GHR
Domain
The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding (PubMed:14678285).
The box 1 motif is required for JAK interaction and/or activation.
The extracellular domain is the ligand-binding domain representing the growth hormone-binding protein (GHBP).
The ubiquitination-dependent endocytosis motif (UbE) is required for recruitment of the ubiquitin conjugation system on to the receptor and for its internalization.
Function
Receptor for pituitary gland growth hormone (GH1) involved in regulating postnatal body growth (PubMed:1549776, PubMed:2825030, PubMed:8943276). On ligand binding, couples to the JAK2/STAT5 pathway (PubMed:1549776, PubMed:15690087, PubMed:2825030, PubMed:8943276).
Growth hormone-binding protein
The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling.
Isoform 2
Up-regulates the production of the soluble Growth hormone-binding protein form (GHBP) and acts as a negative inhibitor of growth hormone signaling.
Involvement in disease
Laron syndrome
LARS
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.
None
The disease is caused by variants affecting the gene represented in this entry.
Growth hormone insensitivity, partial
GHIP
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.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
The soluble form (GHBP) is produced by phorbol ester-promoted proteolytic cleavage at the cell surface (shedding) by ADAM17/TACE (PubMed:11785980). 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).
On GH binding, phosphorylated on tyrosine residues in the cytoplasmic domain by JAK2.
Ubiquitinated by the ECS(SOCS2) complex following ligand-binding and phosphorylation by JAK2, leading to its degradation by the proteasome (PubMed:21980433, PubMed:25505247, PubMed:31182716, PubMed:34857742). Regulation by the ECS(SOCS2) complex acts as a negative feedback loop of growth hormone receptor signaling (PubMed:21980433). Ubiquitination is not sufficient for GHR internalization (By similarity).
Sequence Similarities
Belongs to the type I cytokine receptor family. Type 1 subfamily.
Tissue Specificity
Expressed in various tissues with high expression in liver and skeletal muscle.
Isoform 2
Isoform 2 is expressed in lung, stomach and muscle.
Isoform 4
Predominantly expressed in kidney, bladder, adrenal gland and brain stem (PubMed:1569971). Highly expressed in placental villi (PubMed:1569971, PubMed:8360189).
Cellular localization
- Cell membrane
- Single-pass type I membrane protein
- On growth hormone binding, GHR is ubiquitinated, internalized, down-regulated and transported into a degradative or non-degradative pathway.
- Isoform 2
- Cell membrane
- Single-pass type I membrane protein
- Remains fixed to the cell membrane and is not internalized.
- Growth hormone-binding protein
- Secreted
- Complexed to a substantial fraction of circulating GH.
Alternative names
Growth hormone receptor, GH receptor, Somatotropin receptor, GHR