Growth hormone receptor is a protein that in humans is encoded by the GHRgene.[5] GHR orthologs[6] have been identified in most mammals.
Structure
Growth hormone receptor (GHR) is a transmembrane protein consisting of 620 amino acids. The receptor is part of the Type I cytokine receptor family of receptors. GHR exists in two forms as a full length membrane-bound receptor and as a soluble GH binding protein (GHBP).[7][8] GHR contains two fibronectin type III β domains in its extracellular domain, whereas the intracellular domain contains tyrosine Kinase JAK2 binding sites for SH2 proteins. JAK2 is the primary signal transducer for growth hormone.[9]
Function
This gene encodes a protein that is a transmembrane receptor for growth hormone.[10][11] Binding of growth hormone to the receptor leads to reorientation of a pre-assembled receptor dimer dimerization (the receptor may however also exist as monomers on the cell surface [12]) and the activation of an intra- and intercellular signal transduction pathway leading to growth.[13] A common alternate allele of this gene, called GHRd3, lacks exon three and has been well characterized. 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 (proportional dwarfism). Other splice variants, including one encoding a soluble form of the protein (GHRtr), have been observed but have not been thoroughly characterized.[5] Laron mice (that is mice genetically engineered to carry defective Ghr), have a dramatic reduction in body mass (only reaching 50% of the weight of normal siblings), and also show a ~40% increase in lifespan.
Conserved and variable positions of the GHR protein are evidenced by multiple amino acid sequence comparisons among rodents. The site in yellow emphasizes a Proline shared by all species in blue and represents a protein signature of their common ancestry.[14]
The GHR gene is used in animals as a nuclear DNA phylogenetic marker.[6] The exon 10 has first been experienced to explore the phylogeny of the major groups of Rodentia.[22][23][24]
GHR has also proven useful at lower taxonomic levels, e.g., in octodontoid,[25][14] arvicoline,[26] muroid,[27][28] murine,[29] and peromyscine [30] rodents, in arctoid [31] and felid[32] carnivores, and in dermopterans.[33]
Note that the GHR intron 9 has also been used to investigate the mustelid[34] and hyaenid [35]carnivores phylogenetics.
Antagonists
Growth hormone receptor antagonists such as pegvisomant (trade name Somavert) are used in the treatment of acromegaly.[36] They are used if the tumor of the pituitary gland causing the acromegaly cannot be controlled with surgery or radiation, and the use of somatostatin analogues is unsuccessful. Pegvisomant is delivered as a powder that is mixed with water and injected under the skin.[37]
^Brooks AJ, Waters MJ (September 2010). "The growth hormone receptor: mechanism of activation and clinical implications". Nature Reviews. Endocrinology. 6 (9): 515–25. doi:10.1038/nrendo.2010.123. PMID20664532. S2CID23639819.
^González L, Curto LM, Miquet JG, Bartke A, Turyn D, Sotelo AI (April 2007). "Differential regulation of membrane associated-growth hormone binding protein (MA-GHBP) and growth hormone receptor (GHR) expression by growth hormone (GH) in mouse liver". Growth Hormone & IGF Research. 17 (2): 104–12. doi:10.1016/j.ghir.2006.12.002. PMID17321774.
^Brooks AJ, Dai W, O'Mara ML, Abankwa D, Chhabra Y, Pelekanos RA, Gardon O, Tunny KA, Blucher KM, Morton CJ, Parker MW, Sierecki E, Gambin Y, Gomez GA, Alexandrov K, Wilson IA, Doxastakis M, Mark AE, Waters MJ (May 2014). "Mechanism of activation of protein kinase JAK2 by the growth hormone receptor". Science. 344 (6185): 1249783. doi:10.1126/science.1249783. PMID24833397. S2CID27946074.
^Hellgren G, Jansson JO, Carlsson LM, Carlsson B (June 1999). "The growth hormone receptor associates with Jak1, Jak2 and Tyk2 in human liver". Growth Hormone & IGF Research. 9 (3): 212–8. doi:10.1054/ghir.1999.0111. PMID10502458.
^Adkins RM, Walton AH, Honeycutt RL (March 2003). "Higher-level systematics of rodents and divergence time estimates based on two congruent nuclear genes". Molecular Phylogenetics and Evolution. 26 (3): 409–20. doi:10.1016/S1055-7903(02)00304-4. PMID12644400.
^Honeycutt RL, Rowe DL, Gallardo MH (March 2003). "Molecular systematics of the South American caviomorph rodents: relationships among species and genera in the family Octodontidae". Molecular Phylogenetics and Evolution. 26 (3): 476–89. doi:10.1016/S1055-7903(02)00368-8. hdl:10533/174195. PMID12644405.
^Steppan S, Adkins R, Anderson J (August 2004). "Phylogeny and divergence-date estimates of rapid radiations in muroid rodents based on multiple nuclear genes". Systematic Biology. 53 (4): 533–53. doi:10.1080/10635150490468701. PMID15371245.
^Rowe KC, Reno ML, Richmond DM, Adkins RM, Steppan SJ (April 2008). "Pliocene colonization and adaptive radiations in Australia and New Guinea (Sahul): multilocus systematics of the old endemic rodents (Muroidea: Murinae)". Molecular Phylogenetics and Evolution. 47 (1): 84–101. doi:10.1016/j.ympev.2008.01.001. PMID18313945.
^Fulton TL, Strobeck C (October 2006). "Molecular phylogeny of the Arctoidea (Carnivora): effect of missing data on supertree and supermatrix analyses of multiple gene data sets". Molecular Phylogenetics and Evolution. 41 (1): 165–81. doi:10.1016/j.ympev.2006.05.025. PMID16814570.
^Koepfli KP, Jenks SM, Eizirik E, Zahirpour T, Van Valkenburgh B, Wayne RK (March 2006). "Molecular systematics of the Hyaenidae: relationships of a relictual lineage resolved by a molecular supermatrix". Molecular Phylogenetics and Evolution. 38 (3): 603–20. doi:10.1016/j.ympev.2005.10.017. PMID16503281.
^Schreiber I, Buchfelder M, Droste M, Forssmann K, Mann K, Saller B, Strasburger CJ (January 2007). "Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the German Pegvisomant Observational Study". European Journal of Endocrinology. 156 (1): 75–82. doi:10.1530/eje.1.02312. PMID17218728. S2CID12121175.
