UniProt functional annotation for P10912



	UniProt functional annotation for P10912

UniProt code: P10912.

Organism: Homo sapiens (Human).

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

Function: Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway (By similarity). {ECO:0000250}.

Function: The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling.

Function: Isoform 2 up-regulates the production of GHBP and acts as a negative inhibitor of GH signaling.

Subunit: On growth hormone (GH) binding, forms homodimers and binds JAK2 via a box 1-containing domain. Binding to SOCS3 inhibits JAK2 activation, binding to CIS and SOCS2 inhibits STAT5 activation. Interacts with ADAM17. {ECO:0000250}.

Subcellular location: Cell membrane; Single-pass type I membrane protein. Note=On growth hormone binding, GHR is ubiquitinated, internalized, down-regulated and transported into a degradative or non- degradative pathway. {ECO:0000250}.

Subcellular location: [Isoform 2]: Cell membrane; Single-pass type I membrane protein. Note=Remains fixed to the cell membrane and is not internalized.

Subcellular location: [Growth hormone-binding protein]: Secreted. Note=Complexed to a substantial fraction of circulating GH. {ECO:0000250}.

Tissue specificity: Expressed in various tissues with high expression in liver and skeletal muscle. Isoform 4 is predominantly expressed in kidney, bladder, adrenal gland and brain stem. Isoform 1 expression in placenta is predominant in chorion and decidua. Isoform 4 is highly expressed in placental villi. Isoform 2 is expressed in lung, stomach and muscle. Low levels in liver.

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.

Domain: The extracellular domain is the ligand-binding domain representing the growth hormone-binding protein (GHBP).

Domain: The ubiquitination-dependent endocytosis motif (UbE) is required for recruitment of the ubiquitin conjugation system on to the receptor and for its internalization.

Ptm: The soluble form (GHBP) is produced by phorbol ester-promoted proteolytic cleavage at the cell surface (shedding) by ADAM17/TACE. Shedding is inhibited by growth hormone (GH) binding to the receptor probably due to a conformational change in GHR rendering the receptor inaccessible to ADAM17 (By similarity). {ECO:0000250}.

Ptm: On GH binding, phosphorylated on tyrosine residues in the cytoplasmic domain by JAK2. {ECO:0000250}.

Ptm: On ligand binding, ubiquitinated on lysine residues in the cytoplasmic domain. This ubiquitination is not sufficient for GHR internalization (By similarity). {ECO:0000250}.

Polymorphism: Genetic variation in GHR may act as phenotype modifier in familial hypercholesterolemia [MIM:143890] patients carrying a mutation in the LDLR gene.

Disease: Laron syndrome (LARS) [MIM:262500]: A severe form of growth hormone insensitivity characterized by growth impairment, short stature, dysfunctional growth hormone receptor, and failure to generate insulin-like growth factor I in response to growth hormone. {ECO:0000269|PubMed:10870033, ECO:0000269|PubMed:14678285, ECO:0000269|PubMed:2779634, ECO:0000269|PubMed:8137822, ECO:0000269|PubMed:8450064, ECO:0000269|PubMed:8504296, ECO:0000269|PubMed:9024232, ECO:0000269|PubMed:9661642, ECO:0000269|PubMed:9851797}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Growth hormone insensitivity, partial (GHIP) [MIM:604271]: A disease characterized by partial resistance to growth hormone resulting in short stature. Short stature is defined by a standing height more than 2 standard deviations below the mean (or below the 2.5 percentile) for sex and chronological age, compared with a well-nourished, healthy, genetically relevant population. {ECO:0000269|PubMed:7565946}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: [Isoform 4]: Arises by species-specific retrovirus- mediated alternative splice mimicry. {ECO:0000305}.

Similarity: Belongs to the type I cytokine receptor family. Type 1 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:		Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway (By similarity). {ECO:0000250}.



Function:		The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling.



Function:		Isoform 2 up-regulates the production of GHBP and acts as a negative inhibitor of GH signaling.


Subunit:		On growth hormone (GH) binding, forms homodimers and binds JAK2 via a box 1-containing domain. Binding to SOCS3 inhibits JAK2 activation, binding to CIS and SOCS2 inhibits STAT5 activation. Interacts with ADAM17. {ECO:0000250}.
Subcellular location:		Cell membrane; Single-pass type I membrane protein. Note=On growth hormone binding, GHR is ubiquitinated, internalized, down-regulated and transported into a degradative or non- degradative pathway. {ECO:0000250}.
Subcellular location:		[Isoform 2]: Cell membrane; Single-pass type I membrane protein. Note=Remains fixed to the cell membrane and is not internalized.
Subcellular location:		[Growth hormone-binding protein]: Secreted. Note=Complexed to a substantial fraction of circulating GH. {ECO:0000250}.
Tissue specificity:		Expressed in various tissues with high expression in liver and skeletal muscle. Isoform 4 is predominantly expressed in kidney, bladder, adrenal gland and brain stem. Isoform 1 expression in placenta is predominant in chorion and decidua. Isoform 4 is highly expressed in placental villi. Isoform 2 is expressed in lung, stomach and muscle. Low levels in liver.
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.
Domain:		The extracellular domain is the ligand-binding domain representing the growth hormone-binding protein (GHBP).
Domain:		The ubiquitination-dependent endocytosis motif (UbE) is required for recruitment of the ubiquitin conjugation system on to the receptor and for its internalization.
Ptm:		The soluble form (GHBP) is produced by phorbol ester-promoted proteolytic cleavage at the cell surface (shedding) by ADAM17/TACE. Shedding is inhibited by growth hormone (GH) binding to the receptor probably due to a conformational change in GHR rendering the receptor inaccessible to ADAM17 (By similarity). {ECO:0000250}.
Ptm:		On GH binding, phosphorylated on tyrosine residues in the cytoplasmic domain by JAK2. {ECO:0000250}.
Ptm:		On ligand binding, ubiquitinated on lysine residues in the cytoplasmic domain. This ubiquitination is not sufficient for GHR internalization (By similarity). {ECO:0000250}.
Polymorphism:		Genetic variation in GHR may act as phenotype modifier in familial hypercholesterolemia [MIM:143890] patients carrying a mutation in the LDLR gene.
Disease:		Laron syndrome (LARS) [MIM:262500]: A severe form of growth hormone insensitivity characterized by growth impairment, short stature, dysfunctional growth hormone receptor, and failure to generate insulin-like growth factor I in response to growth hormone. {ECO:0000269\|PubMed:10870033, ECO:0000269\|PubMed:14678285, ECO:0000269\|PubMed:2779634, ECO:0000269\|PubMed:8137822, ECO:0000269\|PubMed:8450064, ECO:0000269\|PubMed:8504296, ECO:0000269\|PubMed:9024232, ECO:0000269\|PubMed:9661642, ECO:0000269\|PubMed:9851797}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Growth hormone insensitivity, partial (GHIP) [MIM:604271]: A disease characterized by partial resistance to growth hormone resulting in short stature. Short stature is defined by a standing height more than 2 standard deviations below the mean (or below the 2.5 percentile) for sex and chronological age, compared with a well-nourished, healthy, genetically relevant population. {ECO:0000269\|PubMed:7565946}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		[Isoform 4]: Arises by species-specific retrovirus- mediated alternative splice mimicry. {ECO:0000305}.
Similarity:		Belongs to the type I cytokine receptor family. Type 1 subfamily. {ECO:0000305}.