Growth hormone receptor explained

Growth hormone receptor is a protein that in humans is encoded by the GHR gene.[1] GHR orthologs[2] 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).[3] [4] 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.[5]

Function

This gene encodes a protein that is a transmembrane receptor for growth hormone.[6] [7] 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 [8]) and the activation of an intra- and intercellular signal transduction pathway leading to growth.[9] 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.[1] 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.

Interactions

Growth hormone receptor has been shown to interact with SGTA,[10] PTPN11,[11] [12] Janus kinase 2,[13] [14] [15] Suppressor of cytokine signaling 1[16] and CISH.[16]

Evolution

The GHR gene is used in animals as a nuclear DNA phylogenetic marker.[2] The exon 10 has first been experienced to explore the phylogeny of the major groups of Rodentia.[17] [18] [19] GHR has also proven useful at lower taxonomic levels, e.g., in octodontoid,[20] [21] arvicoline,[22] muroid,[23] [24] murine,[25] and peromyscine [26] rodents, in arctoid [27] and felid[28] carnivores, and in dermopterans.[29] Note that the GHR intron 9 has also been used to investigate the mustelid[30] and hyaenid [31] carnivores phylogenetics.

Antagonists

Growth hormone receptor antagonists such as pegvisomant (trade name Somavert) are used in the treatment of acromegaly.[32] 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.[33]

See also

External links

Notes and References

  1. Web site: Entrez Gene: GHR growth hormone receptor.
  2. Web site: OrthoMaM phylogenetic marker: GHR coding sequence . 2009-11-18 . https://web.archive.org/web/20150924061911/http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000112964_GHR.xml . 2015-09-24 . dead .
  3. Leung DW, Spencer SA, Cachianes G, Hammonds RG, Collins C, Henzel WJ, Barnard R, Waters MJ, Wood WI . Growth hormone receptor and serum binding protein: purification, cloning and expression . Nature . 330 . 6148 . 537–43 . 1987 . 2825030 . 10.1038/330537a0 . 1987Natur.330..537L . 4370204 .
  4. Postel-Vinay MC, Finidori J . Growth hormone receptor: structure and signal transduction . en-US . European Journal of Endocrinology . 133 . 6 . 654–9 . December 1995 . 8548048 . 10.1530/eje.0.1330654 .
  5. Brooks AJ, Wooh JW, Tunny KA, Waters MJ . Growth hormone receptor; mechanism of action . The International Journal of Biochemistry & Cell Biology . 40 . 10 . 1984–9 . 2008-01-01 . 17888716 . 10.1016/j.biocel.2007.07.008 .
  6. Dehkhoda F, Lee CM, Medina J, Brooks AJ . The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects . Frontiers in Endocrinology . 9 . 35 . 13 February 2018 . 29487568 . 5816795 . 10.3389/fendo.2018.00035 . free .
  7. Brooks AJ, Waters MJ . The growth hormone receptor: mechanism of activation and clinical implications . Nature Reviews. Endocrinology . 6 . 9 . 515–25 . September 2010 . 20664532 . 10.1038/nrendo.2010.123 . 23639819 .
  8. González L, Curto LM, Miquet JG, Bartke A, Turyn D, Sotelo AI . 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 . April 2007 . 17321774 . 10.1016/j.ghir.2006.12.002 .
  9. 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 . Mechanism of activation of protein kinase JAK2 by the growth hormone receptor . Science . 344 . 6185 . 1249783 . May 2014 . 24833397 . 10.1126/science.1249783 . 27946074 .
  10. Schantl JA, Roza M, De Jong AP, Strous GJ . Small glutamine-rich tetratricopeptide repeat-containing protein (SGT) interacts with the ubiquitin-dependent endocytosis (UbE) motif of the growth hormone receptor . The Biochemical Journal . 373 . Pt 3 . 855–63 . August 2003 . 12735788 . 1223544 . 10.1042/BJ20021591 .
  11. Stofega MR, Herrington J, Billestrup N, Carter-Su C . Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B . Molecular Endocrinology . 14 . 9 . 1338–50 . September 2000 . 10976913 . 10.1210/mend.14.9.0513 . free .
  12. Moutoussamy S, Renaudie F, Lago F, Kelly PA, Finidori J . Grb10 identified as a potential regulator of growth hormone (GH) signaling by cloning of GH receptor target proteins . The Journal of Biological Chemistry . 273 . 26 . 15906–12 . June 1998 . 9632636 . 10.1074/jbc.273.26.15906 . free .
  13. Frank SJ, Yi W, Zhao Y, Goldsmith JF, Gilliland G, Jiang J, Sakai I, Kraft AS . Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor . The Journal of Biological Chemistry . 270 . 24 . 14776–85 . June 1995 . 7540178 . 10.1074/jbc.270.24.14776 . free.
  14. VanderKuur JA, Wang X, Zhang L, Campbell GS, Allevato G, Billestrup N, Norstedt G, Carter-Su C . Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase . The Journal of Biological Chemistry . 269 . 34 . 21709–17 . August 1994 . 10.1016/S0021-9258(17)31863-X . 8063815 . free .
  15. Hellgren G, Jansson JO, Carlsson LM, Carlsson B . The growth hormone receptor associates with Jak1, Jak2 and Tyk2 in human liver . Growth Hormone & IGF Research . 9 . 3 . 212–8 . June 1999 . 10502458 . 10.1054/ghir.1999.0111 .
  16. Ram PA, Waxman DJ . SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms . The Journal of Biological Chemistry . 274 . 50 . 35553–61 . December 1999 . 10585430 . 10.1074/jbc.274.50.35553 . free.
  17. Adkins RM, Gelke EL, Rowe D, Honeycutt RL . Molecular phylogeny and divergence time estimates for major rodent groups: evidence from multiple genes . Molecular Biology and Evolution . 18 . 5 . 777–91 . May 2001 . 11319262 . 10.1093/oxfordjournals.molbev.a003860 . free .
  18. Adkins RM, Walton AH, Honeycutt RL . Higher-level systematics of rodents and divergence time estimates based on two congruent nuclear genes . Molecular Phylogenetics and Evolution . 26 . 3 . 409–20 . March 2003 . 12644400 . 10.1016/S1055-7903(02)00304-4 .
  19. Blanga-Kanfi S, Miranda H, Penn O, Pupko T, DeBry RW, Huchon D . Rodent phylogeny revised: analysis of six nuclear genes from all major rodent clades . BMC Evolutionary Biology . 9 . 71 . April 2009 . 1 . 19341461 . 2674048 . 10.1186/1471-2148-9-71 . 2009BMCEE...9...71B . free .
  20. Honeycutt RL, Rowe DL, Gallardo MH . 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 . March 2003 . 12644405 . 10.1016/S1055-7903(02)00368-8 . 10533/174195 . free .
  21. Fabre PH, Upham NS, Emmons LH, Justy F, Leite YL, Carolina Loss A, Orlando L, Tilak MK, Patterson BD, Douzery EJ . Mitogenomic Phylogeny, Diversification, and Biogeography of South American Spiny Rats . Molecular Biology and Evolution . 34 . 3 . 613–633 . March 2017 . 28025278 . 10.1093/molbev/msw261 . free .
  22. Galewski T, Tilak MK, Sanchez S, Chevret P, Paradis E, Douzery EJ . The evolutionary radiation of Arvicolinae rodents (voles and lemmings): relative contribution of nuclear and mitochondrial DNA phylogenies . BMC Evolutionary Biology . 6 . 80 . October 2006 . 17029633 . 1618403 . 10.1186/1471-2148-6-80 . free .
  23. Steppan S, Adkins R, Anderson J . Phylogeny and divergence-date estimates of rapid radiations in muroid rodents based on multiple nuclear genes . Systematic Biology . 53 . 4 . 533–53 . August 2004 . 15371245 . 10.1080/10635150490468701 .
  24. Rowe KC, Reno ML, Richmond DM, Adkins RM, Steppan SJ . 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 . April 2008 . 18313945 . 10.1016/j.ympev.2008.01.001 .
  25. Lecompte E, Aplin K, Denys C, Catzeflis F, Chades M, Chevret P . Phylogeny and biogeography of African Murinae based on mitochondrial and nuclear gene sequences, with a new tribal classification of the subfamily . BMC Evolutionary Biology . 8 . 199 . July 2008 . 1 . 18616808 . 2490707 . 10.1186/1471-2148-8-199 . 2008BMCEE...8..199L . free .
  26. Miller J. R. . Engstrom M. D. . The relationships of major lineages within peromyscine rodents: a molecular phylogenetic hypothesis and systematic reappraisal . J. Mammal. . 89 . 5 . 1279–1295 . 2008 . 10.1644/07-MAMM-A-195.1. free .
  27. Fulton TL, Strobeck C . 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 . October 2006 . 16814570 . 10.1016/j.ympev.2006.05.025 .
  28. Johnson WE, Eizirik E, Pecon-Slattery J, Murphy WJ, Antunes A, Teeling E, O'Brien SJ . The late Miocene radiation of modern Felidae: a genetic assessment . Science . 311 . 5757 . 73–7 . January 2006 . 16400146 . 10.1126/science.1122277 . 2006Sci...311...73J . 41672825 .
  29. Janecka JE, Helgen KM, Lim NT, Baba M, Izawa M, Murphy WJ . Evidence for multiple species of Sunda colugo . Current Biology . 18 . 21 . R1001-2 . November 2008 . 19000793 . 10.1016/j.cub.2008.09.005 . 14945429 . free . 2008CBio...18R1001J .
  30. Koepfli KP, Wayne RK . Type I STS markers are more informative than cytochrome B in phylogenetic reconstruction of the Mustelidae (Mammalia: Carnivora) . Systematic Biology . 52 . 5 . 571–93 . October 2003 . 14530127 . 10.1080/10635150390235368 . free .
  31. Koepfli KP, Jenks SM, Eizirik E, Zahirpour T, Van Valkenburgh B, Wayne RK . Molecular systematics of the Hyaenidae: relationships of a relictual lineage resolved by a molecular supermatrix . Molecular Phylogenetics and Evolution . 38 . 3 . 603–20 . March 2006 . 16503281 . 10.1016/j.ympev.2005.10.017 .
  32. Schreiber I, Buchfelder M, Droste M, Forssmann K, Mann K, Saller B, Strasburger CJ . 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 . January 2007 . 17218728 . 10.1530/eje.1.02312 . 12121175 .
  33. Web site: Scientific Discussion of Somavert. 2004. European Medicines Agency. 2011-04-29. 2018-06-18. https://web.archive.org/web/20180618111805/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000409/WC500054625.pdf. dead.

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