids":["34821076"],"is_preprint":false},{"year":2021,"finding":"NEDD4L E3 ubiquitin ligase directly interacts with GP130 and mediates Lys-27-linked ubiquitination and proteasomal degradation of GP130, thereby negatively regulating IL-6/GP130/STAT3 signaling and keratinocyte hyperplasia; NEDD4L expression is downregulated in psoriatic epidermis and inversely correlates with GP130 and p-STAT3 levels.","method":"Co-immunoprecipitation, ubiquitination assays, Nedd4l knockout mouse (IMQ model), psoriasis patient tissue analysis, NEDD4L overexpression and knockdown","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with ubiquitination assay, in vivo KO model, and clinical sample validation","pmids":["33769697"],"is_preprint":false},{"year":2021,"finding":"CD109 physically interacts with gp130 to promote IL-6/STAT3 pathway activation in glioblastoma stem cells (GSCs), maintaining stemness and tumorigenicity; genetic depletion of CD109 abolished STAT3 activation, GSC self-renewal, and tumorigenicity.","method":"Co-immunoprecipitation of CD109 with gp130, CD109 genetic depletion (siRNA/shRNA), STAT3 phosphorylation assay, sphere-forming and tumor xenograft assays","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP plus functional KD with multiple readouts in single study","pmids":["33986188"],"is_preprint":false},{"year":2021,"finding":"Functional and structural analysis of recessive HIES-associated IL6ST variants showed that pathogenic missense variants (p.Ala517Pro, p.Asn404Tyr, p.Pro498Leu) increase flexibility of the extracellular membrane-proximal domains of GP130, destabilizing hexameric cytokine-receptor signaling complexes (selective for IL-6, IL-11, and variably OSM/IL-27) while sparing the trimeric LIF-GP130-LIFR complex through an additional membrane-proximal interaction.","method":"Exome/genome sequencing, functional cytokine signaling assays in transfected cells and primary patient cells, molecular dynamics simulations, structural modeling of GP130 cytokine receptor complexes","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1-2 — structural modeling combined with functional assays in primary patient cells, provides mechanistic basis for cytokine selectivity","pmids":["33771552"],"is_preprint":false},{"year":2022,"finding":"β-Klotho (KLB) interacts with and stabilizes GP130 by blocking ubiquitin-dependent lysosomal degradation, facilitating IL-6-evoked STAT3-HIF1α signaling; this promotes glycolytic gene transcription and glucose-stimulated insulin secretion in pancreatic β-cells independent of FGF21.","method":"β-cell-specific Klb KO mice, adenovirus-mediated GP130 restoration, Co-immunoprecipitation of KLB with GP130, ubiquitination assay, STAT3/HIF1α signaling assays, glycolysis and GSIS measurements","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with ubiquitination mechanism, conditional KO, adenoviral rescue, multiple orthogonal methods","pmids":["35551509"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of five gp130-containing signaling complexes (CNTF, CLCF1, LIF, IL-27, IL-6) with full receptor ectodomains revealed that all complexes feature acute bends at both signaling receptors bringing membrane-proximal domains to ~30 Å range but with distinct distances and orientations; CLCF1 engagement of its secretion chaperone CRLF1 was also resolved.","method":"Cryo-electron microscopy of five full ectodomain signaling complexes","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures of five distinct complexes providing comprehensive structural framework","pmids":["36930708"],"is_preprint":false}],"current_model":"IL6ST (gp130) is a shared transmembrane signal-transducing β-receptor subunit that forms homodimeric or heterodimeric (with LIFRβ, OSMRβ, or IL-27Rα) receptor complexes upon binding of IL-6 family cytokines, triggering constitutive JAK1/JAK2/Tyk2 activation and sequential phosphorylation of gp130 cytoplasmic tyrosines, which recruits and activates STAT1/STAT3 (which dimerize and translocate to the nucleus), SHP2/Ras/MAPK, and PI3K/Akt signaling cascades; its activity is negatively regulated by SOCS3 (feedback inhibitor), PP2A-mediated Ser-782 dephosphorylation (preventing proteasomal degradation), and NEDD4L-mediated Lys-27 ubiquitination/lysosomal degradation, while soluble gp130 isoforms generated by alternative splicing or intronic polyadenylation selectively inhibit IL-6 trans-signaling; structural studies show that hexameric activation complexes require recruitment of the gp130 immunoglobulin domain by site III of the cytokine, and cytokine selectivity of pathogenic IL6ST variants is explained by differential destabilization of hexameric versus trimeric receptor assemblies."},"narrative":{"teleology":[{"year":1992,"claim":"Establishing gp130 as a shared signal transducer beyond IL-6: demonstration that gp130 served as the signal-transducing receptor for OSM expanded its role from an IL-6-specific co-receptor to a shared platform for multiple cytokines.","evidence":"Cross-linking, anti-gp130 mAb blocking, and gp130 cDNA transfection in COS-7 cells","pmids":["1324910"],"confidence":"High","gaps":["Other cytokines using gp130 not yet identified","Intracellular signaling mechanism downstream of OSM-gp130 not addressed"]},{"year":1993,"claim":"Defining the combinatorial logic of gp130 receptor complexes: gp130 was shown to heterodimerize with LIFRβ for CNTF/LIF signaling (versus homodimerize for IL-6), establishing that different cytokines achieve specificity through distinct receptor partnerships on a common gp130 platform.","evidence":"Reconstitution of tripartite CNTF receptor complex (CNTFRα/LIFRβ/gp130) with ligand binding and tyrosine phosphorylation assays","pmids":["8390097"],"confidence":"High","gaps":["Full complement of IL-6 family cytokines using gp130 not yet catalogued","Structural basis of homo- vs heterodimerization unknown"]},{"year":1995,"claim":"Mapping the intracellular signaling cascades: JAK/STAT, SHP2/MAPK, and accessory kinase (Btk/Tec) pathways were linked to gp130, with SHP2 recruitment mapped to specific phosphotyrosine motifs on gp130's cytoplasmic tail.","evidence":"Co-IP and GST pulldown of SHP2 with gp130/JAK2, phosphopeptide competition; Co-IP of Btk/Tec with gp130 and kinase activation assays","pmids":["7559603","7530500"],"confidence":"High","gaps":["Relative contribution of individual cytoplasmic tyrosines to each pathway not resolved","PI3K pathway linkage not yet directly demonstrated"]},{"year":1998,"claim":"Building the integrated signaling framework and identifying feedback regulation: comprehensive mapping showed gp130 activates JAK1/JAK2/Tyk2 → STAT1/STAT3, SHP2/Ras/MAPK, and PI3K, with SOCS proteins, phosphatases, and PIAS acting as negative regulators; STAT3 was shown to be the dominant effector driving cardiac hypertrophy downstream of gp130.","evidence":"Synthesis of biochemical signaling studies across multiple cell types; adenoviral dominant-negative STAT3 in cardiac myocytes with hypertrophy readouts","pmids":["9716487","9711940"],"confidence":"High","gaps":["In vivo tissue-specific requirements for gp130 not yet established","Mechanism of SOCS3 selectivity for gp130 versus other receptors unknown"]},{"year":2001,"claim":"Resolving the structural mechanism of receptor activation: crystal structure of viral IL-6/gp130 and reconstitution of soluble complexes revealed that hexameric signaling complexes assemble stepwise — a trimeric recognition complex (CHR domains + cytokine + α-receptor) is converted to a hexameric activation complex when cytokine site III recruits the gp130 immunoglobulin domain.","evidence":"X-ray crystallography at 2.4 Å; in vitro reconstitution with size-exclusion chromatography","pmids":["11251120","11412113"],"confidence":"High","gaps":["Structures of heterodimeric complexes (gp130/LIFRβ) not yet solved","How membrane anchoring and geometry influence activation unknown"]},{"year":2003,"claim":"Defining SOCS3 as the quality controller of gp130 signaling and demonstrating hepatoprotection in vivo: SOCS3 knockout revealed that it specifically regulates gp130 (not IL-10R) and controls the STAT1/STAT3 balance; hepatocyte-specific gp130 deletion showed that gp130-STAT3 is essential for the acute-phase response and protection against endotoxin-induced liver injury.","evidence":"Socs3-deficient macrophages with transcriptomics; hepatocyte-specific gp130 conditional KO with LPS challenge","pmids":["12754506","12891556"],"confidence":"High","gaps":["How SOCS3 discriminates gp130 from structurally similar receptors not resolved","Relative contributions of STAT3 vs NF-κB in hepatoprotection not fully dissected"]},{"year":2005,"claim":"Identifying PP2A-mediated stability control: PP2A was shown to dephosphorylate gp130 Ser-782, preventing proteasomal degradation and thereby sustaining gp130 surface levels and IL-6/STAT3 signaling capacity.","evidence":"In vitro phosphatase assay with purified PP2A, okadaic acid and proteasome inhibitor treatment in HepG2 cells","pmids":["15786731"],"confidence":"High","gaps":["Kinase responsible for Ser-782 phosphorylation not identified","Relationship between Ser-782 phosphorylation and ubiquitin-dependent degradation pathways unclear"]},{"year":2008,"claim":"Demonstrating tissue-specific gp130-STAT3 functions in repair and survival: conditional deletion studies established that gp130-STAT3 is cell-autonomously required for bronchiolar epithelial migration during airway repair, for hepatocyte proliferation timing during liver regeneration (via SOCS3 feedback), and for astrocyte survival during neuroinflammation.","evidence":"Epithelium-specific and astrocyte-specific gp130 conditional KOs in injury models; signaling-module knock-in mice dissecting STAT vs Ras arms","pmids":["18467707","18216023","18684959"],"confidence":"High","gaps":["Whether gp130-STAT3 repair functions are universal across epithelia not established","Downstream transcriptional targets mediating repair in each tissue not fully defined"]},{"year":2014,"claim":"Characterizing soluble gp130 isoforms and trans-signaling selectivity: alternative intronic polyadenylation was shown to generate sgp130-E10, a soluble gp130 isoform that specifically inhibits IL-6 trans-signaling (and cluster signaling) by binding IL-6/sIL-6R but not IL-6 alone; sgp130 does not inhibit IL-27 signaling or intracellular autocrine signaling.","evidence":"RNA-seq and RT-PCR identification of sgp130-E10, recombinant Fc-fusion binding assays, cell-cell co-culture cluster signaling assays with sgp130","pmids":["24973212","30279168","15607729"],"confidence":"High","gaps":["Physiological contribution of sgp130-E10 vs. proteolytically shed sgp130 not quantified in vivo","Tissue-specific regulation of intronic polyadenylation not characterized"]},{"year":2020,"claim":"Linking IL6ST mutations to human disease and revealing the structural basis of cytokine selectivity: dominant-negative truncating variants and complete loss-of-function variants cause hyper-IgE syndrome by abolishing signaling through all gp130-dependent cytokines; hypomorphic missense variants (e.g., R281Q) selectively impair hexameric complex signaling (IL-6, IL-11) while sparing trimeric complexes (LIF) because the latter have an additional membrane-proximal stabilizing interaction.","evidence":"Patient exome/genome sequencing, signaling assays in patient-derived cells, lentiviral GP130 reconstitution, molecular dynamics simulations, genome-edited mouse models","pmids":["32207811","31914175","32566365","33771552"],"confidence":"High","gaps":["Full genotype-phenotype spectrum of IL6ST variants not delineated","Structural basis for dominant-negative action of truncated gp130 not resolved at atomic level"]},{"year":2021,"claim":"Identifying NEDD4L-mediated ubiquitination as a degradation pathway: NEDD4L was shown to directly ubiquitinate GP130 via Lys-27-linked chains, targeting it for lysosomal degradation and negatively regulating IL-6/STAT3 signaling; loss of NEDD4L in psoriatic epidermis elevates GP130 and drives keratinocyte hyperplasia.","evidence":"Co-IP, ubiquitination assays, Nedd4l KO mice in psoriasis model, psoriasis patient tissue analysis","pmids":["33769697"],"confidence":"High","gaps":["Whether NEDD4L targets gp130 in other cell types or disease contexts not established","Interplay between NEDD4L-mediated lysosomal and PP2A/Ser-782-mediated proteasomal degradation not resolved"]},{"year":2023,"claim":"Achieving a comprehensive structural view across multiple cytokine complexes: cryo-EM structures of five gp130-containing signaling assemblies (CNTF, CLCF1, LIF, IL-27, IL-6) revealed that all complexes feature conserved acute bends in both signaling receptors but with distinct inter-receptor distances and orientations, providing a structural framework for understanding signaling specificity.","evidence":"Cryo-EM of full ectodomain complexes for five IL-6-family cytokines","pmids":["36930708"],"confidence":"High","gaps":["How distinct membrane-proximal geometries translate to differential JAK/STAT activation remains unknown","No structures of full-length gp130 including transmembrane and intracellular domains"]},{"year":null,"claim":"How the distinct receptor geometries observed across hexameric and trimeric gp130 complexes encode cytokine-specific intracellular signaling outputs (e.g., STAT3 vs STAT1 balance, pathway duration) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No full-length gp130 structure including intracellular domain and JAK contacts","Mechanism coupling extracellular geometry to differential JAK activation unknown","How degradation pathways (NEDD4L, PP2A/Ser-782) are regulated in a cytokine-specific manner not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,6,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[22,23,25]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,27,30]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[22,23,25]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,6,7,10,16,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,11,21,27,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[27,28,34]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[29]}],"complexes":["IL-6/IL-6Rα/gp130 hexamer","LIF/gp130/LIFRβ trimer","CNTF/CNTFRα/gp130/LIFRβ complex","OSM/gp130/OSMRβ complex"],"partners":["JAK1","JAK2","STAT3","SHP2","SOCS3","NEDD4L","KLB","CD109"],"other_free_text":[]},"mechanistic_narrative":"IL6ST (gp130) is the obligate signal-transducing β-receptor subunit shared by all IL-6 family cytokines — including IL-6, IL-11, OSM, LIF, CNTF, and IL-27 — and is essential for coupling extracellular cytokine engagement to intracellular JAK/STAT, SHP2/Ras/MAPK, and PI3K signaling cascades [PMID:9716487, PMID:31914175]. Upon cytokine binding, gp130 forms homodimeric (IL-6, IL-11) or heterodimeric (with LIFRβ or OSMRβ) complexes whose assembly proceeds through a trimeric recognition intermediate to a hexameric activation complex requiring recruitment of the gp130 immunoglobulin domain by cytokine site III; cryo-EM structures of five distinct gp130-containing complexes show conserved acute bends that position membrane-proximal domains within ~30 Å [PMID:11412113, PMID:11251120, PMID:36930708]. Signaling output — predominantly STAT3 activation driving acute-phase responses, cell survival, proliferation, and migration in hepatocytes, cardiomyocytes, epithelial cells, and immune cells — is negatively regulated by SOCS3-mediated feedback that controls STAT1/STAT3 balance, PP2A dephosphorylation of Ser-782 preventing proteasomal turnover, and NEDD4L-catalyzed Lys-27-linked ubiquitination directing lysosomal degradation [PMID:12754506, PMID:15786731, PMID:33769697]. Loss-of-function and dominant-negative IL6ST mutations cause hyper-IgE syndrome, with cytokine selectivity of pathogenic variants explained by differential destabilization of hexameric versus trimeric receptor assemblies [PMID:32207811, PMID:33771552]."},"prefetch_data":{"uniprot":{"accession":"P40189","full_name":"Interleukin-6 receptor subunit beta","aliases":["CDw130","Interleukin-6 signal transducer","Membrane glycoprotein 130","gp130","Oncostatin-M receptor subunit alpha"],"length_aa":918,"mass_kda":103.5,"function":"Signal-transducing molecule (PubMed:2261637). The receptor systems for IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize IL6ST for initiating signal transmission. Binding of IL6 to IL6R induces IL6ST homodimerization and formation of a high-affinity receptor complex, which activates the intracellular JAK-MAPK and JAK-STAT3 signaling pathways (PubMed:19915009, PubMed:2261637, PubMed:23294003). That causes phosphorylation of IL6ST tyrosine residues which in turn activates STAT3 (PubMed:19915009, PubMed:23294003, PubMed:25731159). In parallel, the IL6 signaling pathway induces the expression of two cytokine receptor signaling inhibitors, SOCS1 and SOCS3, which inhibit JAK and terminate the activity of the IL6 signaling pathway as a negative feedback loop (By similarity). Also activates the yes-associated protein 1 (YAP) and NOTCH pathways to control inflammation-induced epithelial regeneration, independently of STAT3 (By similarity). Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL27RA/WSX1 and CNTFR (PubMed:19386761). Mediates signals which regulate immune response, hematopoiesis, pain control and bone metabolism (By similarity). Has a role in embryonic development (By similarity). Essential for survival of motor and sensory neurons and for differentiation of astrocytes (By similarity). Required for expression of TRPA1 in nociceptive neurons (By similarity). Required for the maintenance of PTH1R expression in the osteoblast lineage and for the stimulation of PTH-induced osteoblast differentiation (By similarity). Required for normal trabecular bone mass and cortical bone composition (By similarity) Binds to the soluble IL6:sIL6R complex (hyper-IL6), thereby blocking IL6 trans-signaling. Inhibits sIL6R-dependent acute phase response (PubMed:11121117, PubMed:21990364, PubMed:30279168). Also blocks IL11 cluster signaling through IL11R (PubMed:30279168)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P40189/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL6ST","classification":"Not Classified","n_dependent_lines":32,"n_total_lines":1208,"dependency_fraction":0.026490066225165563},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL6ST","total_profiled":1310},"omim":[{"mim_id":"620565","title":"IMMUNODEFICIENCY 113 WITH AUTOIMMUNITY AND AUTOINFLAMMATION; IMD113","url":"https://www.omim.org/entry/620565"},{"mim_id":"619752","title":"HYPER-IgE SYNDROME 4A, AUTOSOMAL DOMINANT, WITH RECURRENT INFECTIONS; HIES4A","url":"https://www.omim.org/entry/619752"},{"mim_id":"619751","title":"STUVE-WIEDEMANN SYNDROME 2; STWS2","url":"https://www.omim.org/entry/619751"},{"mim_id":"619750","title":"IMMUNODEFICIENCY 94 WITH AUTOINFLAMMATION AND DYSMORPHIC FACIES; IMD94","url":"https://www.omim.org/entry/619750"},{"mim_id":"618523","title":"HYPER-IgE SYNDROME 4B, AUTOSOMAL RECESSIVE, WITH RECURRENT INFECTIONS; HIES4B","url":"https://www.omim.org/entry/618523"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IL6ST"},"hgnc":{"alias_symbol":["GP130","CD130","sGP130","IL-6RB"],"prev_symbol":[]},"alphafold":{"accession":"P40189","domains":[{"cath_id":"2.60.40.10","chopping":"26-124","consensus_level":"high","plddt":87.3712,"start":26,"end":124},{"cath_id":"2.60.40.10","chopping":"131-219","consensus_level":"medium","plddt":92.9653,"start":131,"end":219},{"cath_id":"2.60.40.10","chopping":"223-321","consensus_level":"medium","plddt":95.4317,"start":223,"end":321},{"cath_id":"2.60.40.10","chopping":"333-514","consensus_level":"medium","plddt":91.9837,"start":333,"end":514},{"cath_id":"2.60.40.10","chopping":"526-618","consensus_level":"high","plddt":92.0988,"start":526,"end":618}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P40189","model_url":"https://alphafold.ebi.ac.uk/files/AF-P40189-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P40189-F1-predicted_aligned_error_v6.png","plddt_mean":74.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL6ST","jax_strain_url":"https://www.jax.org/strain/search?query=IL6ST"},"sequence":{"accession":"P40189","fasta_url":"https://rest.uniprot.org/uniprotkb/P40189.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P40189/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P40189"}},"corpus_meta":[{"pmid":"9716487","id":"PMC_9716487","title":"Interleukin-6-type 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33771552","citation_count":29,"is_preprint":false},{"pmid":"8054483","id":"PMC_8054483","title":"Interactions between oncostatin M and the IL-6 signal transducer, gp130.","date":"1994","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/8054483","citation_count":29,"is_preprint":false},{"pmid":"12421668","id":"PMC_12421668","title":"A structural template for gp130-cytokine signaling assemblies.","date":"2002","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/12421668","citation_count":27,"is_preprint":false},{"pmid":"11412113","id":"PMC_11412113","title":"In vitro reconstitution of recognition and activation complexes between interleukin-6 and gp130.","date":"2001","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11412113","citation_count":27,"is_preprint":false},{"pmid":"24971916","id":"PMC_24971916","title":"The IL-6/IL-6R/sgp130 system and Th17 associated cytokines in patients with 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experimental","url":"https://pubmed.ncbi.nlm.nih.gov/24684823","citation_count":21,"is_preprint":false},{"pmid":"31391340","id":"PMC_31391340","title":"Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma.","date":"2019","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/31391340","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48263,"output_tokens":8918,"usd":0.13928},"stage2":{"model":"claude-opus-4-6","input_tokens":12801,"output_tokens":3862,"usd":0.240833},"total_usd":0.380113,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"gp130 (IL6ST) was identified as the signal-transducing receptor (150-kDa binding protein) for oncostatin M (OSM); anti-gp130 monoclonal antibodies blocked OSM binding and biological activity, and COS-7 cells transfected with full-length gp130 cDNA showed increased OSM binding.\",\n      \"method\": \"Chemical cross-linking, immunoprecipitation with anti-gp130 mAbs, transfection of COS-7 cells with gp130 cDNA, growth inhibition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (cross-linking, IP, transfection, functional assay) in a single study\",\n      \"pmids\": [\"1324910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The CNTF receptor complex comprises CNTFRα, LIFRβ, and gp130; CNTF and LIF signaling depends on heterodimerization of gp130 with LIFRβ (unlike IL-6 which requires gp130 homodimerization), and ligand-induced association of these receptor components results in tyrosine phosphorylation of receptor subunits.\",\n      \"method\": \"Receptor complex reconstitution, ligand-binding assays, tyrosine phosphorylation assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution of tripartite receptor complex with functional validation, highly cited foundational study\",\n      \"pmids\": [\"8390097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"gp130 is a shared signal-transducing subunit for IL-11, alongside IL-6, LIF, OSM, and CNTF; an anti-gp130 blocking mAb inhibited IL-11-triggered cell proliferation, and IL-11 stimulation induced gp130 phosphorylation.\",\n      \"method\": \"Blocking mAb inhibition of proliferation assay, receptor phosphorylation assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional and biochemical evidence; replicated across multiple cytokines in the family\",\n      \"pmids\": [\"8020567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"gp130 activates a Ras-independent signal transduction pathway via Jak tyrosine kinase family members and STAT proteins; additionally, ligand-induced homo- or heterodimerization of gp130 is required to activate Jak kinases.\",\n      \"method\": \"Biochemical signaling assays, pathway analysis in hematopoietic cells\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway characterization, reviewed with functional data, but primarily a review synthesizing experimental findings\",\n      \"pmids\": [\"8075593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Btk and Tec tyrosine kinases are constitutively associated with gp130 and are activated upon IL-6 plus soluble IL-6Rα stimulation; Btk activation was specific to gp130 signaling (not IL-3 or G-CSF) in pro-B cells.\",\n      \"method\": \"Co-immunoprecipitation, kinase activation assays in pro-B cell line\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional kinase activation assays demonstrating specificity\",\n      \"pmids\": [\"7530500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SHP2 (Syp) associates with gp130 and JAK2 in response to IL-11 stimulation; the C-terminal SH2 domain of SHP2 mediates the interaction and a YXXV phosphopeptide from gp130 competed with this association.\",\n      \"method\": \"GST pulldown, reciprocal co-immunoprecipitation, phosphopeptide competition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and GST pulldown with peptide competition, multiple orthogonal methods\",\n      \"pmids\": [\"7559603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"gp130 activates the JAK/STAT pathway (JAK1, JAK2, Tyk2; STAT1, STAT3), the SHP2/Ras-MAPK pathway, and PI3K pathways; activated STATs dimerize, translocate to the nucleus, and bind enhancer elements to activate transcription; SOCS proteins, tyrosine phosphatases, and PIAS act as feedback inhibitors of gp130 signaling.\",\n      \"method\": \"Biochemical signaling assays, review of multiple experimental studies\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — synthesis of extensive experimental literature with >1700 citations; multiple orthogonal methods across many labs\",\n      \"pmids\": [\"9716487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The STAT3-dependent signaling pathway downstream of gp130 promotes cardiac myocyte hypertrophy; dominant-negative STAT3 attenuated LIF-induced hypertrophic responses (c-fos and ANF mRNA, protein synthesis), while wild-type STAT3 augmented them, without affecting MAPK activity.\",\n      \"method\": \"Adenovirus-mediated transfection of WT and DN STAT3 in cardiac myocytes, [3H]leucine incorporation, mRNA analysis\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — gain- and loss-of-function with adenoviral dominant-negative construct, multiple functional readouts\",\n      \"pmids\": [\"9711940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The crystal structure (2.4 Å) of viral IL-6 bound to the extracellular domain of human gp130 revealed that two ligand-receptor complexes are cross-linked into a tetramer through direct interactions between the immunoglobulin domain of gp130 (D1/IGD) and site III of viral IL-6, which is necessary for receptor activation.\",\n      \"method\": \"X-ray crystallography at 2.4 Å resolution\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with functional validation of site III interactions\",\n      \"pmids\": [\"11251120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Reconstitution of soluble IL-6/IL-6Rα/gp130 complexes showed that the cytokine-binding homology region (CHR, D2D3) of gp130 forms a trimeric 'recognition' complex with IL-6 and IL-6Rα, while addition of the Ig-like domain (D1/IGD) shifts the complex to a hexameric 'activation' complex; the gp130 IGD is recruited by site III of the cytokine.\",\n      \"method\": \"In vitro reconstitution of soluble receptor complexes, size-exclusion chromatography, protein engineering (hyperactive single-chain hyper-IL-6)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with defined stoichiometry, resolved mechanism of stepwise complex assembly\",\n      \"pmids\": [\"11412113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SOCS3 specifically regulates gp130/IL-6 signaling (not IL-10 signaling); Socs3-deficient macrophages showed prolonged STAT3 phosphorylation after IL-6 stimulation and an expanded transcriptional response dominated by STAT1-mediated IFN-regulated genes, demonstrating that SOCS3 controls the quality (STAT1/STAT3 balance) of the gp130 response.\",\n      \"method\": \"Socs3-deficient mouse macrophages (genetic knockout), phospho-STAT3 and phospho-STAT1 immunoblotting, transcriptomic analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined molecular mechanism and multiple readouts, replicated across cytokines\",\n      \"pmids\": [\"12754506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Hepatocyte-specific deletion of gp130 completely blocked gp130-dependent STAT3 activation and acute phase response gene expression; LPS challenge in gp130-deficient hepatocytes caused acute liver injury with increased hepatocyte apoptosis, elevated TNF-α, and reduced NF-κB activation, demonstrating gp130's hepatocellular protective role.\",\n      \"method\": \"Cre-loxP conditional knockout (hepatocyte-specific), IL-6/OSM/LPS challenge, STAT3 phosphorylation and gene expression assays, apoptosis analysis\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with tissue-specific deletion, multiple molecular and phenotypic readouts\",\n      \"pmids\": [\"12891556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PP2A dephosphorylates gp130 at Ser-782; inhibition of PP2A by okadaic acid promoted Ser-782 phosphorylation and subsequent proteasomal degradation of gp130, thereby suppressing IL-6-induced STAT3 activation. PP1 inhibition had no such effect.\",\n      \"method\": \"In vitro phosphatase assay with purified PP2A, okadaic acid treatment of HepG2 cells, proteasome inhibitor MG115, immunoblotting\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro phosphatase assay combined with pharmacological inhibitors and proteasome blockade, multiple orthogonal methods\",\n      \"pmids\": [\"15786731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Soluble gp130 (sgp130) does not inhibit IL-27 signaling, indicating that IL-27 does not bind gp130 with high affinity despite signaling through a receptor complex containing gp130 and WSX-1.\",\n      \"method\": \"Recombinant sgp130-Fc inhibition assay of IL-27-induced signaling\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay but single lab, single method\",\n      \"pmids\": [\"15607729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Madindoline A (MadA) binds specifically and noncovalently to the extracellular domain of gp130 (KD ~288 μM by SPR), inhibiting gp130 homodimerization and IL-6-dependent STAT3 tyrosine phosphorylation; the HFI moiety alone is insufficient for binding.\",\n      \"method\": \"Affinity precipitation with matrix-bound MadA, surface plasmon resonance (SPR) binding assay, STAT3 phosphorylation in HepG2 cells\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — SPR binding assay with affinity precipitation and functional cell assay, multiple orthogonal methods\",\n      \"pmids\": [\"16086584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Signals through gp130 upregulate Wnt5a via STAT3, leading to N-cadherin upregulation and promotion of cadherin-dependent cell adhesion in cardiomyocytes; dominant-negative STAT3 blocked LIF-induced Wnt5a induction, and antisense Wnt5a cDNA inhibited LIF-induced cell adhesion.\",\n      \"method\": \"LIF stimulation of cultured cardiomyocytes, dominant-negative STAT3 transfection, antisense Wnt5a cDNA, Western blot and mRNA analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with DN-STAT3 and antisense, multiple readouts establishing pathway position\",\n      \"pmids\": [\"15327998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-6/gp130/STAT3 signaling drives vascular smooth muscle cell (VSMC) migration and neointima formation; IL-6 induced gp130 tyrosine phosphorylation, STAT3 recruitment/activation, and cyclin D1 expression; adenovirus-mediated dominant-negative gp130 or STAT3 blocked balloon injury-induced STAT3 phosphorylation, cyclin D1 induction, SMC migration, and neointima formation in rat carotid artery.\",\n      \"method\": \"In vitro IL-6 stimulation of VSMCs, adenoviral dominant-negative constructs, balloon injury rat model, STAT3 phosphorylation/cyclin D1 immunoblotting, siRNA\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro loss-of-function with multiple molecular and phenotypic readouts\",\n      \"pmids\": [\"17322172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Structure-guided mutagenesis of the extracellular domain of sgp130 identified amino acid residues that increase binding affinity to the IL-6/sIL-6R complex; triple mutant T102Y/Q113F/N114L showed additive improvement; NMR analysis of the membrane-proximal domain informed a more stable sgp130Fc variant that selectively inhibits IL-6 trans-signaling.\",\n      \"method\": \"Structure-guided mutagenesis, NMR spectroscopy of membrane-proximal domain, cell proliferation inhibition assay, acute phase gene expression in mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure plus mutagenesis plus functional in vitro and in vivo assays\",\n      \"pmids\": [\"18650419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GP130-STAT3 signaling functions cell-autonomously in bronchiolar epithelial cells to promote cell migration required for airway repair; conditional deletion of Gp130 or Stat3 in pulmonary epithelium prevented restoration of epithelial cell shape and numbers after naphthalene injury; dominant-negative STAT3 inhibited epithelial cell migration in vitro.\",\n      \"method\": \"Conditional (epithelium-specific) Cre-loxP knockout of Gp130 and Stat3 in mice, naphthalene injury model, dominant-negative STAT3 in vitro migration assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — parallel conditional KOs (Gp130 and Stat3) with phenotypic rescue and in vitro mechanistic assay\",\n      \"pmids\": [\"18467707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Astrocyte gp130 expression is required for astrocyte survival during Toxoplasma encephalitis; GFAP-Cre-driven gp130 deletion caused loss of astrocytes in inflammatory lesions, impaired parasite containment, and increased apoptosis of non-infected astrocytes stimulated with TNF, despite intact IFN-γ-induced antiparasitic activity.\",\n      \"method\": \"Astrocyte-specific conditional gp130 KO (GFAP-Cre gp130fl/fl), T. gondii infection model, in vitro parasite growth assay, apoptosis analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with cell-autonomous functional consequence and in vitro mechanistic validation\",\n      \"pmids\": [\"18684959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Hepatocyte gp130-dependent STAT3 activation (not Ras/MAPK) is required for acute phase gene expression and hepatocyte protection during liver regeneration; gp130-ΔRas mice showed enhanced SOCS3 and delayed proliferation; SOCS3 induction by gp130/STAT3 times DNA synthesis during regeneration.\",\n      \"method\": \"Hepatocyte-specific signaling-module knock-in mice (gp130-ΔSTAT and gp130-ΔRas), partial hepatectomy model, LPS challenge, SOCS3 analysis, co-stimulation with IL-6 and HGF\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — parallel signaling-module knock-in mice isolating STAT vs. Ras pathways with multiple readouts\",\n      \"pmids\": [\"18216023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-27p28 acts as a natural antagonist of gp130-mediated signaling independently of EBI3; it antagonized cytokine signaling through gp130 (blocking IL-6-mediated IL-17 and IL-10 production) and IL-27p28-transgenic mice had defective germinal center formation and antibody production.\",\n      \"method\": \"IL-27p28 transgenic mouse model, cytokine stimulation assays, antibody production measurement\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transgenic mouse model with functional in vivo phenotype and in vitro signaling assays\",\n      \"pmids\": [\"21057510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Soluble gp130 (sgp130) can inhibit classic IL-6 signaling when the molar ratio of sIL-6R to IL-6 is in excess, by trapping free IL-6 in IL-6·sIL-6R·sgp130 complexes; in vivo, sgp130Fc blocked IL-6 signaling in the colon but not liver/lung, indicating the colon as a major site of IL-6 trans-signaling.\",\n      \"method\": \"In vitro signaling assays with recombinant proteins at defined molar ratios, in vivo mouse model with sgp130Fc administration\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic in vitro reconstitution of inhibition mechanism combined with in vivo organ-specific validation\",\n      \"pmids\": [\"21990364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Alternative intronic polyadenylation in intron 10 of the gp130 (IL6ST) transcript generates a novel mRNA encoding sgp130-E10, a 70-80 kDa soluble gp130 isoform that binds the IL-6/sIL-6R complex but not IL-6 alone, and specifically inhibits IL-6 trans-signaling.\",\n      \"method\": \"RNA sequencing and RT-PCR, expression in human PBMCs, recombinant protein production as Fc-fusion, IL-6/sIL-6R binding assay, trans-signaling inhibition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — identification of novel mRNA isoform with biochemical and functional characterization\",\n      \"pmids\": [\"24973212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Intracellular IL-23p19 associates with the cytokine receptor subunit gp130 and stimulates gp130-dependent STAT3 activation in endothelial cells, promoting ICAM-1/VCAM-1 upregulation and leukocyte transendothelial migration.\",\n      \"method\": \"Co-immunoprecipitation of IL-23p19 with gp130, immunohistochemistry of patient tissue, STAT3 phosphorylation assays, leukocyte adhesion assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus functional cell assay in single study; clinical patient tissue corroboration\",\n      \"pmids\": [\"26980441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Soluble gp130 inhibits IL-6 and IL-11 cluster signaling (where membrane-bound cytokine:receptor complexes on transmitter cells activate gp130 on receiver cells), but does not inhibit intracellular autocrine classic or trans-signaling.\",\n      \"method\": \"Cell-cell co-culture cluster signaling assay with natural and synthetic membrane-bound IL-6:IL-6R complexes, sgp130 and anti-gp130 antibody blockade\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistically defined assay distinguishing three modes of gp130 signaling, multiple cytokines tested\",\n      \"pmids\": [\"30279168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Breast cancer-derived exosomes contain gp130 protein; exosomal gp130 triggers IL-6 secretion from macrophages and activates gp130/STAT3 signaling (including STAT3 phosphorylation), altering macrophage polarization toward a tumor-associated phenotype; these effects were blocked by a gp130 inhibitor or by preventing exosome uptake.\",\n      \"method\": \"Exosome characterization, macrophage stimulation with cancer-derived exosomes, gp130 inhibitor treatment, STAT3 phosphorylation assay, exosome uptake blockade\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single study with pharmacological inhibition and multiple functional readouts but mechanism of exosomal gp130 action not fully resolved\",\n      \"pmids\": [\"29867925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Dominant-negative truncating mutations in IL6ST (encoding GP130) lacking the recycling motif and all four STAT3-recruiting tyrosine residues accumulate at the cell surface and act in a dominant-negative manner, impairing cellular responses to IL-6, IL-11, LIF, and OSM in heterozygous patient leukocytes and fibroblasts, causing autosomal dominant hyper-IgE syndrome.\",\n      \"method\": \"Patient genetic analysis, overexpression of mutant GP130 constructs, signaling assays in patient-derived heterozygous leukocytes and fibroblasts\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient-derived cells with defined molecular mechanism, multiple cytokines tested, multiple independent kindreds\",\n      \"pmids\": [\"32207811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Complete loss-of-function variants in IL6ST (nonsense and splice variants) abolish signaling by all GP130-dependent cytokines (IL-6, IL-11, IL-27, OSM, LIF); lentiviral reconstitution of GP130 reversed the signaling defect in patient-derived cells, demonstrating that GP130 is the essential common transducer for the entire IL-6 cytokine family.\",\n      \"method\": \"Patient genetic analysis (exome/genome sequencing), signaling assays in patient-derived cells, lentiviral GP130 reconstitution\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic reconstitution in patient-derived cells across all cytokines tested\",\n      \"pmids\": [\"31914175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OSM (from macrophages) signals through its receptor complex including gp130 in cardiomyocytes to promote cardiomyocyte proliferation via Src-mediated Yap Y357 phosphorylation independently of the Hippo pathway; gp130 activation is sufficient to promote cardiomyocyte proliferation and heart regeneration; Yap deletion blocked gp130-induced heart regeneration.\",\n      \"method\": \"Seven genetic mouse lines (conditional KO/KI), RNA sequencing, co-immunoprecipitation, imaging flow cytometry, cardiac injury models, AAV gene therapy\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic models with epistasis analysis, Co-IP, and functional rescue in vivo\",\n      \"pmids\": [\"32600062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A homozygous IL6ST variant (p.R281Q) causes selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, or CNTF signaling; molecular dynamics simulations suggest the variant increases flexibility of GP130 extracellular membrane-proximal domains, destabilizing hexameric cytokine-receptor complexes while the trimeric LIF-GP130-LIFR complex is spared due to an additional membrane-proximal interaction.\",\n      \"method\": \"Patient genetic analysis, transfected cell signaling assays, primary patient-derived cells, genome-edited mouse model, molecular dynamics simulations and structural modeling\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — human patient variant validated in multiple systems with structural modeling and mouse model\",\n      \"pmids\": [\"32566365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The gp130/JAK2/STAT3 pathway mediates sepsis-induced skeletal muscle atrophy (ICUAW); IL6ST knockdown in myotubes diminished IL-6-induced STAT3 phosphorylation and myotube atrophy; muscle-specific Il6st knockout mice had attenuated CLP-induced STAT3 phosphorylation, reduced MuRF1 protein, and less muscle weight loss.\",\n      \"method\": \"Myocyte-specific Il6st conditional KO mice, CLP sepsis model, C2C12 myotube IL6ST knockdown, JAK2/STAT3 inhibitors, RNAseq\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO with pharmacological validation, multiple molecular and phenotypic readouts\",\n      \"pmids\": [\"34821076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NEDD4L E3 ubiquitin ligase directly interacts with GP130 and mediates Lys-27-linked ubiquitination and proteasomal degradation of GP130, thereby negatively regulating IL-6/GP130/STAT3 signaling and keratinocyte hyperplasia; NEDD4L expression is downregulated in psoriatic epidermis and inversely correlates with GP130 and p-STAT3 levels.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, Nedd4l knockout mouse (IMQ model), psoriasis patient tissue analysis, NEDD4L overexpression and knockdown\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with ubiquitination assay, in vivo KO model, and clinical sample validation\",\n      \"pmids\": [\"33769697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD109 physically interacts with gp130 to promote IL-6/STAT3 pathway activation in glioblastoma stem cells (GSCs), maintaining stemness and tumorigenicity; genetic depletion of CD109 abolished STAT3 activation, GSC self-renewal, and tumorigenicity.\",\n      \"method\": \"Co-immunoprecipitation of CD109 with gp130, CD109 genetic depletion (siRNA/shRNA), STAT3 phosphorylation assay, sphere-forming and tumor xenograft assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus functional KD with multiple readouts in single study\",\n      \"pmids\": [\"33986188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Functional and structural analysis of recessive HIES-associated IL6ST variants showed that pathogenic missense variants (p.Ala517Pro, p.Asn404Tyr, p.Pro498Leu) increase flexibility of the extracellular membrane-proximal domains of GP130, destabilizing hexameric cytokine-receptor signaling complexes (selective for IL-6, IL-11, and variably OSM/IL-27) while sparing the trimeric LIF-GP130-LIFR complex through an additional membrane-proximal interaction.\",\n      \"method\": \"Exome/genome sequencing, functional cytokine signaling assays in transfected cells and primary patient cells, molecular dynamics simulations, structural modeling of GP130 cytokine receptor complexes\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structural modeling combined with functional assays in primary patient cells, provides mechanistic basis for cytokine selectivity\",\n      \"pmids\": [\"33771552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"β-Klotho (KLB) interacts with and stabilizes GP130 by blocking ubiquitin-dependent lysosomal degradation, facilitating IL-6-evoked STAT3-HIF1α signaling; this promotes glycolytic gene transcription and glucose-stimulated insulin secretion in pancreatic β-cells independent of FGF21.\",\n      \"method\": \"β-cell-specific Klb KO mice, adenovirus-mediated GP130 restoration, Co-immunoprecipitation of KLB with GP130, ubiquitination assay, STAT3/HIF1α signaling assays, glycolysis and GSIS measurements\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with ubiquitination mechanism, conditional KO, adenoviral rescue, multiple orthogonal methods\",\n      \"pmids\": [\"35551509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of five gp130-containing signaling complexes (CNTF, CLCF1, LIF, IL-27, IL-6) with full receptor ectodomains revealed that all complexes feature acute bends at both signaling receptors bringing membrane-proximal domains to ~30 Å range but with distinct distances and orientations; CLCF1 engagement of its secretion chaperone CRLF1 was also resolved.\",\n      \"method\": \"Cryo-electron microscopy of five full ectodomain signaling complexes\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures of five distinct complexes providing comprehensive structural framework\",\n      \"pmids\": [\"36930708\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL6ST (gp130) is a shared transmembrane signal-transducing β-receptor subunit that forms homodimeric or heterodimeric (with LIFRβ, OSMRβ, or IL-27Rα) receptor complexes upon binding of IL-6 family cytokines, triggering constitutive JAK1/JAK2/Tyk2 activation and sequential phosphorylation of gp130 cytoplasmic tyrosines, which recruits and activates STAT1/STAT3 (which dimerize and translocate to the nucleus), SHP2/Ras/MAPK, and PI3K/Akt signaling cascades; its activity is negatively regulated by SOCS3 (feedback inhibitor), PP2A-mediated Ser-782 dephosphorylation (preventing proteasomal degradation), and NEDD4L-mediated Lys-27 ubiquitination/lysosomal degradation, while soluble gp130 isoforms generated by alternative splicing or intronic polyadenylation selectively inhibit IL-6 trans-signaling; structural studies show that hexameric activation complexes require recruitment of the gp130 immunoglobulin domain by site III of the cytokine, and cytokine selectivity of pathogenic IL6ST variants is explained by differential destabilization of hexameric versus trimeric receptor assemblies.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL6ST (gp130) is the obligate signal-transducing β-receptor subunit shared by all IL-6 family cytokines — including IL-6, IL-11, OSM, LIF, CNTF, and IL-27 — and is essential for coupling extracellular cytokine engagement to intracellular JAK/STAT, SHP2/Ras/MAPK, and PI3K signaling cascades [PMID:9716487, PMID:31914175]. Upon cytokine binding, gp130 forms homodimeric (IL-6, IL-11) or heterodimeric (with LIFRβ or OSMRβ) complexes whose assembly proceeds through a trimeric recognition intermediate to a hexameric activation complex requiring recruitment of the gp130 immunoglobulin domain by cytokine site III; cryo-EM structures of five distinct gp130-containing complexes show conserved acute bends that position membrane-proximal domains within ~30 Å [PMID:11412113, PMID:11251120, PMID:36930708]. Signaling output — predominantly STAT3 activation driving acute-phase responses, cell survival, proliferation, and migration in hepatocytes, cardiomyocytes, epithelial cells, and immune cells — is negatively regulated by SOCS3-mediated feedback that controls STAT1/STAT3 balance, PP2A dephosphorylation of Ser-782 preventing proteasomal turnover, and NEDD4L-catalyzed Lys-27-linked ubiquitination directing lysosomal degradation [PMID:12754506, PMID:15786731, PMID:33769697]. Loss-of-function and dominant-negative IL6ST mutations cause hyper-IgE syndrome, with cytokine selectivity of pathogenic variants explained by differential destabilization of hexameric versus trimeric receptor assemblies [PMID:32207811, PMID:33771552].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing gp130 as a shared signal transducer beyond IL-6: demonstration that gp130 served as the signal-transducing receptor for OSM expanded its role from an IL-6-specific co-receptor to a shared platform for multiple cytokines.\",\n      \"evidence\": \"Cross-linking, anti-gp130 mAb blocking, and gp130 cDNA transfection in COS-7 cells\",\n      \"pmids\": [\"1324910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other cytokines using gp130 not yet identified\", \"Intracellular signaling mechanism downstream of OSM-gp130 not addressed\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Defining the combinatorial logic of gp130 receptor complexes: gp130 was shown to heterodimerize with LIFRβ for CNTF/LIF signaling (versus homodimerize for IL-6), establishing that different cytokines achieve specificity through distinct receptor partnerships on a common gp130 platform.\",\n      \"evidence\": \"Reconstitution of tripartite CNTF receptor complex (CNTFRα/LIFRβ/gp130) with ligand binding and tyrosine phosphorylation assays\",\n      \"pmids\": [\"8390097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full complement of IL-6 family cytokines using gp130 not yet catalogued\", \"Structural basis of homo- vs heterodimerization unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Mapping the intracellular signaling cascades: JAK/STAT, SHP2/MAPK, and accessory kinase (Btk/Tec) pathways were linked to gp130, with SHP2 recruitment mapped to specific phosphotyrosine motifs on gp130's cytoplasmic tail.\",\n      \"evidence\": \"Co-IP and GST pulldown of SHP2 with gp130/JAK2, phosphopeptide competition; Co-IP of Btk/Tec with gp130 and kinase activation assays\",\n      \"pmids\": [\"7559603\", \"7530500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of individual cytoplasmic tyrosines to each pathway not resolved\", \"PI3K pathway linkage not yet directly demonstrated\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Building the integrated signaling framework and identifying feedback regulation: comprehensive mapping showed gp130 activates JAK1/JAK2/Tyk2 → STAT1/STAT3, SHP2/Ras/MAPK, and PI3K, with SOCS proteins, phosphatases, and PIAS acting as negative regulators; STAT3 was shown to be the dominant effector driving cardiac hypertrophy downstream of gp130.\",\n      \"evidence\": \"Synthesis of biochemical signaling studies across multiple cell types; adenoviral dominant-negative STAT3 in cardiac myocytes with hypertrophy readouts\",\n      \"pmids\": [\"9716487\", \"9711940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo tissue-specific requirements for gp130 not yet established\", \"Mechanism of SOCS3 selectivity for gp130 versus other receptors unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolving the structural mechanism of receptor activation: crystal structure of viral IL-6/gp130 and reconstitution of soluble complexes revealed that hexameric signaling complexes assemble stepwise — a trimeric recognition complex (CHR domains + cytokine + α-receptor) is converted to a hexameric activation complex when cytokine site III recruits the gp130 immunoglobulin domain.\",\n      \"evidence\": \"X-ray crystallography at 2.4 Å; in vitro reconstitution with size-exclusion chromatography\",\n      \"pmids\": [\"11251120\", \"11412113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of heterodimeric complexes (gp130/LIFRβ) not yet solved\", \"How membrane anchoring and geometry influence activation unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defining SOCS3 as the quality controller of gp130 signaling and demonstrating hepatoprotection in vivo: SOCS3 knockout revealed that it specifically regulates gp130 (not IL-10R) and controls the STAT1/STAT3 balance; hepatocyte-specific gp130 deletion showed that gp130-STAT3 is essential for the acute-phase response and protection against endotoxin-induced liver injury.\",\n      \"evidence\": \"Socs3-deficient macrophages with transcriptomics; hepatocyte-specific gp130 conditional KO with LPS challenge\",\n      \"pmids\": [\"12754506\", \"12891556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SOCS3 discriminates gp130 from structurally similar receptors not resolved\", \"Relative contributions of STAT3 vs NF-κB in hepatoprotection not fully dissected\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying PP2A-mediated stability control: PP2A was shown to dephosphorylate gp130 Ser-782, preventing proteasomal degradation and thereby sustaining gp130 surface levels and IL-6/STAT3 signaling capacity.\",\n      \"evidence\": \"In vitro phosphatase assay with purified PP2A, okadaic acid and proteasome inhibitor treatment in HepG2 cells\",\n      \"pmids\": [\"15786731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for Ser-782 phosphorylation not identified\", \"Relationship between Ser-782 phosphorylation and ubiquitin-dependent degradation pathways unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating tissue-specific gp130-STAT3 functions in repair and survival: conditional deletion studies established that gp130-STAT3 is cell-autonomously required for bronchiolar epithelial migration during airway repair, for hepatocyte proliferation timing during liver regeneration (via SOCS3 feedback), and for astrocyte survival during neuroinflammation.\",\n      \"evidence\": \"Epithelium-specific and astrocyte-specific gp130 conditional KOs in injury models; signaling-module knock-in mice dissecting STAT vs Ras arms\",\n      \"pmids\": [\"18467707\", \"18216023\", \"18684959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether gp130-STAT3 repair functions are universal across epithelia not established\", \"Downstream transcriptional targets mediating repair in each tissue not fully defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Characterizing soluble gp130 isoforms and trans-signaling selectivity: alternative intronic polyadenylation was shown to generate sgp130-E10, a soluble gp130 isoform that specifically inhibits IL-6 trans-signaling (and cluster signaling) by binding IL-6/sIL-6R but not IL-6 alone; sgp130 does not inhibit IL-27 signaling or intracellular autocrine signaling.\",\n      \"evidence\": \"RNA-seq and RT-PCR identification of sgp130-E10, recombinant Fc-fusion binding assays, cell-cell co-culture cluster signaling assays with sgp130\",\n      \"pmids\": [\"24973212\", \"30279168\", \"15607729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contribution of sgp130-E10 vs. proteolytically shed sgp130 not quantified in vivo\", \"Tissue-specific regulation of intronic polyadenylation not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linking IL6ST mutations to human disease and revealing the structural basis of cytokine selectivity: dominant-negative truncating variants and complete loss-of-function variants cause hyper-IgE syndrome by abolishing signaling through all gp130-dependent cytokines; hypomorphic missense variants (e.g., R281Q) selectively impair hexameric complex signaling (IL-6, IL-11) while sparing trimeric complexes (LIF) because the latter have an additional membrane-proximal stabilizing interaction.\",\n      \"evidence\": \"Patient exome/genome sequencing, signaling assays in patient-derived cells, lentiviral GP130 reconstitution, molecular dynamics simulations, genome-edited mouse models\",\n      \"pmids\": [\"32207811\", \"31914175\", \"32566365\", \"33771552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full genotype-phenotype spectrum of IL6ST variants not delineated\", \"Structural basis for dominant-negative action of truncated gp130 not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying NEDD4L-mediated ubiquitination as a degradation pathway: NEDD4L was shown to directly ubiquitinate GP130 via Lys-27-linked chains, targeting it for lysosomal degradation and negatively regulating IL-6/STAT3 signaling; loss of NEDD4L in psoriatic epidermis elevates GP130 and drives keratinocyte hyperplasia.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, Nedd4l KO mice in psoriasis model, psoriasis patient tissue analysis\",\n      \"pmids\": [\"33769697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NEDD4L targets gp130 in other cell types or disease contexts not established\", \"Interplay between NEDD4L-mediated lysosomal and PP2A/Ser-782-mediated proteasomal degradation not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Achieving a comprehensive structural view across multiple cytokine complexes: cryo-EM structures of five gp130-containing signaling assemblies (CNTF, CLCF1, LIF, IL-27, IL-6) revealed that all complexes feature conserved acute bends in both signaling receptors but with distinct inter-receptor distances and orientations, providing a structural framework for understanding signaling specificity.\",\n      \"evidence\": \"Cryo-EM of full ectodomain complexes for five IL-6-family cytokines\",\n      \"pmids\": [\"36930708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How distinct membrane-proximal geometries translate to differential JAK/STAT activation remains unknown\", \"No structures of full-length gp130 including transmembrane and intracellular domains\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct receptor geometries observed across hexameric and trimeric gp130 complexes encode cytokine-specific intracellular signaling outputs (e.g., STAT3 vs STAT1 balance, pathway duration) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length gp130 structure including intracellular domain and JAK contacts\", \"Mechanism coupling extracellular geometry to differential JAK activation unknown\", \"How degradation pathways (NEDD4L, PP2A/Ser-782) are regulated in a cytokine-specific manner not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 6, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [22, 23, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 27, 30]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [22, 23, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 6, 7, 10, 16, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 11, 21, 27, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [27, 28, 34]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"complexes\": [\n      \"IL-6/IL-6Rα/gp130 hexamer\",\n      \"LIF/gp130/LIFRβ trimer\",\n      \"CNTF/CNTFRα/gp130/LIFRβ complex\",\n      \"OSM/gp130/OSMRβ complex\"\n    ],\n    \"partners\": [\n      \"JAK1\",\n      \"JAK2\",\n      \"STAT3\",\n      \"SHP2\",\n      \"SOCS3\",\n      \"NEDD4L\",\n      \"KLB\",\n      \"CD109\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}