UniProt functional annotation for P40189



	UniProt functional annotation for P40189

UniProt code: P40189.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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 activate 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). 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). {ECO:0000250|UniProtKB:Q00560, ECO:0000269|PubMed:19915009, ECO:0000269|PubMed:2261637, ECO:0000269|PubMed:23294003, ECO:0000269|PubMed:25731159, ECO:0000269|PubMed:28747427, ECO:0000269|PubMed:30309848}.

Function: [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). {ECO:0000269|PubMed:11121117, ECO:0000269|PubMed:21990364, ECO:0000269|PubMed:30279168}.

Subunit: Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; associates with the complex IL6:IL6R but does not interact with IL6 (PubMed:12829785, PubMed:2261637). Forms heterodimers composed of LIFR and IL6ST (type I OSM receptor) which are activated by LIF and OSM (PubMed:8999038). Also forms heterodimers composed of OSMR and IL6ST (type II receptor) which are activated by OSM but not by LIF (PubMed:8999038). Interacts with HCK (PubMed:9406996). Interacts with INPP5D/SHIP1 (By similarity). Interacts with SRC and YES (PubMed:25731159). {ECO:0000250|UniProtKB:Q00560, ECO:0000269|PubMed:12829785, ECO:0000269|PubMed:14527405, ECO:0000269|PubMed:2261637, ECO:0000269|PubMed:25731159, ECO:0000269|PubMed:8999038, ECO:0000269|PubMed:9406996}.

Subunit: (Microbial infection) The homodimer binds two molecules of herpes virus 8/HHV-8 protein vIL-6. {ECO:0000269|PubMed:11238858, ECO:0000269|PubMed:11251120}.

Subcellular location: [Isoform 1]: Cell membrane {ECO:0000269|PubMed:19915009}; Single-pass type I membrane protein {ECO:0000255}.

Subcellular location: [Isoform 2]: Secreted {ECO:0000269|PubMed:24629561}.

Tissue specificity: Found in all the tissues and cell lines examined (PubMed:2261637). Expression not restricted to IL6 responsive cells (PubMed:2261637). {ECO:0000269|PubMed:2261637}.

Tissue specificity: [Isoform 2]: Expressed in blood serum (at protein level) (PubMed:24629561). {ECO:0000269|PubMed:24629561}.

Induction: LIF and OSM activate the type I OSM receptor while only OSM can activate the type II OSM receptor. {ECO:0000269|PubMed:8999038}.

Domain: The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.

Domain: The box 1 motif is required for JAK interaction and/or activation.

Ptm: Phosphorylation of Ser-782 down-regulates cell surface expression. {ECO:0000269|PubMed:10811661}.

Ptm: 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). {ECO:0000269|PubMed:11098061, ECO:0000269|PubMed:11251120, ECO:0000269|PubMed:16335952, ECO:0000269|PubMed:19139490, ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19915009}.

Disease: Hyper-IgE recurrent infection syndrome 4, autosomal recessive (HIES4) [MIM:618523]: 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. {ECO:0000269|PubMed:28747427, ECO:0000269|PubMed:30309848}. Note=The disease is caused by variants affecting the gene represented in this entry.

Biotechnology: Two extracellular parts of IL6ST/gp130 linked to the Fc- portions of a human IgG1 antibody (sgp130Fc) inhibit IL6 trans- signaling by the IL6:IL6R complex and has no affinity of IL6 or IL6R alone (PubMed:11121117, PubMed:21990364, PubMed:30279168). Also blocks IL11 cluster signaling through IL11R (PubMed:30279168, PubMed:26876177). {ECO:0000269|PubMed:11121117, ECO:0000269|PubMed:21990364, ECO:0000269|PubMed:26876177, ECO:0000269|PubMed:30279168}.

Similarity: Belongs to the type I cytokine receptor family. Type 2 subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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 activate 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). 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). {ECO:0000250\|UniProtKB:Q00560, ECO:0000269\|PubMed:19915009, ECO:0000269\|PubMed:2261637, ECO:0000269\|PubMed:23294003, ECO:0000269\|PubMed:25731159, ECO:0000269\|PubMed:28747427, ECO:0000269\|PubMed:30309848}.



Function:		[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). {ECO:0000269\|PubMed:11121117, ECO:0000269\|PubMed:21990364, ECO:0000269\|PubMed:30279168}.


Subunit:		Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; associates with the complex IL6:IL6R but does not interact with IL6 (PubMed:12829785, PubMed:2261637). Forms heterodimers composed of LIFR and IL6ST (type I OSM receptor) which are activated by LIF and OSM (PubMed:8999038). Also forms heterodimers composed of OSMR and IL6ST (type II receptor) which are activated by OSM but not by LIF (PubMed:8999038). Interacts with HCK (PubMed:9406996). Interacts with INPP5D/SHIP1 (By similarity). Interacts with SRC and YES (PubMed:25731159). {ECO:0000250\|UniProtKB:Q00560, ECO:0000269\|PubMed:12829785, ECO:0000269\|PubMed:14527405, ECO:0000269\|PubMed:2261637, ECO:0000269\|PubMed:25731159, ECO:0000269\|PubMed:8999038, ECO:0000269\|PubMed:9406996}.
Subunit:		(Microbial infection) The homodimer binds two molecules of herpes virus 8/HHV-8 protein vIL-6. {ECO:0000269\|PubMed:11238858, ECO:0000269\|PubMed:11251120}.
Subcellular location:		[Isoform 1]: Cell membrane {ECO:0000269\|PubMed:19915009}; Single-pass type I membrane protein {ECO:0000255}.
Subcellular location:		[Isoform 2]: Secreted {ECO:0000269\|PubMed:24629561}.
Tissue specificity:		Found in all the tissues and cell lines examined (PubMed:2261637). Expression not restricted to IL6 responsive cells (PubMed:2261637). {ECO:0000269\|PubMed:2261637}.
Tissue specificity:		[Isoform 2]: Expressed in blood serum (at protein level) (PubMed:24629561). {ECO:0000269\|PubMed:24629561}.
Induction:		LIF and OSM activate the type I OSM receptor while only OSM can activate the type II OSM receptor. {ECO:0000269\|PubMed:8999038}.
Domain:		The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.
Domain:		The box 1 motif is required for JAK interaction and/or activation.
Ptm:		Phosphorylation of Ser-782 down-regulates cell surface expression. {ECO:0000269\|PubMed:10811661}.
Ptm:		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). {ECO:0000269\|PubMed:11098061, ECO:0000269\|PubMed:11251120, ECO:0000269\|PubMed:16335952, ECO:0000269\|PubMed:19139490, ECO:0000269\|PubMed:19159218, ECO:0000269\|PubMed:19915009}.
Disease:		Hyper-IgE recurrent infection syndrome 4, autosomal recessive (HIES4) [MIM:618523]: 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. {ECO:0000269\|PubMed:28747427, ECO:0000269\|PubMed:30309848}. Note=The disease is caused by variants affecting the gene represented in this entry.
Biotechnology:		Two extracellular parts of IL6ST/gp130 linked to the Fc- portions of a human IgG1 antibody (sgp130Fc) inhibit IL6 trans- signaling by the IL6:IL6R complex and has no affinity of IL6 or IL6R alone (PubMed:11121117, PubMed:21990364, PubMed:30279168). Also blocks IL11 cluster signaling through IL11R (PubMed:30279168, PubMed:26876177). {ECO:0000269\|PubMed:11121117, ECO:0000269\|PubMed:21990364, ECO:0000269\|PubMed:26876177, ECO:0000269\|PubMed:30279168}.
Similarity:		Belongs to the type I cytokine receptor family. Type 2 subfamily. {ECO:0000305}.