Description: Homo sapiens growth hormone receptor (GHR), transcript variant 1, mRNA. RefSeq Summary (NM_000163): This gene encodes a member of the type I cytokine receptor family, which is a transmembrane receptor for growth hormone. Binding of growth hormone to the receptor leads to receptor dimerization and the activation of an intra- and intercellular signal transduction pathway leading to growth. Mutations in this gene have been associated with Laron syndrome, also known as the growth hormone insensitivity syndrome (GHIS), a disorder characterized by short stature. In humans and rabbits, but not rodents, growth hormone binding protein (GHBP) is generated by proteolytic cleavage of the extracellular ligand-binding domain from the mature growth hormone receptor protein. Multiple alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jun 2011]. Transcript (Including UTRs) Position: hg19 chr5:42,423,877-42,721,980 Size: 298,104 Total Exon Count: 10 Strand: + Coding Region Position: hg19 chr5:42,565,977-42,719,526 Size: 153,550 Coding Exon Count: 9
ID:GHR_HUMAN DESCRIPTION: RecName: Full=Growth hormone receptor; Short=GH receptor; AltName: Full=Somatotropin receptor; Contains: RecName: Full=Growth hormone-binding protein; Short=GH-binding protein; Short=GHBP; AltName: Full=Serum-binding protein; Flags: Precursor; FUNCTION: Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway (By similarity). 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 (By similarity). Binding to SOCS3 inhibits JAK2 activation, binding to CIS and SOCS2 inhibits STAT5 activation (By similarity). Interacts with ADAM17 (By similarity). INTERACTION: Q16829:DUSP7; NbExp=2; IntAct=EBI-286316, EBI-1265847; P01241:GH1; NbExp=3; IntAct=EBI-286316, EBI-1026046; P16333:NCK1; NbExp=2; IntAct=EBI-286316, EBI-389883; Q9JLI4:Ncoa6 (xeno); NbExp=2; IntAct=EBI-286316, EBI-286271; P18031:PTPN1; NbExp=5; IntAct=EBI-286316, EBI-968788; P17706:PTPN2; NbExp=8; IntAct=EBI-286316, EBI-984930; P26045:PTPN3; NbExp=4; IntAct=EBI-286316, EBI-1047946; P43378:PTPN9; NbExp=2; IntAct=EBI-286316, EBI-742898; P23467:PTPRB; NbExp=3; IntAct=EBI-286316, EBI-1265766; Q9HD43:PTPRH; NbExp=4; IntAct=EBI-286316, EBI-1267176; Q12913:PTPRJ; NbExp=2; IntAct=EBI-286316, EBI-2264500; 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 (By similarity). 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 (By similarity). 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). PTM: On GH binding, phosphorylated on tyrosine residues in the cytoplasmic domain by JAK2 (By similarity). PTM: On ligand binding, ubiquitinated on lysine residues in the cytoplasmic domain. This ubiquitination is not sufficient for GHR internalization (By similarity). POLYMORPHISM: Genetic variation in GHR may act as phenotype modifier in familial hypercholesterolemia [MIM:143890] patients carrying a mutation in the LDLR gene. DISEASE: Defects in GHR are a cause of 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. DISEASE: Defects in GHR may be a cause of idiopathic short stature autosomal (ISSA) [MIM:604271]. Short stature is defined by a subnormal rate of growth. SIMILARITY: Belongs to the type I cytokine receptor family. Type 1 subfamily. SIMILARITY: Contains 1 fibronectin type-III domain. WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GHR";
Genetic Association Studies of Complex Diseases and Disorders
Acromegaly Ignacio Bernabeu , et al. The Journal of clinical endocrinology and metabolism 2010 95(1):222-9, The exon 3-deleted growth hormone receptor is associated with better response to pegvisomant therapy in acromegaly., The Journal of clinical endocrinology and metabolism 2010 95(1):222-9.
The exon 3 deletion in the GHR predicts an improved response to pegvisomant therapy in acromegaly.
blood pressure, arterial hypertension Kokubo, Y. et al. 2006, Association of sixty-one non-synonymous polymorphisms in forty-one hypertension candidate genes with blood pressure variation and hypertension, Hypertens Res 2006 29(8) 611-9.
cholesterol height Ihara, K. et al. 2007, The Leu544Ile polymorphism of the growth hormone receptor gene affects the serum cholesterol levels during GH treatment in children with GH deficiency, Clin Endocrinol (Oxf) 2007.
The Leu544Ile polymorphism of the GHR gene is associated with cholesterol levels in boys with GH deficiency.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P10912
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.
Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary