GHR

Official Full Name

growth hormone receptor

Organism

Homo sapiens

GeneID

2690

Background

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]

Synonyms

GHBP; GHIP;

Bio Chemical Class

Cytokine receptor

Protein Sequence

MDLWQLLLTLALAGSSDAFSGSEATAAILSRAPWSLQSVNPGLKTNSSKEPKFTKCRSPERETFSCHWTDEVHHGTKNLGPIQLFYTRRNTQEWTQEWKECPDYVSAGENSCYFNSSFTSIWIPYCIKLTSNGGTVDEKCFSVDEIVQPDPPIALNWTLLNVSLTGIHADIQVRWEAPRNADIQKGWMVLEYELQYKEVNETKWKMMDPILTTSVPVYSLKVDKEYEVRVRSKQRNSGNYGEFSEVLYVTLPQMSQFTCEEDFYFPWLLIIIFGIFGLTVMLFVFLFSKQQRIKMLILPPVPVPKIKGIDPDLLKEGKLEEVNTILAIHDSYKPEFHSDDSWVEFIELDIDEPDEKTEESDTDRLLSSDHEKSHSNLGVKDGDSGRTSCCEPDILETDFNANDIHEGTSEVAQPQRLKGEADLLCLDQKNQNNSPYHDACPATQQPSVIQAEKNKPQPLPTEGAESTHQAAHIQLSNPSSLSNIDFYAQVSDITPAGSVVLSPGQKNKAGMSQCDMHPEMVSLCQENFLMDNAYFCEADAKKCIPVAPHIKVESHIQPSLNQEDIYITTESLTTAAGRPGTGEHVPGSEMPVPDYTSIHIVQSPQGLILNATALPLPDKEFLSSCGYVSTDQLNKIMP

Open

Disease

Binge eating disorder, Obesity, Pituitary gland disorder, Short stature

Approved Drug

2 +

Clinical Trial Drug

8 +

Discontinued Drug

1 +

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Detailed Information

Belonging to the type I cytokine receptor family, Growth Hormone Receptor (GHR) is essential for human growth and metabolism. Comprising three primary domains, this transmembrane glycoprotein is: an extracellular domain with five possible glycosylation sites for hormone binding (amino acids 1-246), a hydrophobic transmembrane segment (amino acids 247-270), and an intracellular domain (350 amino acids) responsible for signal transduction. The structure of the receptor allows it to interact with growth hormone (GH), a 22 kDa polypeptide hormone with 191 amino acids and two disulfide linkages forming its distinctive loop shape: one joining cysteine residues at positions 53 and 164, and another linking sites 181 and 189.

GHR is expressed throughout many human tissues including the liver, brain, skeletal muscle, heart, kidneys, lungs, pancreas, reproductive organs, adipose tissue, fibroblasts, and lymphocytes. Cells show exceptionally high GHR expression throughout fetal and neonatal stages, which makes them very responsive to growth hormone activation. GH's binding to GHR starts many cellular reactions that support development and growth. The production of growth hormone binding protein (GHBP) by proteolytic cleavage of the receptor's extracellular domain distinguishes GHR activity in humans and rabbits. Though this mechanism is especially lacking in rats, stressing significant species variations in GH control, this soluble form may change GH signaling and serve as a store for growth hormone in plasma.

Signaling Pathways and Molecular Mechanisms

Growth hormone and GHR combine to set off a complicated cascade of chemical processes that coordinate cellular reactions. GH binding to GHR starts receptor dimerization and activates many signaling pathways working together to control gene expression and cellular activity. The GHR-JAK2 pathway, where JAK2 kinase activation causes phosphorylation of many tyrosine residues on GHR, is where the main signal transduction takes place. Particularly STAT5B, this phosphorylation process draws STAT proteins, which dimerize and go to the nucleus to control target gene expression.

Controlling metabolic activities, the phosphorylated GHR/JAK2 complex also draws insulin receptor substrates (IRS1 and IRS2), therefore activating the PI3K-Akt pathway. Moreover, JAK2 activation causes Shc protein phosphorylation, which forms a complex with Sos and Grb2-bound growth factor receptor 2. Ras protein is activated by this combination, which starts the MEK-Erk signaling pathway controlling cell division and differentiation.

The GHR-Src route offers a different signaling mechanism. Although JAK2 is still the principal mediator of GH effects, Src family kinases activate small GTPases and phospholipase D to cause certain cellular responses. Adding further intricacy to GH signaling, this JAK2-independent route affects cell migration, proliferation, and differentiation.

Figure 1 illustrates the synthesis, processing, and signaling pathways of the Growth Hormone Receptor (GHR), including its ER synthesis, glycosylation, chaperone-assisted Golgi transport, membrane arrival, endocytosis with or without growth hormone (GH), and subsequent signal transduction mechanisms. Figure 1. Life cycle of the GHR. (Strous GJ, et al., 2020)

c-Fos and IGF-1 are two important target genes controlled by GH signaling. Rapid but temporary responses of the c-Fos gene to GH stimulation via many pathways—MEK-Erk, PI3K-Akt, and STAT proteins—play vital roles in signal transduction, cell proliferation, and differentiation. Regulated mostly by the JAK2-STAT5B pathway, IGF-1, considered the most significant downstream target of GH activity, regulates most of GH's physiological effects, including skeletal growth, muscle mass development, and metabolic control.

Clinical Implications and Therapeutic Applications

GHR's therapeutic relevance goes beyond its basic function in growth and development. GHR gene mutations may cause many diseases, most notably Laron Syndrome (growth hormone insensitivity syndrome, GHIS), which causes notable metabolic changes and major growth retardation. Another major clinical condition is Growth Hormone Deficiency (GHD), which shows as slower growth rate in children and produces different metabolic and physiological changes in adults, including higher fat mass, lower muscular strength, lower bone density, cognitive impairment, and cardiovascular risk factors.

The GH-GHR system's therapeutic uses are still growing outside of conventional growth diseases. Studies have shown encouraging outcomes in metabolic control, tissue regeneration, anti-aging treatments, and assisted reproduction as well as severe burn therapy. The finding of GHBP's function as a GH reservoir and signaling modulator has provided new therapeutic options, implying possible uses in creating new treatment plans for GH-related diseases.

Promising further therapeutic uses in the future, ongoing study keeps revealing new facets of GHR function and control. The intricate signaling pathways started by GH-GHR interaction show the amazing intricacy of this system and its possible use as a therapeutic target across many medical disorders.

References:

Strous GJ, Almeida ADS, et al. Growth Hormone Receptor Regulation in Cancer and Chronic Diseases. Front Endocrinol (Lausanne). 2020 Nov 18;11:597573.
Wang Y, Kim M, Buckley C, et al. Growth hormone receptor agonists and antagonists: From protein expression and purification to long-acting formulations. Protein Sci. 2023;32(9):e4727.
Brooks AJ, Waters MJ. The growth hormone receptor: mechanism of activation and clinical implications. Nat Rev Endocrinol. 2010;6(9):515-525.

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