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Gene Review

GHR  -  growth hormone receptor

Homo sapiens

Synonyms: GH receptor, GHBP, Growth hormone receptor, Somatotropin receptor
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Disease relevance of GHR

  • The use of FITC-labeled mAb263 and hGH is of potential use for the study of GHR levels in patients exhibiting different types of growth disorders [1].
  • We have previously described two families (H and M) with GH binding protein-positive Laron Syndrome (LS), proposed to have one or more post GHR signaling defects [2].
  • In this study, we investigated the role of human growth hormone (GH) and its receptor (GHR) in human prostate cancer [3].
  • We first demonstrated mRNA expression of GHR and of its exon 9-truncated isoform (GHR(tr)) in benign prostate hyperplasia (BPH) and prostate adenocarcinoma patient tissues, as well as in LNCaP, PC3 and DU145 human prostate cancer cell lines [3].
  • Synthesis of the GHR antagonist pegvisomant has provided another agent with which to treat patients with acromegaly [4].

Psychiatry related information on GHR

  • The effects of food deprivation on the hepatic level growth hormone receptor (GHR) were investigated in black seabream (Acanthopagrus schlegeli) both at the protein level (by radioreceptor assay) and at the mRNA level (by ribonuclease protection assay) [5].
  • RESULTS: GHR adolescents showed impairments in immediate logical memory, verbal working memory, CPT-IP performance, and fine motor skills [6].

High impact information on GHR


Chemical compound and disease context of GHR


Biological context of GHR

  • These results indicate that the D112G mutation in the GH-1 gene causes production of bioinactive GH, which prevents dimerization of GHR and is therefore responsible for the patient's short stature [16].
  • Both hGH and bGH stimulated tyrosine phosphorylation of a 95-kDa protein in cells transfected with WT GHR, but bGH was less effective in cells expressing mutant GHR [17].
  • We conclude that whereas endocytosis and degradation require the ubiquitin system, they are independent of GHR signal transduction [18].
  • The implications of these findings with regard to GH signaling and GHR down-regulation are discussed [19].
  • The ubiquitin-proteasome system is required in growth hormone receptor (GHR) endocytosis [18].

Anatomical context of GHR

  • By anti-GHR cytoplasmic domain immunoblotting, we observed that the remnant induced in response to phorbol ester or platelet-derived growth factor has a reliable pattern of appearance and disappearance in both mouse preadipocytes endogenously expressing GHR and transfected fibroblasts expressing rabbit GHR [20].
  • No proteins showed increased tyrosyl phosphorylation in CHO cells expressing GHR1-294, GHR4P-->A, or GHR delta P [21].
  • This modification did not alter the rate and extent of receptor-bound growth hormone internalization as compared with a functional GHR, nor did it change its turnover and transport to the plasma membrane [18].
  • Northern blot analysis revealed a 5.5-kb GHR messenger RNA (mRNA) species, but semiquantitative RT-PCR revealed no difference in GHR mRNA expression by normal and OA chondrocytes [22].
  • As part of an effort to define the local effects of the placentally expressed members of the GH/Prl family of hormones on the placenta, we have identified an isoform (hGHRd3) of the growth hormone receptor expressed in the placental villi. hGHRd3 mRNA differs from the liver GHR mRNA by the deletion of a 66-base pair segment encoding exon 3 [23].

Associations of GHR with chemical compounds

  • In two unrelated families, the same GHR mutation was identified, resulting in the substitution of a highly conserved aspartate residue by histidine at position 152 (D152H) of the exoplasmic domain, within the postulated interface sequence involved in homodimerization [24].
  • Deletion and alanine substitution mutagenesis indicated that, similar to other TACE substrates, the spacing of residues in this region, more than their identity, influences GHR cleavage susceptibility [25].
  • Here, we have sought to determine whether constitutively active receptor can be created in the absence of the extracellular domain by substituting it with high affinity leucine zippers to create dimers of the growth hormone receptor (GHR) signaling domain [26].
  • Lactacystin, a specific proteasome inhibitor, did not appreciably change the time course of remnant appearance or clearance but allowed detection of the GHR stub, a receptor fragment slightly smaller than the remnant but containing the C terminus of the remnant (receptor cytoplasmic domain) [20].
  • In situ hybridization using the same digoxigenin-labeled oligoprobe localized the GHR mRNA in the granulosa cells of dominant and antral follicles, corpus luteum, corpora albicans and the endothelium of blood vessels [27].

Physical interactions of GHR

  • Comparisons with the hGH-hGHR complex reveal how hGH can bind to the two distinctly different receptor binding surfaces [28].
  • In 1993, GH receptor (GHR) was first observed to bind to the tyrosine kinase JAK2 [29].
  • We found that GHR interacts with SGT [30].
  • The crystal structure of human GH bound to human GHR did not resolve this extreme N-terminal region of the receptor but our data indicate that the N-terminal loop undertakes a 180 degrees turn bringing it into close proximity to the hormone-binding domain in a fashion analogous to the prolactin receptor [31].
  • For peptides endowed with hGM-CSF binding activity were identified and the postulated homology between the binding sites of hGM-CSFR alpha GHR was confirmed [32].

Enzymatic interactions of GHR

  • Once activated, JAK2 tyrosyl-phosphorylates both itself and the cytoplasmic domain of GHR [33].
  • We conclude that GH induces activation of STAT3 and STAT5b by two different pathways: one primarily dependent on activation of JAK2 (STAT3) and another that is additionally reliant on the presence of an intact and tyrosine-phosphorylated GHR cytoplasmic domain (STAT5b) [34].
  • The disulfide-linked form of the hGHR accounted for a substantial fraction of the receptors that became tyrosine phosphorylated early into hGH treatment [35].

Regulatory relationships of GHR

  • In conclusion, hGH 44-191 binds with low affinity to the GHR and at supraphysiologic levels stimulates proliferation of FDC-P1-hGHR cells [36].
  • Synthetic tyrosine phosphorylated peptides corresponding to the GH receptor sequence around the three tyrosines inhibited Stat5 DNA-binding activity while their non-phosphorylated counterparts were ineffective [37].
  • Preliminary studies have clearly demonstrated the effectiveness of the GH receptor antagonist in suppressing IGF-I levels in acromegalic patients previously unresponsive to somatostatin analogues [38].
  • CONCLUSIONS: Most patients with NF1 have localised neurofibromas that express GHR [39].
  • One recipient of rhIGF-I developed papilledema, which resolved spontaneously. rhIGF-I therapy did not alter serum IGF-binding protein-3 concentrations. rhIGF-I treatment is effective in stimulating skeletal growth in GH receptor deficiency [40].

Other interactions of GHR


Analytical, diagnostic and therapeutic context of GHR


  1. Differential expression of surface membrane growth hormone receptor on human peripheral blood lymphocytes detected by dual fluorochrome flow cytometry. Badolato, R., Bond, H.M., Valerio, G., Petrella, A., Morrone, G., Waters, M.J., Venuta, S., Tenore, A. J. Clin. Endocrinol. Metab. (1994) [Pubmed]
  2. Activation of the signal transducers and activators of transcription signaling pathway by growth hormone (GH) in skin fibroblasts from normal and GH binding protein-positive Laron Syndrome children. Freeth, J.S., Silva, C.M., Whatmore, A.J., Clayton, P.E. Endocrinology (1998) [Pubmed]
  3. Growth hormone (GH) receptors in prostate cancer: gene expression in human tissues and cell lines and characterization, GH signaling and androgen receptor regulation in LNCaP cells. Weiss-Messer, E., Merom, O., Adi, A., Karry, R., Bidosee, M., Ber, R., Kaploun, A., Stein, A., Barkey, R.J. Mol. Cell. Endocrinol. (2004) [Pubmed]
  4. Clinical pharmacology of human growth hormone and its secretagogues. Root, A.W., Root, M.J. Curr. Drug Targets Immune Endocr. Metabol. Disord. (2002) [Pubmed]
  5. Effects of food deprivation on expression of growth hormone receptor and proximate composition in liver of black seabream Acanthopagrus schlegeli. Deng, L., Zhang, W.M., Lin, H.R., Cheng, C.H. Comp. Biochem. Physiol. B, Biochem. Mol. Biol. (2004) [Pubmed]
  6. The Palau Early Psychosis Study: Neurocognitive functioning in high-risk adolescents. Myles-Worsley, M., Ord, L.M., Ngiralmau, H., Weaver, S., Blailes, F., Faraone, S.V. Schizophr. Res. (2007) [Pubmed]
  7. Mechanism of signaling by growth hormone receptor. Argetsinger, L.S., Carter-Su, C. Physiol. Rev. (1996) [Pubmed]
  8. A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Dos Santos, C., Essioux, L., Teinturier, C., Tauber, M., Goffin, V., Bougnères, P. Nat. Genet. (2004) [Pubmed]
  9. Mutations of the growth hormone receptor in children with idiopathic short stature. The Growth Hormone Insensitivity Study Group. Goddard, A.D., Covello, R., Luoh, S.M., Clackson, T., Attie, K.M., Gesundheit, N., Rundle, A.C., Wells, J.A., Carlsson, L.M. N. Engl. J. Med. (1995) [Pubmed]
  10. Growth hormone-receptor gene in Laron dwarfism. Bass, S., Wells, J. N. Engl. J. Med. (1990) [Pubmed]
  11. Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. Leung, K.C., Doyle, N., Ballesteros, M., Sjogren, K., Watts, C.K., Low, T.H., Leong, G.M., Ross, R.J., Ho, K.K. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  12. Growth hormone receptor expression and function in meningiomas: effect of a specific receptor antagonist. Friend, K.E., Radinsky, R., McCutcheon, I.E. J. Neurosurg. (1999) [Pubmed]
  13. Pharmacological therapy for acromegaly: a critical review. Muller, A.F., Van Der Lely, A.J. Drugs (2004) [Pubmed]
  14. The first homozygous mutation (S226I) in the highly-conserved WSXWS-like motif of the GH receptor causing Laron syndrome: supression of GH secretion by GnRH analogue therapy not restored by dihydrotestosterone administration. Jorge, A.A., Souza, S.C., Arnhold, I.J., Mendonca, B.B. Clin. Endocrinol. (Oxf) (2004) [Pubmed]
  15. Regulation of growth hormone receptor gene expression. Schwartzbauer, G., Menon, R.K. Mol. Genet. Metab. (1998) [Pubmed]
  16. Biologically inactive growth hormone caused by an amino acid substitution. Takahashi, Y., Shirono, H., Arisaka, O., Takahashi, K., Yagi, T., Koga, J., Kaji, H., Okimura, Y., Abe, H., Tanaka, T., Chihara, K. J. Clin. Invest. (1997) [Pubmed]
  17. A single arginine residue determines species specificity of the human growth hormone receptor. Souza, S.C., Frick, G.P., Wang, X., Kopchick, J.J., Lobo, R.B., Goodman, H.M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  18. Growth hormone receptor ubiquitination, endocytosis, and degradation are independent of signal transduction via Janus kinase 2. Alves dos Santos, C.M., ten Broeke, T., Strous, G.J. J. Biol. Chem. (2001) [Pubmed]
  19. Growth hormone (GH)-induced dimerization inhibits phorbol ester-stimulated GH receptor proteolysis. Zhang, Y., Guan, R., Jiang, J., Kopchick, J.J., Black, R.A., Baumann, G., Frank, S.J. J. Biol. Chem. (2001) [Pubmed]
  20. Growth hormone receptor is a target for presenilin-dependent gamma-secretase cleavage. Cowan, J.W., Wang, X., Guan, R., He, K., Jiang, J., Baumann, G., Black, R.A., Wolfe, M.S., Frank, S.J. J. Biol. Chem. (2005) [Pubmed]
  21. Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase. VanderKuur, J.A., Wang, X., Zhang, L., Campbell, G.S., Allevato, G., Billestrup, N., Norstedt, G., Carter-Su, C. J. Biol. Chem. (1994) [Pubmed]
  22. Increased insulin-like growth factor 1 production by human osteoarthritic chondrocytes is not dependent on growth hormone action. Doré, S., Abribat, T., Rousseau, N., Brazeau, P., Tardif, G., DiBattista, J.A., Cloutier, J.M., Pelletier, J.P., Martel-Pelletier, J. Arthritis Rheum. (1995) [Pubmed]
  23. Functional characterization of the alternatively spliced, placental human growth hormone receptor. Urbanek, M., Russell, J.E., Cooke, N.E., Liebhaber, S.A. J. Biol. Chem. (1993) [Pubmed]
  24. A single amino acid substitution in the exoplasmic domain of the human growth hormone (GH) receptor confers familial GH resistance (Laron syndrome) with positive GH-binding activity by abolishing receptor homodimerization. Duquesnoy, P., Sobrier, M.L., Duriez, B., Dastot, F., Buchanan, C.R., Savage, M.O., Preece, M.A., Craescu, C.T., Blouquit, Y., Goossens, M. EMBO J. (1994) [Pubmed]
  25. Metalloprotease-mediated GH receptor proteolysis and GHBP shedding. Determination of extracellular domain stem region cleavage site. Wang, X., He, K., Gerhart, M., Huang, Y., Jiang, J., Paxton, R.J., Yang, S., Lu, C., Menon, R.K., Black, R.A., Baumann, G., Frank, S.J. J. Biol. Chem. (2002) [Pubmed]
  26. Growth hormone (GH)-independent dimerization of GH receptor by a leucine zipper results in constitutive activation. Behncken, S.N., Billestrup, N., Brown, R., Amstrup, J., Conway-Campbell, B., Waters, M.J. J. Biol. Chem. (2000) [Pubmed]
  27. Identification and cellular localization of growth hormone receptor gene expression in the human ovary. Sharara, F.I., Nieman, L.K. J. Clin. Endocrinol. Metab. (1994) [Pubmed]
  28. The X-ray structure of a growth hormone-prolactin receptor complex. Somers, W., Ultsch, M., De Vos, A.M., Kossiakoff, A.A. Nature (1994) [Pubmed]
  29. SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone. Carter-Su, C., Rui, L., Stofega, M.R. Recent Prog. Horm. Res. (2000) [Pubmed]
  30. Small glutamine-rich tetratricopeptide repeat-containing protein (SGT) interacts with the ubiquitin-dependent endocytosis (UbE) motif of the growth hormone receptor. Schantl, J.A., Roza, M., De Jong, A.P., Strous, G.J. Biochem. J. (2003) [Pubmed]
  31. Identification of novel sites in the ovine growth hormone receptor involved in binding hormone and conferring species specificity. Allan, G.J., Shand, J.H., Beattie, J., Flint, D.J. Eur. J. Biochem. (1999) [Pubmed]
  32. Binding of human GM-CSF to synthetic peptides of the alpha subunit of its receptor. Di Bartolo, V., Danè, A., Cassano, E., Viganò, S., Chiello, E., Verniani, D., Beffy, P., Pegoraro, S., Hamdan, M., Rovero, P., Revoltella, R.P. J. Recept. Signal Transduct. Res. (1996) [Pubmed]
  33. Growth-hormone signal transduction. Campbell, G.S. J. Pediatr. (1997) [Pubmed]
  34. Growth hormone receptor cytoplasmic domain differentially promotes tyrosine phosphorylation of signal transducers and activators of transcription 5b and 3 by activated JAK2 kinase. Yi, W., Kim, S.O., Jiang, J., Park, S.H., Kraft, A.S., Waxman, D.J., Frank, S.J. Mol. Endocrinol. (1996) [Pubmed]
  35. Treatment of IM-9 cells with human growth hormone (GH) promotes rapid disulfide linkage of the GH receptor. Frank, S.J., Gilliland, G., Van Epps, C. Endocrinology (1994) [Pubmed]
  36. Human growth hormone fragments 1-43 and 44-191: in vitro somatogenic activity and receptor binding characteristics in human and nonprimate systems. Rowlinson, S.W., Waters, M.J., Lewis, U.J., Barnard, R. Endocrinology (1996) [Pubmed]
  37. The role of GH receptor tyrosine phosphorylation in Stat5 activation. Hansen, J.A., Hansen, L.H., Wang, X., Kopchick, J.J., Gouilleux, F., Groner, B., Nielsen, J.H., Møldrup, A., Galsgaard, E.D., Billestrup, N. J. Mol. Endocrinol. (1997) [Pubmed]
  38. New medical approaches in pituitary adenomas. Colao, A., Di Sarno, A., Marzullo, P., Di Somma, C., Cerbone, G., Landi, M.L., Faggiano, A., Merola, B., Lombardi, G. Horm. Res. (2000) [Pubmed]
  39. Identification of growth hormone receptor in localised neurofibromas of patients with neurofibromatosis type 1. Cunha, K.S., Barboza, E.P., Da Fonseca, E.C. J. Clin. Pathol. (2003) [Pubmed]
  40. A randomized, double blind, placebo-controlled trial on safety and efficacy of recombinant human insulin-like growth factor-I in children with growth hormone receptor deficiency. Guevara-Aguirre, J., Vasconez, O., Martinez, V., Martinez, A.L., Rosenbloom, A.L., Diamond, F.B., Gargosky, S.E., Nonoshita, L., Rosenfeld, R.G. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  41. Growth hormone is a human macrophage activating factor. Priming of human monocytes for enhanced release of H2O2. Warwick-Davies, J., Lowrie, D.B., Cole, P.J. J. Immunol. (1995) [Pubmed]
  42. A novel C-terminal growth hormone receptor (GHR) mutation results in impaired GHR-STAT5 but normal STAT-3 signaling. Tiulpakov, A., Rubtsov, P., Dedov, I., Peterkova, V., Bezlepkina, O., Chrousos, G.P., Hochberg, Z. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  43. The Growth Response to Growth Hormone (GH) Treatment in Children with Isolated GH Deficiency Is Independent of the Presence of the Exon 3-Minus Isoform of the GH Receptor. Blum, W.F., Machinis, K., Shavrikova, E.P., Keller, A., Stobbe, H., Pfaeffle, R.W., Amselem, S. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  44. Growth hormone (GH) and prolactin receptors in human peripheral blood mononuclear cells: relation with age and GH-binding protein. Bresson, J.L., Jeay, S., Gagnerault, M.C., Kayser, C., Beressi, N., Wu, Z., Kinet, S., Dardenne, M., Postel-Vinay, M.C. Endocrinology (1999) [Pubmed]
  45. A conformationally sensitive GHR [growth hormone (GH) receptor] antibody: impact on GH signaling and GHR proteolysis. Jiang, J., Wang, X., He, K., Li, X., Chen, C., Sayeski, P.P., Waters, M.J., Frank, S.J. Mol. Endocrinol. (2004) [Pubmed]
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