Affinage

IL6ST

Interleukin-6 receptor subunit beta · UniProt P40189

Length
918 aa
Mass
103.5 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1992 High

    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

    PMID:1324910

    Open questions at the time
    • Other cytokines using gp130 not yet identified
    • Intracellular signaling mechanism downstream of OSM-gp130 not addressed
  2. 1993 High

    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

    PMID:8390097

    Open questions at the time
    • Full complement of IL-6 family cytokines using gp130 not yet catalogued
    • Structural basis of homo- vs heterodimerization unknown
  3. 1995 High

    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

    PMID:7530500 PMID:7559603

    Open questions at the time
    • Relative contribution of individual cytoplasmic tyrosines to each pathway not resolved
    • PI3K pathway linkage not yet directly demonstrated
  4. 1998 High

    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

    PMID:9711940 PMID:9716487

    Open questions at the time
    • In vivo tissue-specific requirements for gp130 not yet established
    • Mechanism of SOCS3 selectivity for gp130 versus other receptors unknown
  5. 2001 High

    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

    PMID:11251120 PMID:11412113

    Open questions at the time
    • Structures of heterodimeric complexes (gp130/LIFRβ) not yet solved
    • How membrane anchoring and geometry influence activation unknown
  6. 2003 High

    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

    PMID:12754506 PMID:12891556

    Open questions at the time
    • How SOCS3 discriminates gp130 from structurally similar receptors not resolved
    • Relative contributions of STAT3 vs NF-κB in hepatoprotection not fully dissected
  7. 2005 High

    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

    PMID:15786731

    Open questions at the time
    • Kinase responsible for Ser-782 phosphorylation not identified
    • Relationship between Ser-782 phosphorylation and ubiquitin-dependent degradation pathways unclear
  8. 2008 High

    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

    PMID:18216023 PMID:18467707 PMID:18684959

    Open questions at the time
    • Whether gp130-STAT3 repair functions are universal across epithelia not established
    • Downstream transcriptional targets mediating repair in each tissue not fully defined
  9. 2014 High

    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

    PMID:15607729 PMID:24973212 PMID:30279168

    Open questions at the time
    • Physiological contribution of sgp130-E10 vs. proteolytically shed sgp130 not quantified in vivo
    • Tissue-specific regulation of intronic polyadenylation not characterized
  10. 2020 High

    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

    PMID:31914175 PMID:32207811 PMID:32566365 PMID:33771552

    Open questions at the time
    • Full genotype-phenotype spectrum of IL6ST variants not delineated
    • Structural basis for dominant-negative action of truncated gp130 not resolved at atomic level
  11. 2021 High

    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

    PMID:33769697

    Open questions at the time
    • 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
  12. 2023 High

    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

    PMID:36930708

    Open questions at the time
    • How distinct membrane-proximal geometries translate to differential JAK/STAT activation remains unknown
    • No structures of full-length gp130 including transmembrane and intracellular domains

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 1
Partners
CD109JAK1JAK2KLBNEDD4LSHP2SOCS3STAT3
Complex memberships
CNTF/CNTFRα/gp130/LIFRβ complexIL-6/IL-6Rα/gp130 hexamerLIF/gp130/LIFRβ trimerOSM/gp130/OSMRβ complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 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. Chemical cross-linking, immunoprecipitation with anti-gp130 mAbs, transfection of COS-7 cells with gp130 cDNA, growth inhibition assay The Journal of biological chemistry High 1324910
1993 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. Receptor complex reconstitution, ligand-binding assays, tyrosine phosphorylation assays Science High 8390097
1994 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. Blocking mAb inhibition of proliferation assay, receptor phosphorylation assay European journal of immunology High 8020567
1994 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. Biochemical signaling assays, pathway analysis in hematopoietic cells Stem cells Medium 8075593
1995 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. Co-immunoprecipitation, kinase activation assays in pro-B cell line Blood High 7530500
1995 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. GST pulldown, reciprocal co-immunoprecipitation, phosphopeptide competition assay The Journal of biological chemistry High 7559603
1998 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. Biochemical signaling assays, review of multiple experimental studies The Biochemical journal High 9716487
1998 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. Adenovirus-mediated transfection of WT and DN STAT3 in cardiac myocytes, [3H]leucine incorporation, mRNA analysis Circulation High 9711940
2001 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. X-ray crystallography at 2.4 Å resolution Science High 11251120
2001 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. In vitro reconstitution of soluble receptor complexes, size-exclusion chromatography, protein engineering (hyperactive single-chain hyper-IL-6) Biochemistry High 11412113
2003 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. Socs3-deficient mouse macrophages (genetic knockout), phospho-STAT3 and phospho-STAT1 immunoblotting, transcriptomic analysis Nature immunology High 12754506
2003 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. Cre-loxP conditional knockout (hepatocyte-specific), IL-6/OSM/LPS challenge, STAT3 phosphorylation and gene expression assays, apoptosis analysis Gastroenterology High 12891556
2005 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. In vitro phosphatase assay with purified PP2A, okadaic acid treatment of HepG2 cells, proteasome inhibitor MG115, immunoblotting Molecular and cellular biochemistry High 15786731
2005 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. Recombinant sgp130-Fc inhibition assay of IL-27-induced signaling Biochemical and biophysical research communications Medium 15607729
2005 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. Affinity precipitation with matrix-bound MadA, surface plasmon resonance (SPR) binding assay, STAT3 phosphorylation in HepG2 cells Biochemistry High 16086584
2004 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. LIF stimulation of cultured cardiomyocytes, dominant-negative STAT3 transfection, antisense Wnt5a cDNA, Western blot and mRNA analysis FEBS letters High 15327998
2007 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. In vitro IL-6 stimulation of VSMCs, adenoviral dominant-negative constructs, balloon injury rat model, STAT3 phosphorylation/cyclin D1 immunoblotting, siRNA Circulation research High 17322172
2008 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. Structure-guided mutagenesis, NMR spectroscopy of membrane-proximal domain, cell proliferation inhibition assay, acute phase gene expression in mouse model The Journal of biological chemistry High 18650419
2008 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. Conditional (epithelium-specific) Cre-loxP knockout of Gp130 and Stat3 in mice, naphthalene injury model, dominant-negative STAT3 in vitro migration assay The American journal of pathology High 18467707
2008 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. Astrocyte-specific conditional gp130 KO (GFAP-Cre gp130fl/fl), T. gondii infection model, in vitro parasite growth assay, apoptosis analysis Journal of immunology High 18684959
2008 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. 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 The Journal of biological chemistry High 18216023
2010 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. IL-27p28 transgenic mouse model, cytokine stimulation assays, antibody production measurement Nature immunology High 21057510
2011 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. In vitro signaling assays with recombinant proteins at defined molar ratios, in vivo mouse model with sgp130Fc administration The Journal of biological chemistry High 21990364
2014 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. 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 The Journal of biological chemistry High 24973212
2016 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. Co-immunoprecipitation of IL-23p19 with gp130, immunohistochemistry of patient tissue, STAT3 phosphorylation assays, leukocyte adhesion assays Science signaling Medium 26980441
2018 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. Cell-cell co-culture cluster signaling assay with natural and synthetic membrane-bound IL-6:IL-6R complexes, sgp130 and anti-gp130 antibody blockade Science signaling High 30279168
2018 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. Exosome characterization, macrophage stimulation with cancer-derived exosomes, gp130 inhibitor treatment, STAT3 phosphorylation assay, exosome uptake blockade Frontiers in immunology Medium 29867925
2020 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. Patient genetic analysis, overexpression of mutant GP130 constructs, signaling assays in patient-derived heterozygous leukocytes and fibroblasts The Journal of experimental medicine High 32207811
2020 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. Patient genetic analysis (exome/genome sequencing), signaling assays in patient-derived cells, lentiviral GP130 reconstitution The Journal of experimental medicine High 31914175
2020 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. Seven genetic mouse lines (conditional KO/KI), RNA sequencing, co-immunoprecipitation, imaging flow cytometry, cardiac injury models, AAV gene therapy Circulation High 32600062
2020 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. Patient genetic analysis, transfected cell signaling assays, primary patient-derived cells, genome-edited mouse model, molecular dynamics simulations and structural modeling Bone research High 32566365
2021 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. Myocyte-specific Il6st conditional KO mice, CLP sepsis model, C2C12 myotube IL6ST knockdown, JAK2/STAT3 inhibitors, RNAseq Journal of cachexia, sarcopenia and muscle High 34821076
2021 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. Co-immunoprecipitation, ubiquitination assays, Nedd4l knockout mouse (IMQ model), psoriasis patient tissue analysis, NEDD4L overexpression and knockdown EMBO reports High 33769697
2021 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. Co-immunoprecipitation of CD109 with gp130, CD109 genetic depletion (siRNA/shRNA), STAT3 phosphorylation assay, sphere-forming and tumor xenograft assays JCI insight Medium 33986188
2021 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. Exome/genome sequencing, functional cytokine signaling assays in transfected cells and primary patient cells, molecular dynamics simulations, structural modeling of GP130 cytokine receptor complexes The Journal of allergy and clinical immunology High 33771552
2022 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. 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 Nature metabolism High 35551509
2023 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. Cryo-electron microscopy of five full ectodomain signaling complexes Science advances High 36930708

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. The Biochemical journal 1718 9716487
1993 LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science (New York, N.Y.) 623 8390097
2011 Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. The Journal of clinical investigation 532 21881215
2003 SOCS3 regulates the plasticity of gp130 signaling. Nature immunology 352 12754506
2015 The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. Current opinion in immunology 351 25749511
1997 Signaling mechanisms through gp130: a model of the cytokine system. Cytokine & growth factor reviews 288 9620640
2004 Acquiring signalling specificity from the cytokine receptor gp130. Trends in genetics : TIG 247 14698616
2001 Structure of an extracellular gp130 cytokine receptor signaling complex. Science (New York, N.Y.) 222 11251120
2010 gp130 at the nexus of inflammation, autoimmunity, and cancer. Journal of leukocyte biology 209 20610800
1998 Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes. Circulation 189 9711940
2021 Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting. Journal of cachexia, sarcopenia and muscle 170 34821076
1994 Signal transduction through gp130 that is shared among the receptors for the interleukin 6 related cytokine subfamily. Stem cells (Dayton, Ohio) 168 8075593
2000 Receptor recognition by gp130 cytokines. The EMBO journal 164 10835339
2018 Breast Cancer-Derived Exosomes Alter Macrophage Polarization via gp130/STAT3 Signaling. Frontiers in immunology 159 29867925
2010 A role for IL-27p28 as an antagonist of gp130-mediated signaling. Nature immunology 151 21057510
1992 Interleukin-6 signal transducer gp130 mediates oncostatin M signaling. The Journal of biological chemistry 151 1324910
2000 gp130 Cytokine family and bone cells. Cytokine 150 11023660
2020 gp130 Controls Cardiomyocyte Proliferation and Heart Regeneration. Circulation 146 32600062
1995 Association and activation of Btk and Tec tyrosine kinases by gp130, a signal transducer of the interleukin-6 family of cytokines. Blood 146 7530500
2011 Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor. The Journal of biological chemistry 145 21990364
2007 Survival pathways in hypertrophy and heart failure: the gp130-STAT3 axis. Basic research in cardiology 137 17530315
2007 Survival pathways in hypertrophy and heart failure: the gp130-STAT axis. Basic research in cardiology 137 17918316
2020 Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome. The Journal of experimental medicine 115 32207811
2008 Astrocyte gp130 expression is critical for the control of Toxoplasma encephalitis. Journal of immunology (Baltimore, Md. : 1950) 110 18684959
1996 Gp130, a shared signal transducing receptor component for hematopoietic and neuropoietic cytokines. Journal of neurochemistry 109 8666978
2010 GP130 cytokines and bone remodelling in health and disease. BMB reports 106 20797312
2008 Epigallocatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production. Proceedings of the National Academy of Sciences of the United States of America 106 18796608
2021 A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn's disease. Nature 102 33789339
2004 Predominant expression of the long isoform of GP130-like (GPL) receptor is required for interleukin-31 signaling. European cytokine network 82 15627637
2018 Selective loss of function variants in IL6ST cause Hyper-IgE syndrome with distinct impairments of T-cell phenotype and function. Haematologica 79 30309848
2003 Lack of gp130 expression in hepatocytes promotes liver injury. Gastroenterology 78 12891556
2016 Bazedoxifene as a Novel GP130 Inhibitor for Pancreatic Cancer Therapy. Molecular cancer therapeutics 75 27535971
1999 CSF and serum levels of soluble interleukin-6 receptors (sIL-6R and sgp130), but not of interleukin-6 are altered in multiple sclerosis. Journal of neuroimmunology 70 10505978
2004 Shared cytokine signaling receptors: structural insights from the gp130 system. Advances in protein chemistry 69 15500860
2018 Soluble gp130 prevents interleukin-6 and interleukin-11 cluster signaling but not intracellular autocrine responses. Science signaling 66 30279168
2011 The gp130 receptor cytokine family: regulators of adipocyte development and function. Current pharmaceutical design 64 21375496
2008 GP130-STAT3 regulates epithelial cell migration and is required for repair of the bronchiolar epithelium. The American journal of pathology 61 18467707
2008 Structure-guided optimization of the interleukin-6 trans-signaling antagonist sgp130. The Journal of biological chemistry 59 18650419
1995 Syp associates with gp130 and Janus kinase 2 in response to interleukin-11 in 3T3-L1 mouse preadipocytes. The Journal of biological chemistry 56 7559603
2014 Epithelial gp130/Stat3 functions: an intestinal signaling node in health and disease. Seminars in immunology 54 24434062
2009 Cytokine signalling via gp130 in gastric cancer. Biochimica et biophysica acta 54 19665497
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