UniProt functional annotation for Q00560



	UniProt functional annotation for Q00560

UniProt code: Q00560.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Signal-transducing molecule (PubMed:1602143). 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:1602143, PubMed:10661409). That causes phosphorylation of IL6ST tyrosine residues which in turn activates STAT3 (PubMed:10661409). 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 (PubMed:9202125). Also activates the yes-associated protein 1 (YAP) and NOTCH pathways to control inflammation-induced epithelial regeneration, independently of STAT3 (PubMed:25731159). Mediates signals which regulate immune response, hematopoiesis, pain control and bone metabolism (PubMed:10661409, PubMed:26255596, PubMed:25057188, PubMed:8552649). Has a role in embryonic development (PubMed:10661409). Essential for survival of motor and sensory neurons and for differentiation of astrocytes (PubMed:10377352). Required for expression of TRPA1 in nociceptive neurons (PubMed:25057188). Required for the maintenance of PTH1R expression in the osteoblast lineage and for the stimulation of PTH-induced osteoblast differentiation (PubMed:25228504). Required for normal trabecular bone mass and cortical bone composition (PubMed:24339143, PubMed:9348227, PubMed:26255596). {ECO:0000250|UniProtKB:P40189, ECO:0000269|PubMed:10377352, ECO:0000269|PubMed:10661409, ECO:0000269|PubMed:1602143, ECO:0000269|PubMed:24339143, ECO:0000269|PubMed:25057188, ECO:0000269|PubMed:25228504, ECO:0000269|PubMed:25731159, ECO:0000269|PubMed:26255596, ECO:0000269|PubMed:8552649, ECO:0000269|PubMed:9202125, ECO:0000269|PubMed:9348227}.

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 (By similarity). Forms heterodimers composed of LIFR and IL6ST (type I OSM receptor) which are activated by LIF and OSM. Also forms heterodimers composed of OSMR and IL6ST (type II receptor) which are activated by OSM but not by LIF. Interacts with HCK (By similarity). Interacts with INPP5D/SHIP1 (PubMed:17105399). Interacts with SRC and YES (By similarity). {ECO:0000250|UniProtKB:P40189, ECO:0000269|PubMed:17105399, ECO:0000269|PubMed:9920829}.

Subcellular location: Cell membrane {ECO:0000250|UniProtKB:P40189}; Single-pass type I membrane protein {ECO:0000255}.

Tissue specificity: Expression not restricted to IL6-responsive cells. Found in tissues such as brain, heart, thymus, spleen, kidney, lung and liver. Found in all the cell lines tested except BaF-B03. Expressed paraventricular nucleus of the hypothalamus (PubMed:28402851). {ECO:0000269|PubMed:1602143, ECO:0000269|PubMed:28402851}.

Developmental stage: In embryonic stem cells it is found from day 6 of gestation. It reaches a peak on day 8 and gradually declines during the rest of embryogenesis. {ECO:0000269|PubMed:1602143}.

Induction: In paraventricular nucleus of the hypothalamus, expression is enhanced by obesity. {ECO:0000269|PubMed:28402851}.

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-780 down-regulates cell surface expression. {ECO:0000250|UniProtKB:P40189}.

Ptm: Heavily N-glycosylated. Glycosylation is required for protein stability and localization in plasma membrane but not for ligand binding. {ECO:0000250|UniProtKB:P40189}.

Disruption phenotype: Progressively lethal between 12.5 dpc and birth (PubMed:8552649). Embryos show hypoplastic ventricular myocardium without septal and trabecular defect, reduced numbers of pluripotential and committed hematopoietic progenitors in liver and reduced differentiated lineages in thymus (PubMed:8552649). Impaired differentiation of astrocytes and decreased number of dorsal root ganglion and motor neurons at 18.5 dpc (PubMed:10377352). Decreased volume of mineralized trabecular bones, while number of osteoclasts is increased (PubMed:9348227, PubMed:26255596). Conditional knockout from the entire osteoblast lineage or specifically in osteocytes causes no significant skeletal or morphological defects but mice show 30% lower trabecular bone formation rate and larger cortical diameter compared to wild type (PubMed:24339143, PubMed:26255596). Conditional knockout in primary nociceptive afferents causes reduced sensitivity to mechanical stimulation due to reduced sensitivity of nociceptive neurons and reduces TRPA1 mRNA expression in dorsal root ganglion neurons (PubMed:25057188). {ECO:0000269|PubMed:10377352, ECO:0000269|PubMed:24339143, ECO:0000269|PubMed:25057188, ECO:0000269|PubMed:26255596, ECO:0000269|PubMed:8552649, ECO:0000269|PubMed:9348227}.

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

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Signal-transducing molecule (PubMed:1602143). 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:1602143, PubMed:10661409). That causes phosphorylation of IL6ST tyrosine residues which in turn activates STAT3 (PubMed:10661409). 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 (PubMed:9202125). Also activates the yes-associated protein 1 (YAP) and NOTCH pathways to control inflammation-induced epithelial regeneration, independently of STAT3 (PubMed:25731159). Mediates signals which regulate immune response, hematopoiesis, pain control and bone metabolism (PubMed:10661409, PubMed:26255596, PubMed:25057188, PubMed:8552649). Has a role in embryonic development (PubMed:10661409). Essential for survival of motor and sensory neurons and for differentiation of astrocytes (PubMed:10377352). Required for expression of TRPA1 in nociceptive neurons (PubMed:25057188). Required for the maintenance of PTH1R expression in the osteoblast lineage and for the stimulation of PTH-induced osteoblast differentiation (PubMed:25228504). Required for normal trabecular bone mass and cortical bone composition (PubMed:24339143, PubMed:9348227, PubMed:26255596). {ECO:0000250\|UniProtKB:P40189, ECO:0000269\|PubMed:10377352, ECO:0000269\|PubMed:10661409, ECO:0000269\|PubMed:1602143, ECO:0000269\|PubMed:24339143, ECO:0000269\|PubMed:25057188, ECO:0000269\|PubMed:25228504, ECO:0000269\|PubMed:25731159, ECO:0000269\|PubMed:26255596, ECO:0000269\|PubMed:8552649, ECO:0000269\|PubMed:9202125, ECO:0000269\|PubMed:9348227}.


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 (By similarity). Forms heterodimers composed of LIFR and IL6ST (type I OSM receptor) which are activated by LIF and OSM. Also forms heterodimers composed of OSMR and IL6ST (type II receptor) which are activated by OSM but not by LIF. Interacts with HCK (By similarity). Interacts with INPP5D/SHIP1 (PubMed:17105399). Interacts with SRC and YES (By similarity). {ECO:0000250\|UniProtKB:P40189, ECO:0000269\|PubMed:17105399, ECO:0000269\|PubMed:9920829}.
Subcellular location:		Cell membrane {ECO:0000250\|UniProtKB:P40189}; Single-pass type I membrane protein {ECO:0000255}.
Tissue specificity:		Expression not restricted to IL6-responsive cells. Found in tissues such as brain, heart, thymus, spleen, kidney, lung and liver. Found in all the cell lines tested except BaF-B03. Expressed paraventricular nucleus of the hypothalamus (PubMed:28402851). {ECO:0000269\|PubMed:1602143, ECO:0000269\|PubMed:28402851}.
Developmental stage:		In embryonic stem cells it is found from day 6 of gestation. It reaches a peak on day 8 and gradually declines during the rest of embryogenesis. {ECO:0000269\|PubMed:1602143}.
Induction:		In paraventricular nucleus of the hypothalamus, expression is enhanced by obesity. {ECO:0000269\|PubMed:28402851}.
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-780 down-regulates cell surface expression. {ECO:0000250\|UniProtKB:P40189}.
Ptm:		Heavily N-glycosylated. Glycosylation is required for protein stability and localization in plasma membrane but not for ligand binding. {ECO:0000250\|UniProtKB:P40189}.
Disruption phenotype:		Progressively lethal between 12.5 dpc and birth (PubMed:8552649). Embryos show hypoplastic ventricular myocardium without septal and trabecular defect, reduced numbers of pluripotential and committed hematopoietic progenitors in liver and reduced differentiated lineages in thymus (PubMed:8552649). Impaired differentiation of astrocytes and decreased number of dorsal root ganglion and motor neurons at 18.5 dpc (PubMed:10377352). Decreased volume of mineralized trabecular bones, while number of osteoclasts is increased (PubMed:9348227, PubMed:26255596). Conditional knockout from the entire osteoblast lineage or specifically in osteocytes causes no significant skeletal or morphological defects but mice show 30% lower trabecular bone formation rate and larger cortical diameter compared to wild type (PubMed:24339143, PubMed:26255596). Conditional knockout in primary nociceptive afferents causes reduced sensitivity to mechanical stimulation due to reduced sensitivity of nociceptive neurons and reduces TRPA1 mRNA expression in dorsal root ganglion neurons (PubMed:25057188). {ECO:0000269\|PubMed:10377352, ECO:0000269\|PubMed:24339143, ECO:0000269\|PubMed:25057188, ECO:0000269\|PubMed:26255596, ECO:0000269\|PubMed:8552649, ECO:0000269\|PubMed:9348227}.
Similarity:		Belongs to the type I cytokine receptor family. Type 2 subfamily. {ECO:0000305}.