Growth hormone receptor: Difference between revisions

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{{Short description|A protein involved in the binding of the growth hormone}}
{{Infobox_gene}}
{{Infobox_gene}}
'''Growth hormone receptor''' is a [[protein]] that in humans is encoded by the ''GHR'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GHR growth hormone receptor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2690| accessdate = }}</ref> GHR [[orthologs]] <ref name="OrthoMaM">{{cite web | title = OrthoMaM phylogenetic marker: GHR coding sequence | url = http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000112964_GHR.xml }}</ref> have been identified in most [[mammals]].
'''Growth hormone receptor''' is a [[protein]] that in humans is encoded by the ''GHR'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GHR growth hormone receptor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2690| access-date = }}</ref> GHR [[orthologs]] <ref name="OrthoMaM">{{cite web | title = OrthoMaM phylogenetic marker: GHR coding sequence | url = http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000112964_GHR.xml }}</ref> have been identified in most [[mammals]].


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== Function ==
{{PBB_Summary
| section_title =  
| summary_text = This gene encodes a protein that is a transmembrane receptor for [[growth hormone]]. Binding of growth hormone to the receptor leads to receptor [[Dimer (chemistry)|dimerization]] (the receptor may however also exist as a pre-assembled non-functional dimer <ref>Gonzalez, L., L. M. Curto, et al. (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 Horm IGF Res 17(2): 104-112.</ref>) and the activation of an intra- and intercellular signal transduction pathway leading to growth. 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.<ref name="entrez"/> 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==
This gene encodes a protein that is a transmembrane receptor for [[growth hormone]].<ref>{{cite journal | vauthors = Dehkhoda F, Lee CM, Medina J, Brooks AJ | title = The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects | journal = Frontiers in Endocrinology | volume = 9 | pages = 35 | date = 13 February 2018 | pmid = 29487568 | doi = 10.3389/fendo.2018.00035 }}</ref><ref name="pmid20664532">{{cite journal | vauthors = Brooks AJ, Waters MJ | title = The growth hormone receptor: mechanism of activation and clinical implications | journal = Nature Reviews. Endocrinology | volume = 6 | issue = 9 | pages = 515–25 | date = September 2010 | pmid = 20664532 | doi = 10.1038/nrendo.2010.123 }}</ref> Binding of growth hormone to the receptor leads to reorientation of a pre-assembled receptor dimer [[Dimer (chemistry)|dimerization]] (the receptor may however also exist as monomers on the cell surface <ref name="pmid17321774">{{cite journal | vauthors = González L, Curto LM, Miquet JG, Bartke A, Turyn D, Sotelo AI | title = Differential regulation of membrane associated-growth hormone binding protein (MA-GHBP) and growth hormone receptor (GHR) expression by growth hormone (GH) in mouse liver | journal = Growth Hormone & IGF Research | volume = 17 | issue = 2 | pages = 104–12 | date = April 2007 | pmid = 17321774 | doi = 10.1016/j.ghir.2006.12.002 }}</ref>) and the activation of an intra- and intercellular signal transduction pathway leading to growth.<ref name="pmid24833397">{{cite journal | vauthors = 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 | title = Mechanism of activation of protein kinase JAK2 by the growth hormone receptor | journal = Science | volume = 344 | issue = 6185 | pages = 1249783 | date = May 2014 | pmid = 24833397 | doi = 10.1126/science.1249783 }}</ref> 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.<ref name="entrez"/> 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.
Growth hormone receptor has been shown to [[Protein-protein interaction|interact]] with [[SGTA]],<ref name=pmid12735788>{{cite journal |last=Schantl |first=Julia A |authorlink= |author2=Roza Marcel |author3=De Jong Ad P |author4=Strous Ger J  |date=August 2003  |title=Small glutamine-rich tetratricopeptide repeat-containing protein (SGT) interacts with the ubiquitin-dependent endocytosis (UbE) motif of the growth hormone receptor |journal=Biochem. J. |volume=373 |issue=Pt 3 |pages=855–63 |publisher= |location = England| issn = 0264-6021| pmid = 12735788 |doi = 10.1042/BJ20021591 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = | pmc = 1223544 }}</ref> [[PTPN11]],<ref name=pmid10976913>{{cite journal |doi=10.1210/me.14.9.1338 |last=Stofega |first=M R |authorlink= |author2=Herrington J |author3=Billestrup N |author4=Carter-Su C |date=September 2000  |title=Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B |journal=Mol. Endocrinol. |volume=14 |issue=9 |pages=1338–50 |publisher= |location = UNITED STATES| issn = 0888-8809| pmid = 10976913 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid9632636>{{cite journal |doi=10.1074/jbc.273.26.15906 |last=Moutoussamy |first=S |authorlink= |author2=Renaudie F |author3=Lago F |author4=Kelly P A |author5=Finidori J |date=June 1998  |title=Grb10 identified as a potential regulator of growth hormone (GH) signaling by cloning of GH receptor target proteins |journal=J. Biol. Chem. |volume=273 |issue=26 |pages=15906–12 |publisher= |location = UNITED STATES| issn = 0021-9258| pmid = 9632636 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref> [[Janus kinase 2]],<ref name=pmid7540178>{{cite journal |doi=10.1074/jbc.270.24.14776 |last=Frank |first=S J |authorlink= |author2=Yi W |author3=Zhao Y |author4=Goldsmith J F |author5=Gilliland G |author6=Jiang J |author7=Sakai I |author8=Kraft A S  |date=June 1995  |title=Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor |journal=J. Biol. Chem. |volume=270 |issue=24 |pages=14776–85 |publisher= |location = UNITED STATES| issn = 0021-9258| pmid = 7540178 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid8063815>{{cite journal |last=VanderKuur |first=J A |authorlink= |author2=Wang X |author3=Zhang L |author4=Campbell G S |author5=Allevato G |author6=Billestrup N |author7=Norstedt G |author8=Carter-Su C |date=August 1994  |title=Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase |journal=J. Biol. Chem. |volume=269 |issue=34 |pages=21709–17 |publisher= |location = UNITED STATES| issn = 0021-9258| pmid = 8063815 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid10502458>{{cite journal |last=Hellgren |first=G |authorlink= |author2=Jansson J O |author3=Carlsson L M |author4=Carlsson B |date=June 1999  |title=The growth hormone receptor associates with Jak1, Jak2 and Tyk2 in human liver |journal=Growth Horm. IGF Res. |volume=9 |issue=3 |pages=212–8 |publisher= |location = SCOTLAND| issn = 1096-6374| pmid = 10502458 |doi = 10.1054/ghir.1999.0111 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref> [[Suppressor of cytokine signaling 1]]<ref name=pmid10585430>{{cite journal |doi=10.1074/jbc.274.50.35553 |last=Ram |first=P A |authorlink= |author2=Waxman D J |date=December 1999  |title=SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms |journal=J. Biol. Chem. |volume=274 |issue=50 |pages=35553–61 |publisher= |location = UNITED STATES| issn = 0021-9258| pmid = 10585430 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref> and [[CISH]].<ref name=pmid10585430/>
[[File:Euryzygomatomyinae GHR AA.svg|thumb|right|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.<ref name="Fabre2017"/>]]
 
== Interactions ==
 
Growth hormone receptor has been shown to [[Protein-protein interaction|interact]] with [[SGTA]],<ref name=pmid12735788>{{cite journal | vauthors = Schantl JA, Roza M, De Jong AP, Strous GJ | title = Small glutamine-rich tetratricopeptide repeat-containing protein (SGT) interacts with the ubiquitin-dependent endocytosis (UbE) motif of the growth hormone receptor | journal = The Biochemical Journal | volume = 373 | issue = Pt 3 | pages = 855–63 | date = August 2003 | pmid = 12735788 | pmc = 1223544 | doi = 10.1042/BJ20021591 }}</ref> [[PTPN11]],<ref name=pmid10976913>{{cite journal | vauthors = Stofega MR, Herrington J, Billestrup N, Carter-Su C | title = Mutation of the SHP-2 binding site in growth hormone (GH) receptor prolongs GH-promoted tyrosyl phosphorylation of GH receptor, JAK2, and STAT5B | journal = Molecular Endocrinology | volume = 14 | issue = 9 | pages = 1338–50 | date = September 2000 | pmid = 10976913 | doi = 10.1210/me.14.9.1338 }}</ref><ref name=pmid9632636>{{cite journal | vauthors = Moutoussamy S, Renaudie F, Lago F, Kelly PA, Finidori J | title = Grb10 identified as a potential regulator of growth hormone (GH) signaling by cloning of GH receptor target proteins | journal = The Journal of Biological Chemistry | volume = 273 | issue = 26 | pages = 15906–12 | date = June 1998 | pmid = 9632636 | doi = 10.1074/jbc.273.26.15906 }}</ref> [[Janus kinase 2]],<ref name=pmid7540178>{{cite journal | vauthors = Frank SJ, Yi W, Zhao Y, Goldsmith JF, Gilliland G, Jiang J, Sakai I, Kraft AS | title = Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor | journal = The Journal of Biological Chemistry | volume = 270 | issue = 24 | pages = 14776–85 | date = June 1995 | pmid = 7540178 | doi = 10.1074/jbc.270.24.14776 }}</ref><ref name=pmid8063815>{{cite journal | vauthors = VanderKuur JA, Wang X, Zhang L, Campbell GS, Allevato G, Billestrup N, Norstedt G, Carter-Su C | title = Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase | journal = The Journal of Biological Chemistry | volume = 269 | issue = 34 | pages = 21709–17 | date = August 1994 | pmid = 8063815 }}</ref><ref name=pmid10502458>{{cite journal | vauthors = Hellgren G, Jansson JO, Carlsson LM, Carlsson B | title = The growth hormone receptor associates with Jak1, Jak2 and Tyk2 in human liver | journal = Growth Hormone & IGF Research | volume = 9 | issue = 3 | pages = 212–8 | date = June 1999 | pmid = 10502458 | doi = 10.1054/ghir.1999.0111 }}</ref> [[Suppressor of cytokine signaling 1]]<ref name=pmid10585430>{{cite journal | vauthors = Ram PA, Waxman DJ | title = SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms | journal = The Journal of Biological Chemistry | volume = 274 | issue = 50 | pages = 35553–61 | date = December 1999 | pmid = 10585430 | doi = 10.1074/jbc.274.50.35553 }}</ref> and [[CISH]].<ref name=pmid10585430/>


==Evolution==
==Evolution==
The '''''GHR''''' gene is used in animals as a [[nuclear DNA]] phylogenetic marker.<ref name="OrthoMaM"/> The exon 10 has first been experienced to explore the phylogeny of the major groups of [[Rodentia]].<ref name="pmid11319262">{{cite journal |vauthors=Adkins RM, Gelke EL, Rowe D, Honeycutt RL | title = Molecular phylogeny and divergence time estimates for major rodent groups: evidence from multiple genes. | journal = Mol Biol Evol | volume = 18 | issue = 5 | pages = 777–791 | year = 2001 | pmid = 11319262 | doi = 10.1093/oxfordjournals.molbev.a003860| url = | issn = }}</ref><ref name="pmid12644400 ">{{cite journal |author1=Adkins R. M. |author2=Walton A. H. |author3=Honeycutt R. L. | title = Higher-level systematics of rodents and divergence time estimates based on two congruent nuclear genes | journal = Mol. Phylogenet. Evol. | volume = 26 | issue = 3| pages = 409–420 | year = 2003 | pmid = 12644400 | doi = 10.1016/S1055-7903(02)00304-4| url = | issn = }}</ref><ref name="pmid19341461">{{cite journal |author1=Blanga-Kanfi S. |author2=Miranda H. |author3=Penn O. |author4=Pupko T. |author5=DeBry R. W. |author6=Huchon D. | title = Rodent phylogeny revised: analysis of six nuclear genes from all major rodent clades | journal = BMC Evol. Biol. | volume = 9| pages = 71 | year = 2009 | pmid = 19341461 | doi = 10.1186/1471-2148-9-71| url = http://www.biomedcentral.com/1471-2148/9/71 | issn = | pmc = 2674048 }}</ref>
The '''''GHR''''' gene is used in animals as a [[nuclear DNA]] phylogenetic marker.<ref name="OrthoMaM"/> The exon 10 has first been experienced to explore the phylogeny of the major groups of [[Rodentia]].<ref name="pmid11319262">{{cite journal | vauthors = Adkins RM, Gelke EL, Rowe D, Honeycutt RL | title = Molecular phylogeny and divergence time estimates for major rodent groups: evidence from multiple genes | journal = Molecular Biology and Evolution | volume = 18 | issue = 5 | pages = 777–91 | date = May 2001 | pmid = 11319262 | doi = 10.1093/oxfordjournals.molbev.a003860 }}</ref><ref name="pmid12644400 ">{{cite journal | vauthors = Adkins RM, Walton AH, Honeycutt RL | title = Higher-level systematics of rodents and divergence time estimates based on two congruent nuclear genes | journal = Molecular Phylogenetics and Evolution | volume = 26 | issue = 3 | pages = 409–20 | date = March 2003 | pmid = 12644400 | doi = 10.1016/S1055-7903(02)00304-4 }}</ref><ref name="pmid19341461">{{cite journal | vauthors = Blanga-Kanfi S, Miranda H, Penn O, Pupko T, DeBry RW, Huchon D | title = Rodent phylogeny revised: analysis of six nuclear genes from all major rodent clades | journal = BMC Evolutionary Biology | volume = 9 | pages = 71 | date = April 2009 | pmid = 19341461 | pmc = 2674048 | doi = 10.1186/1471-2148-9-71 | url = http://www.biomedcentral.com/1471-2148/9/71 }}</ref>
GHR has also proven useful at lower [[taxonomic]] levels, ''e.g.'', in octodontoid,<ref name="pmid12644405">{{cite journal |author1=Honeycutt R. L. |author2=Rowe D. L. |author3=Gallardo M. H. | title = Molecular systematics of the South American caviomorph rodents: relationships among species and genera in the family Octodontidae | journal = Mol. Phylogenet. Evol. | volume = 26 | issue = 3 | pages = 476–489 | year = 2003 | pmid = 12644405 | doi = 10.1016/S1055-7903(02)00368-8| url = | issn = }}</ref> arvicoline,<ref name="pmid17029633">{{cite journal |author1=Galewski T. |author2=Tilak M. |author3=Sanchez S. |author4=Chevret P. |author5=Paradis E. |author6=Douzery E. J. P. | title = The evolutionary radiation of Arvicolinae rodents (voles and lemmings): relative contribution of nuclear and mitochondrial DNA phylogenies | journal = BMC Evol. Biol. | volume = 6| pages = 80 | year = 2006 | pmid = 17029633 | doi = 10.1186/1471-2148-6-80| url = http://www.biomedcentral.com/1471-2148/6/80 | issn = | pmc = 1618403 }}</ref> muroid,<ref name="pmid15371245">{{cite journal |author1=Steppan S. J. |author2=Adkins R. M. |author3=Anderson J. | title = Phylogeny and divergence-date estimates of rapid radiations in muroid rodents based on multiple nuclear genes | journal = Syst. Biol. | volume = 53 | issue = 4 | pages = 533–553 | year = 2004 | pmid = 15371245 | doi = 10.1080/10635150490468701| url = | issn = }}</ref><ref name="pmid18313945">{{cite journal |author1=Rowe K. C. |author2=Reno M. L. |author3=Richmond D. M. |author4=Adkins R. M. |author5=Steppan S. J. | title = Pliocene colonization and adaptive radiations in Australia and New Guinea (Sahul): multilocus systematics of the old endemic rodents (Muroidea: Murinae) | journal = Mol. Phylogenet. Evol. | volume = 47 | issue = 1 | pages = 84–101 | year = 2008 | pmid = 18313945 | doi = 10.1016/j.ympev.2008.01.001| url = | issn = }}</ref> murine,<ref name="pmid18616808">{{cite journal |author1=Lecompte E. |author2=Aplin K. |author3=Denys C. |author4=Catzeflis F. |author5=Chades M. |author6=Chevret P. | title = Phylogeny and biogeography of African Murinae based on mitochondrial and nuclear gene sequences, with a new tribal classification of the subfamily | journal = BMC Evol. Biol. | volume = 8| pages = 199 | year = 2008 | pmid = 18616808 | doi = 10.1186/1471-2148-8-199| url = http://www.biomedcentral.com/1471-2148/8/199/ | issn = | pmc = 2490707 }}</ref> and peromyscine <ref name="Miller2008">{{cite journal |author1=Miller J. R. |author2=Engstrom M. D. | title = The relationships of major lineages within peromyscine rodents: a molecular phylogenetic hypothesis and systematic reappraisal | journal = J. Mammal. | volume = 89 | issue = 5 | pages = 1279–1295 | year = 2008 | pmid = | doi = 10.1644/07-MAMM-A-195.1| url = | issn = }}</ref> rodents, in arctoid <ref name="pmid16814570">{{cite journal |author1=Fulton T. L. |author2=Strobeck C. | title = Molecular phylogeny of the Arctoidea (Carnivora): effect of missing data on supertree and supermatrix analyses of multiple gene data sets | journal = Mol. Phylogenet. Evol. | volume = 41 | issue = 1 | pages = 165–181 | year = 2006 | pmid = 16814570 | doi = 10.1016/j.ympev.2006.05.025| url = | issn = }}</ref> and [[felid]] <ref name="pmid16400146">{{cite journal |author1=Johnson W. E. |author2=Eizirik E. |author3=Pecon-Slattery J. |author4=Murphy W. J. |author5=Antunes A. |author6=Teeling E. |author7=O'Brien S. J. | title = The late Miocene radiation of modern Felidae: a genetic assessment | journal = Science | volume = 311 | issue = 5757 | pages = 73–77 | year = 2006 | pmid = 16400146 | doi = 10.1126/science.1122277| url = | issn = }}</ref> carnivores, and in [[dermoptera]]ns.<ref name="pmid19000793">{{cite journal | author = Janecka J. E., Helgen K. M., Lim N. T., Baba M., Izawa M., Boeadi & Murphy W. J. | title = Evidence for multiple species of Sunda colugo | journal = Curr. Biol. | volume = 18 | issue = 21 | pages = R1001–R1002 | year = 2008 | pmid = 19000793 | doi = 10.1016/j.cub.2008.09.005| url = | issn = }}</ref>
GHR has also proven useful at lower [[Taxonomy (biology)|taxonomic]] levels, ''e.g.'', in octodontoid,<ref name="pmid12644405">{{cite journal | vauthors = Honeycutt RL, Rowe DL, Gallardo MH | title = Molecular systematics of the South American caviomorph rodents: relationships among species and genera in the family Octodontidae | journal = Molecular Phylogenetics and Evolution | volume = 26 | issue = 3 | pages = 476–89 | date = March 2003 | pmid = 12644405 | doi = 10.1016/S1055-7903(02)00368-8 }}</ref><ref name="Fabre2017">{{cite journal | vauthors = Fabre PH, Upham NS, Emmons LH, Justy F, Leite YL, Carolina Loss A, Orlando L, Tilak MK, Patterson BD, Douzery EJ | title = Mitogenomic Phylogeny, Diversification, and Biogeography of South American Spiny Rats | journal = Molecular Biology and Evolution | volume = 34 | issue = 3 | pages = 613–633 | date = March 2017 | pmid = 28025278 | doi = 10.1093/molbev/msw261 | url = https://academic.oup.com/mbe/article/34/3/613/2739699/Mitogenomic-Phylogeny-Diversification-and }}</ref> arvicoline,<ref name="pmid17029633">{{cite journal | vauthors = Galewski T, Tilak MK, Sanchez S, Chevret P, Paradis E, Douzery EJ | title = The evolutionary radiation of Arvicolinae rodents (voles and lemmings): relative contribution of nuclear and mitochondrial DNA phylogenies | journal = BMC Evolutionary Biology | volume = 6 | pages = 80 | date = October 2006 | pmid = 17029633 | pmc = 1618403 | doi = 10.1186/1471-2148-6-80 | url = http://www.biomedcentral.com/1471-2148/6/80 }}</ref> muroid,<ref name="pmid15371245">{{cite journal | vauthors = Steppan S, Adkins R, Anderson J | title = Phylogeny and divergence-date estimates of rapid radiations in muroid rodents based on multiple nuclear genes | journal = Systematic Biology | volume = 53 | issue = 4 | pages = 533–53 | date = August 2004 | pmid = 15371245 | doi = 10.1080/10635150490468701 }}</ref><ref name="pmid18313945">{{cite journal | vauthors = Rowe KC, Reno ML, Richmond DM, Adkins RM, Steppan SJ | title = Pliocene colonization and adaptive radiations in Australia and New Guinea (Sahul): multilocus systematics of the old endemic rodents (Muroidea: Murinae) | journal = Molecular Phylogenetics and Evolution | volume = 47 | issue = 1 | pages = 84–101 | date = April 2008 | pmid = 18313945 | doi = 10.1016/j.ympev.2008.01.001 }}</ref> murine,<ref name="pmid18616808">{{cite journal | vauthors = Lecompte E, Aplin K, Denys C, Catzeflis F, Chades M, Chevret P | title = Phylogeny and biogeography of African Murinae based on mitochondrial and nuclear gene sequences, with a new tribal classification of the subfamily | journal = BMC Evolutionary Biology | volume = 8 | pages = 199 | date = July 2008 | pmid = 18616808 | pmc = 2490707 | doi = 10.1186/1471-2148-8-199 | url = http://www.biomedcentral.com/1471-2148/8/199/ }}</ref> and peromyscine <ref name="Miller2008">{{cite journal |author1=Miller J. R. |author2=Engstrom M. D. | title = The relationships of major lineages within peromyscine rodents: a molecular phylogenetic hypothesis and systematic reappraisal | journal = J. Mammal. | volume = 89 | issue = 5 | pages = 1279–1295 | year = 2008 | pmid = | doi = 10.1644/07-MAMM-A-195.1| url = | issn = }}</ref> rodents, in arctoid <ref name="pmid16814570">{{cite journal | vauthors = Fulton TL, Strobeck C | title = Molecular phylogeny of the Arctoidea (Carnivora): effect of missing data on supertree and supermatrix analyses of multiple gene data sets | journal = Molecular Phylogenetics and Evolution | volume = 41 | issue = 1 | pages = 165–81 | date = October 2006 | pmid = 16814570 | doi = 10.1016/j.ympev.2006.05.025 }}</ref> and [[felid]] <ref name="pmid16400146">{{cite journal | vauthors = Johnson WE, Eizirik E, Pecon-Slattery J, Murphy WJ, Antunes A, Teeling E, O'Brien SJ | title = The late Miocene radiation of modern Felidae: a genetic assessment | journal = Science | volume = 311 | issue = 5757 | pages = 73–7 | date = January 2006 | pmid = 16400146 | doi = 10.1126/science.1122277 }}</ref> carnivores, and in [[dermoptera]]ns.<ref name="pmid19000793">{{cite journal | vauthors = Janecka JE, Helgen KM, Lim NT, Baba M, Izawa M, Murphy WJ | title = Evidence for multiple species of Sunda colugo | journal = Current Biology | volume = 18 | issue = 21 | pages = R1001-2 | date = November 2008 | pmid = 19000793 | doi = 10.1016/j.cub.2008.09.005 }}</ref>
Note that the GHR intron 9 has also been used to investigate the [[mustelid]] <ref name="pmid14530127">{{cite journal |author1=Koepfli K. P. |author2=Wayne R. K. | title = Type I STS markers are more informative than cytochrome B in phylogenetic reconstruction of the Mustelidae (Mammalia: Carnivora) | journal = Syst. Biol. | volume = 52 | issue = 5 | pages = 571–593 | year = 2003 | pmid = 14530127 | doi = 10.1080/10635150390235368| url = | issn = }}</ref> and hyaenid <ref name="pmid16503281">{{cite journal |author1=Koepfli K. P. |author2=Jenks S. M. |author3=Eizirik E. |author4=Zahirpour T. |author5=Van Valkenburgh B. |author6=Wayne R. K. | title = Molecular systematics of the Hyaenidae: relationships of a relictual lineage resolved by a molecular supermatrix | journal = Mol. Phylogenet. Evol. | volume = 38 | issue = 3 | pages = 603–620 | year = 2006 | pmid = 16503281 | doi = 10.1016/j.ympev.2005.10.017| url = | issn = }}</ref> [[carnivores]] phylogenetics.
Note that the GHR intron 9 has also been used to investigate the [[mustelid]] <ref name="pmid14530127">{{cite journal | vauthors = Koepfli KP, Wayne RK | title = Type I STS markers are more informative than cytochrome B in phylogenetic reconstruction of the Mustelidae (Mammalia: Carnivora) | journal = Systematic Biology | volume = 52 | issue = 5 | pages = 571–93 | date = October 2003 | pmid = 14530127 | doi = 10.1080/10635150390235368 }}</ref> and hyaenid <ref name="pmid16503281">{{cite journal | vauthors = Koepfli KP, Jenks SM, Eizirik E, Zahirpour T, Van Valkenburgh B, Wayne RK | title = Molecular systematics of the Hyaenidae: relationships of a relictual lineage resolved by a molecular supermatrix | journal = Molecular Phylogenetics and Evolution | volume = 38 | issue = 3 | pages = 603–20 | date = March 2006 | pmid = 16503281 | doi = 10.1016/j.ympev.2005.10.017 }}</ref> [[carnivores]] phylogenetics.


==Antagonists==
==Antagonists==
Growth hormone [[receptor antagonist]]s such as [[pegvisomant]] (trade name ''Somavert'') are used in the treatment of [[acromegaly]].<ref name="Schreiber">{{cite journal | last=Schreiber | first=I |author2=Buchfelder M |author3=Droste M | title=Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the German Pegvisomant Observational Study | journal=European Journal of Endocrinology | volume=156 | issue=1 | pages=75–82 | date=January 2007 | url=http://www.eje-online.org/cgi/content/full/156/1/75?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=Schreiber&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=156&resourcetype=HWCIT | pmid=17218728 | doi=10.1530/eje.1.02312 |display-authors=etal}}</ref> 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 [[Subcutaneous injection|under the skin]].<ref name=ema>{{cite web|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000409/WC500054625.pdf|title=Scientific Discussion of Somavert|year=2004|publisher=European Medicines Agency}}</ref>
Growth hormone [[receptor antagonist]]s such as [[pegvisomant]] (trade name ''Somavert'') are used in the treatment of [[acromegaly]].<ref name="Schreiber">{{cite journal | vauthors = Schreiber I, Buchfelder M, Droste M, Forssmann K, Mann K, Saller B, Strasburger CJ | title = Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the German Pegvisomant Observational Study | journal = European Journal of Endocrinology | volume = 156 | issue = 1 | pages = 75–82 | date = January 2007 | pmid = 17218728 | doi = 10.1530/eje.1.02312 | url = http://www.eje-online.org/cgi/content/full/156/1/75?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=Schreiber&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=156&resourcetype=HWCIT }}</ref> 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 [[Subcutaneous injection|under the skin]].<ref name=ema>{{cite web|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000409/WC500054625.pdf|title=Scientific Discussion of Somavert|year=2004|publisher=European Medicines Agency}}</ref>


==See also==
== See also ==
* [[Hypothalamic–pituitary–somatic axis]]
* [[Hypothalamic–pituitary–somatic axis]]


==References==
== References ==
{{reflist}}
{{reflist}}


==External links==
== External links ==
* {{MeshName|Somatotropin+receptors}}
* {{MeshName|Somatotropin+receptors}}
* [http://ghr.nlm.nih.gov/handbook/illustrations/gh;jsessionid=38C6FF829262C710E269F048A93E9ECC Illustration at nih.gov]
* [http://ghr.nlm.nih.gov/handbook/illustrations/gh;jsessionid=38C6FF829262C710E269F048A93E9ECC Illustration at nih.gov]
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{{GH/IGF-1 axis signaling modulators}}
{{GH/IGF-1 axis signaling modulators}}


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{{PDB_Gallery|geneid=2690}}
{{PDB_Gallery|geneid=2690}}

Latest revision as of 12:43, 5 December 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Wikidata
View/Edit Human

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.

Function

This gene encodes a protein that is a transmembrane receptor for growth hormone.[3][4] 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 [5]) and the activation of an intra- and intercellular signal transduction pathway leading to growth.[6] 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.

File:Euryzygomatomyinae GHR AA.svg
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.[7]

Interactions

Growth hormone receptor has been shown to interact with SGTA,[8] PTPN11,[9][10] Janus kinase 2,[11][12][13] Suppressor of cytokine signaling 1[14] and CISH.[14]

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.[15][16][17] GHR has also proven useful at lower taxonomic levels, e.g., in octodontoid,[18][7] arvicoline,[19] muroid,[20][21] murine,[22] and peromyscine [23] rodents, in arctoid [24] and felid [25] carnivores, and in dermopterans.[26] Note that the GHR intron 9 has also been used to investigate the mustelid [27] and hyaenid [28] carnivores phylogenetics.

Antagonists

Growth hormone receptor antagonists such as pegvisomant (trade name Somavert) are used in the treatment of acromegaly.[29] 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.[30]

See also

References

  1. ↑ 1.0 1.1 "Entrez Gene: GHR growth hormone receptor".
  2. ↑ 2.0 2.1 "OrthoMaM phylogenetic marker: GHR coding sequence".
  3. ↑ Dehkhoda F, Lee CM, Medina J, Brooks AJ (13 February 2018). "The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects". Frontiers in Endocrinology. 9: 35. doi:10.3389/fendo.2018.00035. PMID 29487568.
  4. ↑ 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. PMID 20664532.
  5. ↑ 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. PMID 17321774.
  6. ↑ 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. PMID 24833397.
  7. ↑ 7.0 7.1 Fabre PH, Upham NS, Emmons LH, Justy F, Leite YL, Carolina Loss A, Orlando L, Tilak MK, Patterson BD, Douzery EJ (March 2017). "Mitogenomic Phylogeny, Diversification, and Biogeography of South American Spiny Rats". Molecular Biology and Evolution. 34 (3): 613–633. doi:10.1093/molbev/msw261. PMID 28025278.
  8. ↑ Schantl JA, Roza M, De Jong AP, Strous GJ (August 2003). "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. doi:10.1042/BJ20021591. PMC 1223544. PMID 12735788.
  9. ↑ Stofega MR, Herrington J, Billestrup N, Carter-Su C (September 2000). "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. doi:10.1210/me.14.9.1338. PMID 10976913.
  10. ↑ Moutoussamy S, Renaudie F, Lago F, Kelly PA, Finidori J (June 1998). "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. doi:10.1074/jbc.273.26.15906. PMID 9632636.
  11. ↑ Frank SJ, Yi W, Zhao Y, Goldsmith JF, Gilliland G, Jiang J, Sakai I, Kraft AS (June 1995). "Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor". The Journal of Biological Chemistry. 270 (24): 14776–85. doi:10.1074/jbc.270.24.14776. PMID 7540178.
  12. ↑ VanderKuur JA, Wang X, Zhang L, Campbell GS, Allevato G, Billestrup N, Norstedt G, Carter-Su C (August 1994). "Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase". The Journal of Biological Chemistry. 269 (34): 21709–17. PMID 8063815.
  13. ↑ 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. PMID 10502458.
  14. ↑ 14.0 14.1 Ram PA, Waxman DJ (December 1999). "SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms". The Journal of Biological Chemistry. 274 (50): 35553–61. doi:10.1074/jbc.274.50.35553. PMID 10585430.
  15. ↑ Adkins RM, Gelke EL, Rowe D, Honeycutt RL (May 2001). "Molecular phylogeny and divergence time estimates for major rodent groups: evidence from multiple genes". Molecular Biology and Evolution. 18 (5): 777–91. doi:10.1093/oxfordjournals.molbev.a003860. PMID 11319262.
  16. ↑ 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. PMID 12644400.
  17. ↑ Blanga-Kanfi S, Miranda H, Penn O, Pupko T, DeBry RW, Huchon D (April 2009). "Rodent phylogeny revised: analysis of six nuclear genes from all major rodent clades". BMC Evolutionary Biology. 9: 71. doi:10.1186/1471-2148-9-71. PMC 2674048. PMID 19341461.
  18. ↑ 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. PMID 12644405.
  19. ↑ Galewski T, Tilak MK, Sanchez S, Chevret P, Paradis E, Douzery EJ (October 2006). "The evolutionary radiation of Arvicolinae rodents (voles and lemmings): relative contribution of nuclear and mitochondrial DNA phylogenies". BMC Evolutionary Biology. 6: 80. doi:10.1186/1471-2148-6-80. PMC 1618403. PMID 17029633.
  20. ↑ 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. PMID 15371245.
  21. ↑ 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. PMID 18313945.
  22. ↑ Lecompte E, Aplin K, Denys C, Catzeflis F, Chades M, Chevret P (July 2008). "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. doi:10.1186/1471-2148-8-199. PMC 2490707. PMID 18616808.
  23. ↑ Miller J. R.; Engstrom M. D. (2008). "The relationships of major lineages within peromyscine rodents: a molecular phylogenetic hypothesis and systematic reappraisal". J. Mammal. 89 (5): 1279–1295. doi:10.1644/07-MAMM-A-195.1.
  24. ↑ 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. PMID 16814570.
  25. ↑ Johnson WE, Eizirik E, Pecon-Slattery J, Murphy WJ, Antunes A, Teeling E, O'Brien SJ (January 2006). "The late Miocene radiation of modern Felidae: a genetic assessment". Science. 311 (5757): 73–7. doi:10.1126/science.1122277. PMID 16400146.
  26. ↑ Janecka JE, Helgen KM, Lim NT, Baba M, Izawa M, Murphy WJ (November 2008). "Evidence for multiple species of Sunda colugo". Current Biology. 18 (21): R1001–2. doi:10.1016/j.cub.2008.09.005. PMID 19000793.
  27. ↑ Koepfli KP, Wayne RK (October 2003). "Type I STS markers are more informative than cytochrome B in phylogenetic reconstruction of the Mustelidae (Mammalia: Carnivora)". Systematic Biology. 52 (5): 571–93. doi:10.1080/10635150390235368. PMID 14530127.
  28. ↑ 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. PMID 16503281.
  29. ↑ 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. PMID 17218728.
  30. ↑ "Scientific Discussion of Somavert" (PDF). European Medicines Agency. 2004.

External links


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