IL6ST
The protein encoded by this gene is a signal transducer shared by many cytokines, including interleukin 6 (IL6), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and oncostatin M (OSM). This protein functions as a part of the cytokine receptor complex. The activation of this protein is dependent upon the binding of cytokines to their receptors. vIL6, a protein related to IL6 and encoded by the Kaposi sarcoma-associated herpesvirus, can bypass the interleukin 6 receptor (IL6R) and directly activate this protein. Knockout studies in mice suggested a critical role of the gene encoding this protein in regulating myocyte apoptosis. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq]
Full Name
interleukin 6 signal transducer (gp130, oncostatin M receptor)
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:2261637, PubMed:19915009, 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).
Isoform 2
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).
Biological Process
Ciliary neurotrophic factor-mediated signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Cytokine-mediated signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Glycogen metabolic processIEA:Ensembl
Interleukin-27-mediated signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Interleukin-6-mediated signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Intestinal epithelial cell developmentManual Assertion Based On ExperimentIDA:UniProtKB
Leukemia inhibitory factor signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of apoptotic processManual Assertion Based On ExperimentTAS:BHF-UCL
Negative regulation of interleukin-6-mediated signaling pathwayIDA:BHF-UCL
Negative regulation of neuron apoptotic processManual Assertion Based On ExperimentIMP:UniProtKB
Oncostatin-M-mediated signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of acute inflammatory response1 PublicationIC:BHF-UCL
Positive regulation of adaptive immune response1 PublicationIC:BHF-UCL
Positive regulation of astrocyte differentiationIEA:Ensembl
Positive regulation of cardiac muscle hypertrophyManual Assertion Based On ExperimentTAS:BHF-UCL
Positive regulation of cell population proliferationManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of Notch signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of osteoblast differentiationManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of platelet aggregationManual Assertion Based On ExperimentTAS:ARUK-UCL
Positive regulation of T cell proliferationManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of tyrosine phosphorylation of STAT proteinManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of vascular endothelial growth factor productionManual Assertion Based On ExperimentTAS:BHF-UCL
Response to cytokineManual Assertion Based On ExperimentIDA:BHF-UCL
Cellular Location
Isoform 1: Cell membrane
Isoform 2: Secreted
Involvement in disease
Hyper-IgE recurrent infection syndrome 4, autosomal recessive (HIES4):
An immunologic disorder characterized by recurrent infections, mainly affecting the respiratory tract, skin and eye, and skeletal abnormalities including craniosynostosis and scoliosis. Immunologic workup shows increased serum IgE, intermittent eosinophilia, impaired development of certain B- and T-cell populations, as well as impaired acute-phase response. Disease onset is in early childhood.
Topology
Extracellular: 23-619
Helical: 620-641
Cytoplasmic: 642-918
PTM
Phosphorylation of Ser-782 down-regulates cell surface expression.
Heavily N-glycosylated (PubMed:11098061, PubMed:16335952, PubMed:19159218, PubMed:19139490, PubMed:11251120).
Glycosylation is required for protein stability and localization in plasma membrane but not for ligand binding (PubMed:19915009).
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Datasheet