Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The growth hormone receptor: mechanism of activation and clinical implications

Abstract

Growth hormone is widely used clinically to promote growth and anabolism and for other purposes. Its actions are mediated via the growth hormone receptor, both directly by tyrosine kinase activation and indirectly by induction of insulin-like growth factor 1 (IGF-1). Insensitivity to growth hormone (Laron syndrome) can result from mutations in the growth hormone receptor and can be treated with IGF-1. This treatment is, however, not fully effective owing to the loss of the direct actions of growth hormone and altered availability of exogenous IGF-1. Excessive activation of the growth hormone receptor by circulating growth hormone results in gigantism and acromegaly, whereas cell transformation and cancer can occur in response to autocrine activation of the receptor. Advances in understanding the mechanism of receptor activation have led to a model in which the growth hormone receptor exists as a constitutive dimer. Binding of the hormone realigns the subunits by rotation and closer apposition, resulting in juxtaposition of the catalytic domains of the associated tyrosine-protein kinase JAK2 below the cell membrane. This change results in activation of JAK2 by transphosphorylation, then phosphorylation of receptor tyrosines in the cytoplasmic domain, which enables binding of adaptor proteins, as well as direct phosphorylation of target proteins. This model is discussed in the light of salient information from closely related class 1 cytokine receptors, such as the erythropoietin, prolactin and thrombopoietin receptors.

Key Points

  • The growth hormone receptor mediates a wide range of growth-related and metabolic actions, both directly and via insulin-like growth factor 1 (IGF-1)

  • Receptor loss-of-function, predominantly owing to mutations in the extracellular domain, results in growth hormone insensitivity or Laron syndrome

  • Receptor gain-of-function mutations are not known, but excessive receptor stimulation by growth hormone leads to gigantism, adult acromegaly and cancer (if autocrine growth hormone signaling is involved)

  • The hormone–receptor complex is well-defined at a molecular level for the extracellular domain

  • The growth hormone receptor exists as a constitutive dimer, and activation involves rearrangement of the receptor subunits to align the tyrosine-protein kinases JAK2 and Src bound below the cell membrane for activation

  • JAK2 and the Src family of proto-oncogene tyrosine-protein kinases initiate signaling, the former involving the key transcription factor signal transducer and activator of transcription 5b

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Major physiological actions of growth hormone and insulin-like growth factor 1 action.
Figure 2: Locations of known point mutations in the extracellular domain of the human growth hormone receptor associated with impaired postnatal growth.
Figure 3: Signaling pathways of growth hormone.
Figure 4: Model for the activation of the growth hormone receptor by growth hormone.

References

  1. Waxman, D. J. & O'Connor, C. Growth hormone regulation of sex-dependent liver gene expression. Mol. Endocrinol. 20, 2613–2629 (2006).

    CAS  PubMed  Article  Google Scholar 

  2. Lichanska, A. M. & Waters, M. J. How growth hormone controls growth, obesity and sexual dimorphism. Trends Genet. 24, 41–47 (2008).

    CAS  PubMed  Article  Google Scholar 

  3. Lanning, N. J. & Carter-Su, C. Recent advances in growth hormone signaling. Rev. Endocr. Metab. Disord. 7, 225–235 (2006).

    CAS  PubMed  Article  Google Scholar 

  4. Waters, M. J. et al. Growth hormone as a cytokine. Clin. Exp. Pharmacol. Physiol. 26, 760–764 (1999).

    CAS  PubMed  Article  Google Scholar 

  5. Rowland, J. E. et al. In vivo analysis of growth hormone receptor signaling domains and their associated transcripts. Mol. Cell. Biol. 25, 66–77 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Barclay, J. L. et al. In vivo targeting of the growth hormone receptor (GHR) Box1 sequence demonstrates that the GHR does not signal exclusively through JAK2. Mol. Endocrinol. 24, 204–217 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Laron, Z., Ginsberg, S. & Webb, M. Nonalcoholic fatty liver in patients with Laron syndrome and GH gene deletion. Growth Horm. IGF Res. 18, 434–438 (2008).

    CAS  PubMed  Article  Google Scholar 

  8. Slot, K. A. et al. Reduced recruitment and survival of primordial and growing follicles in GH-receptor deficient mice. Reproduction 131, 525–532 (2006).

    CAS  PubMed  Article  Google Scholar 

  9. Sotiropoulos, A. et al. Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation. Proc. Natl Acad. Sci. USA 103, 7315–7320 (2006).

    CAS  PubMed  Article  Google Scholar 

  10. Wang, J., Zhou, J., Cheng, C. M., Kopchick, J. J. & Bondy, C. A. Evidence supporting dual, IGF-1 independent and IGF-1 dependent, roles for GH in promoting longitudinal bone growth. J. Endocrinol. 180, 247–255 (2004).

    CAS  PubMed  Article  Google Scholar 

  11. Lindahl, A., Isgaard, J., Carlsson, L. & Isaksson, O. G. Differential effects of growth hormone and insulin-like growth factor 1 on colony formation of epiphyseal chondrocytes in suspension culture in rats of different ages. Endocrinology 121, 1061–1069 (1987).

    CAS  PubMed  Article  Google Scholar 

  12. Blackmore, D. G., Golmohammadi, M. G., Large, B., Waters, M. J. & Rietze, R. L. Exercise increases neural stem cell number in a growth hormone-dependent manner, augmenting the regenerative response in aged mice. Stem Cells 27, 2044–2052 (2009).

    CAS  PubMed  Article  Google Scholar 

  13. McLenachan, S., Lum, M. G., Waters, M. J. & Turnley, A. M. Growth hormone promotes proliferation of adult neurosphere cultures. Growth Horm. IGF Res. 19, 212–218 (2009).

    CAS  PubMed  Article  Google Scholar 

  14. Rosenbloom, A. L. Insulin-like growth factor-1 therapy of short stature. J. Pediatr. Endocrinol. Metab. 21, 301–315 (2008).

    CAS  PubMed  Google Scholar 

  15. Lupu, F., Terwilliger, J. D., Lee, K., Segre, G. V. & Efstradiatis, A. Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev. Biol. 229, 141–162 (2001).

    CAS  PubMed  Article  Google Scholar 

  16. Møller, N. & Jørgensen, J. O. Effects of growth hormone on glucose, lipid and protein metabolism in human subjects. Endocr. Rev. 30, 152–177 (2009).

    PubMed  Article  CAS  Google Scholar 

  17. Simon, D., Léger, J. & Carel, J. C. Optimal use of growth hormone therapy for maximizing adult height in children born small for gestational age. Best Pract. Res. Clin. Endocrinol. Metab. 22, 525–537 (2008).

    CAS  PubMed  Article  Google Scholar 

  18. Labarta, J. I. et al. Growth and growth hormone treatment in short stature children born small for gestational age. Pediatr. Endocrinol. Rev. 6 (Suppl. 3), 350–357 (2009).

    PubMed  Google Scholar 

  19. Bakker, B., Frane, J., Anhalt, H., Lippe, B. & Rosenfeld, R. G. Height velocity targets from the national cooperative growth study for first-year growth hormone responses in short children. J. Clin. Endocrinol. Metab. 93, 352–357 (2008).

    CAS  PubMed  Article  Google Scholar 

  20. Hokken-Koelega, A. C. et al. Placebo-controlled, double blind, cross over trial of growth hormone treatment in prepubertal children with chronic renal failure. Lancet 338, 585–590 (1991).

    CAS  PubMed  Article  Google Scholar 

  21. Mehls, O. et al. Growth hormone treatment in short children with chronic kidney disease. Acta Paediatr. 97, 1159–1164 (2008).

    CAS  Article  PubMed  Google Scholar 

  22. Blum, W. F. et al. Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: Two year results of a randomized, controlled, multicenter trial. J. Clin. Endocrinol. Metab. 92, 219–228 (2007).

    CAS  PubMed  Article  Google Scholar 

  23. Bryant, J., Baxter, L., Cave, C. B. & Milne, R. Recombinant GH for idiopathic short stature in children and adolescents. Cochrane Database Systematic Reviews, Issue 3. Art No.: CD004440. doi:10.1002/14651858.CD004440.pub2 (2007).

  24. Cohen, P. et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature. J. Clin. Endocrinol. Metab. 93, 4210–4217 (2008).

    CAS  PubMed  Article  Google Scholar 

  25. Romano, A. A. et al. Growth response, near adult height and patterns of growth and puberty in patients with Noonan syndrome treated with growth hormone. J. Clin. Endocrinol. Metab. 94, 2338–2344 (2009).

    CAS  PubMed  Article  Google Scholar 

  26. Davenport, M. L. et al. Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial. J. Clin. Endocrinol. Metab. 92, 3406–3416 (2007).

    CAS  PubMed  Article  Google Scholar 

  27. Goldstone, A. P. et al. Recommendations for the diagnosis and management of Prader–Willi syndrome. J. Clin. Endocrinol. Metab. 93, 4183–4197 (2008).

    CAS  PubMed  Article  Google Scholar 

  28. Burman, P., Ritzén, E. M. & Lindgren, A. C. Endocrine dysfunction in Prader–Willi syndrome: a review with special reference to GH. Endocr. Rev. 22, 787–799 (2001).

    CAS  PubMed  Article  Google Scholar 

  29. Simon, D. & Bechtold, S. Effects of growth hormone treatment on growth in children with juvenile idiopathic arthritis. Horm. Res. 72 (Suppl. 1), 55–59 (2009).

    CAS  PubMed  Article  Google Scholar 

  30. Feldt-Rasmussen, B. & El Nahas, M. Potential role of growth factors with particular focus on growth hormone and insulin-like growth factor 1 in the management of chronic kidney disease. Semin. Nephrol. 29, 50–58 (2009).

    CAS  PubMed  Article  Google Scholar 

  31. Tesselaar, K. & Miedema, F. Growth hormone resurrects adult human thymus during HIV-1 infection. J. Clin. Invest. 118, 844–847 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Burger, A. G., Monson, J. P., Colao, A. M. & Klibanski, A. Cardiovascular risk in patients with growth hormone deficiency: effects of growth hormone substitution. Endocr. Pract. 12, 682–689 (2006).

    PubMed  Article  Google Scholar 

  33. Boschetti, M. et al. Replacement therapy and cardiovascular diseases. J. Endocrinol. Invest. 31 (9 Suppl.), 85–90 (2008).

    CAS  PubMed  Google Scholar 

  34. Widdowson, W. M. & Gibney, J. The effect of GH replacement on exercise capacity in patients with GH deficiency: a metaanalysis. J. Clin. Endocrinol. Metab. 93, 4413–4417 (2008).

    CAS  PubMed  Article  Google Scholar 

  35. Saller, B. et al. Healthcare utilization, quality of life and patient-reported outcomes during two years of GH replacement therapy in GH-deficient adults-comparison between Sweden, The Netherlands and Germany. Eur. J. Endocrinol. 154, 843–850 (2006).

    CAS  PubMed  Article  Google Scholar 

  36. Kolibianakis, E. M., Venetis, C. A., Diedrich, K., Tarlatzis, B. C. & Griesinger, G. Addition of growth hormone to gonadotrophins in ovarian stimulation of poor responders treated by in vitro fertilization: a systematic review and meta-analysis. Hum. Reprod. Update 15, 613–622 (2009).

    CAS  PubMed  Article  Google Scholar 

  37. Melmed, S. Acromegaly pathogenesis and treatment. J. Clin. Invest. 119, 3189–3202 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Thankamony, G. N., Dunger, D. B. & Acerini, C. L. Pegvisomant: current and potential novel therapeutic applications. Expert Opin. Biol. Ther. 9, 1553–1563 (2009).

    CAS  PubMed  Article  Google Scholar 

  39. Wilkinson-Berka, J. L. et al. An antisense oligonucleotide targeting the GH receptor inhibits neovascularization in a mouse model of retinopathy. Mol. Vis. 13, 1529–1538 (2007).

    CAS  PubMed  Google Scholar 

  40. Luft, R. The use of hypophysectomy in juvenile diabetes mellitus with vascular complications. Diabetes 11, 461–462 (1962).

    CAS  PubMed  Google Scholar 

  41. Waters, M. J. & Barclay, J. L. Does growth hormone drive breast and other cancers? Endocrinology 148, 4533–4535 (2007).

    CAS  PubMed  Article  Google Scholar 

  42. Divisova, J. et al. The growth hormone receptor antagonist pegvisomant blocks both mammary gland development and MCF-7 breast cancer xenograft growth. Breast Cancer Res. Treat. 98, 315–327 (2006).

    CAS  PubMed  Article  Google Scholar 

  43. Dagnaes-Hansen, F., Duan, H., Rasmussen, L. M., Friend, K. E. & Flyvbjerg, A. Growth hormone receptor antagonist administration inhibits growth of human colorectal carcinoma in nude mice. Anticancer Res. 24, 3735–3742 (2004).

    CAS  PubMed  Google Scholar 

  44. Godowski, P. J. et al. Characterization of the human growth hormone receptor gene and demonstration of a partial deletion in two patients with Laron-type dwarfism. Proc. Natl Acad. Sci. USA 86, 8083–8087 (1989).

    CAS  PubMed  Article  Google Scholar 

  45. de Vos, A. M., Ultsch, M. & Kossiakoff, A. A. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science 255, 306–312 (1992).

    CAS  PubMed  Article  Google Scholar 

  46. Waters, M. J. In Handbook of Physiology Vol. 5 Ch 13, section 7 (eds Kostyo, J. L. & Goodman, H. M.) 397–444 (Oxford Press, Oxford, 1999).

    Google Scholar 

  47. Wells, J. A. Binding in the growth hormone receptor complex. Proc. Natl Acad. Sci. USA 93, 1–6 (1996).

    CAS  PubMed  Article  Google Scholar 

  48. Fuh, G. et al. Rational design of potent antagonists to the human growth hormone receptor. Science 256, 1677–1680 (1992).

    CAS  PubMed  Article  Google Scholar 

  49. Cunningham, B. C. et al. Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science 254, 821–825 (1991).

    CAS  PubMed  Article  Google Scholar 

  50. Brown, R. J. et al. Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. Nat. Struct. Mol. Biol. 12, 814–821 (2005).

    CAS  PubMed  Article  Google Scholar 

  51. Gent, J., van Kerkhof, P., Roza, M., Bu, G. & Strous, G. J. Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis. Proc. Natl Acad. Sci. USA 99, 9858–9863 (2002).

    CAS  PubMed  Article  Google Scholar 

  52. Rowlinson, S. W. et al. Activation of chimeric and full-length growth hormone receptors by growth hormone receptor monoclonal antibodies. A specific conformational change may be required for full-length receptor signaling. J. Biol. Chem. 273, 5307–5314 (1998).

    CAS  PubMed  Article  Google Scholar 

  53. Gadd, S. L. & Clevenger, C. V. Ligand-independent dimerization of the human prolactin receptor isoforms: functional implications. Mol. Endocrinol. 20, 2734–2746 (2006).

    CAS  PubMed  Article  Google Scholar 

  54. Livnah, O. et al. Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science 283, 987–990 (1999).

    CAS  PubMed  Article  Google Scholar 

  55. Constantinescu, S. N. et al. Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain. Proc. Natl Acad. Sci. USA 98, 4379–4384 (2001).

    CAS  PubMed  Article  Google Scholar 

  56. Wan, Y., Zheng, Y. Z., Harris, J. M., Brown, R. & Waters, M. J. Epitope map for a GH receptor agonist monoclonal antibody, MAb 263. Mol. Endocrinol. 17, 2240–2250 (2003).

    CAS  PubMed  Article  Google Scholar 

  57. Poger, D. & Mark, A. E. Turning the growth hormone receptor on: evidence that hormone binding induces subunit rotation. Proteins 78, 1163–1174 (2010).

    CAS  PubMed  Article  Google Scholar 

  58. Kuo, C. B., Coss, D. & Walker, A. M. Prolactin receptor antagonists. Endocrine 9, 121–131 (1998).

    CAS  PubMed  Article  Google Scholar 

  59. Constantinescu, S. N., Huang, L. J., Nam, H. & Lodish, H. F. The erythropoietin receptor cytosolic juxtamembrane domain contains an essential, precisely oriented, hydrophobic motif. Mol. Cell 7, 377–385 (2001).

    CAS  PubMed  Article  Google Scholar 

  60. Liu, W., Kawahara, M., Ueda, H. & Nagamune, T. Construction of a fluorescein-responsive chimeric receptor with strict ligand dependency. Biotechnol. Bioeng. 101, 975–984 (2008).

    CAS  PubMed  Article  Google Scholar 

  61. Livnah, O. et al. An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation. Nat. Struct. Biol. 5, 993–1004 (1998).

    CAS  PubMed  Article  Google Scholar 

  62. Syed, R. S. et al. Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature 395, 511–516 (1998).

    CAS  PubMed  Article  Google Scholar 

  63. Liu, W., Kawahara, M., Ueda, H. & Nagamune, T. The influence of domain structures on the signal transduction of chimeric receptors derived from the erythropoietin receptor. J. Biochem. 145, 575–584 (2009).

    CAS  PubMed  Article  Google Scholar 

  64. Jin, H., Lanning, N. J. & Carter-Su, C. JAK2, but not Src family kinases, is required for STAT, ERK, and Akt signaling in response to growth hormone in preadipocytes and hepatoma cells. Mol. Endocrinol. 22, 1825–1841 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Rowlinson, S. W. et al. An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway. Nat. Cell Biol. 10, 740–747 (2008).

    CAS  PubMed  Article  Google Scholar 

  66. Zhang, F., Zhang, Q., Tengholm, A. & Sjöholm, A. Involvement of JAK2 and Src kinase tyrosine phosphorylation in human growth hormone-stimulated increases in cytosolic free Ca2+ and insulin secretion. Am. J. Physiol. Cell Physiol. 291, C466–C475 (2006).

    CAS  PubMed  Article  Google Scholar 

  67. Lannutti, B. J. & Drachman, J. G. Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors. Blood 103, 3736–3743 (2004).

    CAS  Article  PubMed  Google Scholar 

  68. Tilbrook, P. A., Ingley, E., Williams, J. H., Hibbs, M. L. & Klinken, S. P. Lyn tyrosine kinase is essential for erythropoietin-induced differentiation of J2E erythroid cells. EMBO J. 16, 1610–1619 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Chin, H. et al. Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway. Blood 91, 3734–3745 (1998).

    CAS  PubMed  Google Scholar 

  70. Fresno Vara, J. A., Carretero, M. V., Gerónimo, H., Ballmer-Hofer, K. & Martín-Pérez, J. Stimulation of c-Src by prolactin is independent of Jak2. Biochem. J. 345, 17–24 (2000).

    PubMed  PubMed Central  Article  Google Scholar 

  71. Boudot, C. et al. Involvement of the Src kinase Lyn in phospholipase C-gamma 2 phosphorylation and phosphatidylinositol 3-kinase activation in Epo signalling. Biochem. Biophys. Res. Commun. 300, 437–442 (2003).

    CAS  PubMed  Article  Google Scholar 

  72. Liu, W., Kawahara, M., Ueda, H. & Nagamune, T. The influence of domain structures on the signal transduction of chimeric receptors derived from the erythropoietin receptor. J. Biochem. 145, 575–584 (2009).

    CAS  PubMed  Article  Google Scholar 

  73. Giordanetto, F. & Kroemer, R. T. Prediction of the structure of human Janus kinase 2 (JAK2) comprising JAK homology domains 1 through 7. Protein Eng. 15, 727–737 (2002).

    CAS  PubMed  Article  Google Scholar 

  74. He, K. et al. Janus kinase 2 determinants for growth hormone receptor association, surface assembly, and signaling. Mol. Endocrinol. 17, 2211–2227 (2003).

    CAS  PubMed  Article  Google Scholar 

  75. Saharinen, P., Vihinen, M. & Silvennoinen, O. Autoinhibition of Jak2 tyrosine kinase is dependent on specific regions in its pseudokinase domain. Mol. Biol. Cell 14, 1448–1459 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Lacronique, V. et al. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 278, 1309–1312 (1997).

    CAS  PubMed  Article  Google Scholar 

  77. Kralovics, R. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–1790 (2005).

    CAS  Article  Google Scholar 

  78. Lee, T. S. et al. Mechanisms of constitutive activation of Janus kinase 2-V617F revealed at the atomic level through molecular dynamics simulations. Cancer 115, 1692–1700 (2009).

    CAS  PubMed  Article  Google Scholar 

  79. Lu, X., Huang, L. J. & Lodish, H. F. Dimerization by a cytokine receptor is necessary for constitutive activation of JAK2V617F. J. Biol. Chem. 283, 5258–5266 (2008).

    CAS  PubMed  Article  Google Scholar 

  80. Zhao, L. et al. A JAK2 interdomain linker relays Epo receptor engagement signals to kinase activation. J. Biol. Chem. 284, 26988–26998 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Yang, N., Wang, X., Jiang, J. & Frank, S. J. Role of the growth hormone (GH) receptor transmembrane domain in receptor predimerization and GH-induced activation. Mol. Endocrinol. 21, 1642–1655 (2007).

    CAS  PubMed  Article  Google Scholar 

  82. Lu, X., Gross, A. W. & Lodish, H. F. Active conformation of the erythropoietin receptor: random and cysteine-scanning mutagenesis of the extracellular juxtamembrane and transmembrane domains. J. Biol. Chem. 281, 7002–7011 (2006).

    CAS  PubMed  Article  Google Scholar 

  83. Onishi, M. et al. Identification of an oncogenic form of the thrombopoietin receptor MPL using retrovirus-mediated gene transfer. Blood 88, 1399–1406 (1996).

    CAS  PubMed  Google Scholar 

  84. Ding, J. et al. The Asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity. Blood 114, 3325–3328 (2009).

    CAS  PubMed  Article  Google Scholar 

  85. Ding, J. et al. Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood 103, 4198–4200 (2004).

    CAS  PubMed  Article  Google Scholar 

  86. Nakamura, T. et al. A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis. Blood 107, 4300–4307 (2006).

    CAS  PubMed  Article  Google Scholar 

  87. Kim, M. J. et al. NMR structural studies of interactions of a small, nonpeptidyl tpo mimic with the thrombopoietin receptor extracellular juxtamembrane and transmembrane domains. J. Biol. Chem. 282, 14253–14261 (2007).

    CAS  PubMed  Article  Google Scholar 

  88. Kuter, D. J. Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia. Annu. Rev. Med. 60, 193–206 (2009).

    CAS  PubMed  Article  Google Scholar 

  89. Adriani, M. et al. Functional interaction of common gamma-chain and growth hormone receptor signaling apparatus. J. Immunol. 177, 6889–6895 (2006).

    CAS  PubMed  Article  Google Scholar 

  90. De Ravin, S. S. & Malech, H. L. Partially corrected X-linked severe combined immunodeficiency: long-term problems and treatment options. Immunol. Res. 43, 223–242 (2009).

    PubMed  Article  Google Scholar 

  91. Savage, M. O., Burran, C. P. & Rosenfeld, R. G. The continuum of growth hormone-IGF-1 axis defects causing short stature: diagnostic and therapeutic challenges. Clin. Endocrinol. 72, 721–728 (2010).

    CAS  Article  Google Scholar 

  92. Rosenfeld, R. G. et al. Defects in growth hormone receptor signaling. Trends Endocrinol. Metab. 18, 134–141 (2007).

    CAS  PubMed  Article  Google Scholar 

  93. Savage, M. O. et al. Endocrine assessment, molecular characterization and treatment of growth hormone insensitivity disorders. Nat. Clin. Pract. Endocrinol. Metab. 2, 395–407 (2006).

    CAS  PubMed  Article  Google Scholar 

  94. Wojcik, J. et al. Four contiguous amino acid substitutions, identified in patients with Laron syndrome, differently affect the binding affinity and intracellular trafficking of the growth hormone receptor. J. Clin. Endocrinol. Metab. 83, 4481–4489 (1998).

    CAS  PubMed  Google Scholar 

  95. Walker, J. L. et al. A novel mutation affecting the interdomain link region of the growth hormone receptor in a Vietnamese girl, and response to long term treatment with recombinant insulin-like growth factor-1. J. Clin. Endocrinol. Metab. 83, 2554–2561 (1998).

    CAS  PubMed  Google Scholar 

  96. Baumgartner, J. W., Wells, C. A., Chen, C. M. & Waters, M. J. The role of the WSXWS equivalent motif in growth hormone receptor function. J. Biol. Chem. 269, 29094–29101 (1994).

    CAS  PubMed  Google Scholar 

  97. Conway-Campbell, B. L., Brooks, A. J., Robinson, P. J., Perani, M. & Waters, M. J. The extracellular domain of the GH receptor interacts with coactivator activator to promote cell proliferation. Mol. Endocrinol. 22, 2190–2102 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Enberg, B. et al. Characterisation of novel missense mutations in the GH receptor gene causing severe growth retardation. Eur. J. Endocrinol. 143, 71–76 (2000).

    CAS  PubMed  Article  Google Scholar 

  99. Ayling, R. M. et al. A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat. Genet. 16, 13–14 (1997).

    CAS  PubMed  Article  Google Scholar 

  100. Milward, A. et al. Growth hormone (GH) insensitivity syndrome due to a GH receptor truncated after Box1, resulting in isolated failure of STAT5 signal transduction. J. Clin. Endocrinol. Metab. 89, 1259–1266 (2004).

    CAS  PubMed  Article  Google Scholar 

  101. Tiulpakov, A. et al. A novel C-terminal growth hormone receptor (GHR) mutation results in impaired GHR-STAT5 but normal STAT-3 signaling. J. Clin. Endocrinol. Metab. 90, 542–547 (2005).

    CAS  PubMed  Article  Google Scholar 

  102. Kofoed, E. M. et al. Growth hormone insensitivity associated with a STAT5b mutation. N. Engl. J. Med. 349, 1139–1147 (2003).

    CAS  PubMed  Article  Google Scholar 

  103. Harrison, S. M., Barnard, R., Ho, K. K. Y., Rajkovic, I. & Waters, M. J. Control of growth hormone (GH) binding protein release from human hepatoma cells expressing full length GH receptor. Endocrinology 136, 651–659 (1995).

    CAS  PubMed  Article  Google Scholar 

  104. Barnard, R. & Waters, M. J. The serum growth hormone binding protein: pregnant with possibilities. J. Endocrinol. 153, 1–14 (1997).

    CAS  PubMed  Article  Google Scholar 

  105. Chernausek, S. D. et al. Long-term treatment with recombinant insulin-like growth factor (IGF)-1 in children with severe IGF-1 deficiency due to growth hormone insensitivity. J. Clin. Endocrinol. Metab. 92, 902–910 (2007).

    CAS  PubMed  Article  Google Scholar 

  106. Fintini, D., Brufani, C. & Cappa, M. Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency. Ther. Clin. Risk Manag. 5, 553–559 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Tonella, P., Flück, C. E. & Mullis, P. E. IGF-1 treatment in primary GH insensitivity: effect of recombinant human IGF-1 and rhIGF-1/rhIGFBP-3 complex. Horm. Res. Paediatr. 73, 140–147 (2010).

    CAS  PubMed  Article  Google Scholar 

  108. Ogueta, S., Muñoz, J., Obregon, E., Delgado-Baeza, E. & García-Ruiz, J. P. Prolactin is a component of the human synovial fluid and modulates the growth and chondrogenic differentiation of bone marrow derived mesenchymal stem cells. Mol. Cell. Endocrinol. 190, 51–63 (2002).

    CAS  PubMed  Article  Google Scholar 

  109. Dos Santos, C. et al. A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat. Genet. 36, 720–724 (2004).

    CAS  PubMed  Article  Google Scholar 

  110. Wassenaar, M. J. et al. Impact of the exon-3 deleted growth hormone (GH) receptor polymorphism on baseline height and growth response to recombinant human GH therapy in GH-deficient (GHD) and non-GHD children with short stature: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 94, 3721–3730 (2009).

    CAS  PubMed  Article  Google Scholar 

  111. Montefusco, L. et al. d3-Growth hormone receptor polymorphism in acromegaly: effects on metabolic phenotype. Clin. Endocrinol. (Oxf.) 72, 661–667 (2010).

    CAS  Article  Google Scholar 

  112. Mercado, M. et al. Clinical and biochemical impact of the d3 growth hormone receptor genotype in acromegaly. J. Clin. Endocrinol. Metab. 93, 3411–3415 (2008).

    CAS  PubMed  Article  Google Scholar 

  113. Gunnell, D. J. et al. Height, leg length and cancer risk: a systematic review. Epidemiol. Rev. 23, 313–342 (2001).

    CAS  PubMed  Article  Google Scholar 

  114. Ahlgren, M., Melbye, M., Wohlfaht, J. & Sørensen, T. I. Growth patterns and risk of breast cancer in women. N. Engl. J. Med. 351, 1619–1626 (2004).

    CAS  PubMed  Article  Google Scholar 

  115. Shevah, O. & Laron, Z. Patients with congenital deficiency of IGF-1 seem protected from the development of malignancies: a preliminary report. Growth Horm. IGF Res. 17, 54–57 (2006).

    PubMed  Article  CAS  Google Scholar 

  116. Shen, Q. et al. Advanced rat mammary cancers are growth hormone dependent. Endocrinology 148, 4536–4544 (2007).

    CAS  PubMed  Article  Google Scholar 

  117. Zhang, X. et al. Inhibition of estrogen-independent mammary carcinogenesis by disruption of growth hormone signaling. Carcinogenesis 28, 143–150 (2007).

    PubMed  Article  Google Scholar 

  118. Ikeno, Y. et al. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J. Gerontol. A Biol. Sci. Med. Sci. 64, 522–529 (2009).

    PubMed  Article  CAS  Google Scholar 

  119. Samani, A. A., Yakar, S., Le Roith, D. & Brodt, P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr. Rev. 28, 20–47 (2007).

    CAS  PubMed  Article  Google Scholar 

  120. Beekman, R. & Touw, I. P. G-CSF and its receptor in myeloid malignancy. Blood 115, 5131–5136 (2010).

    CAS  PubMed  Article  Google Scholar 

  121. Constantinescu, S. N., Girardot, M. & Pecquet, C. Mining for JAK-STAT mutations in cancer. Trends Biochem. Sci. 33, 122–131 (2008).

    CAS  PubMed  Article  Google Scholar 

  122. Zhu, T. et al. Oncogenic transformation of human mammary epithelial cells by autocrine growth hormone. Cancer Res. 65, 317–324 (2005).

    CAS  PubMed  Google Scholar 

  123. Brunet-Dunand, S. E. et al. Autocrine human growth hormone promotes tumor angiogenesis in mammary carcinoma. Endocrinology 150, 1341–1352 (2009).

    CAS  PubMed  Article  Google Scholar 

  124. Perry, J. K., Mohankumar, K. M., Emerald, B. S., Mertani, H. C. & Lobie, P. E. The contribution of growth hormone to mammary neoplasia. J. Mammary Gland Biol. Neoplasia 13, 131–145 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  125. Raccurt, M. et al. High stromal and epithelial human GH gene expression is associated with proliferative disorders of the mammary gland. J. Endocrinol. 175, 307–318 (2002).

    CAS  PubMed  Article  Google Scholar 

  126. Mol, J. A. et al. Expression of the gene encoding growth hormone in the human mammary gland. J. Clin. Endocrinol. Metab. 80, 3094–3096 (1995).

    CAS  PubMed  Google Scholar 

  127. Ergun-Longmire, B. et al. Growth hormone treatment and risk of second neoplasms in the childhood cancer survivor. J. Clin. Endocrinol. Metab. 91, 3494–3498 (2006).

    CAS  PubMed  Article  Google Scholar 

  128. Gebre-Medhin, M., Kindblom, L. G., Wennbo, H., Tornell, J. & Meis-Kindblom, J. M. Growth hormone receptor is expressed in human breast cancer. Am. J. Pathol. 158, 1217–1222 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Lincoln, D. T. et al. Up-regulation of growth hormone receptor immunoreactivity in human melanoma. Anticancer Res. 19, 1919–1931 (1999).

    CAS  PubMed  Google Scholar 

  130. García-Caballero, T. et al. Increased expression of growth hormone and prolactin receptors in hepatocellular carcinoma. Endocrine 12, 265–271 (2000).

    PubMed  Article  Google Scholar 

  131. Conway-Campbell, B. L. et al. Nuclear targeting of the growth hormone receptor results in dysregulation of cell proliferation and tumorigenesis. Proc. Natl Acad. Sci. USA 104, 13331–13336 (2007).

    CAS  PubMed  Article  Google Scholar 

  132. Lin, S. Y. et al. Nuclear localization of EGF receptor and its potential role as a transcription factor. Nat. Cell Biol. 3, 802–808 (2001).

    CAS  PubMed  Article  Google Scholar 

  133. Carpenter, G. & Liao, H. J. Trafficking of receptor tyrosine kinases to the nucleus. Exp. Cell Res. 315, 1556–1566 (2009).

    CAS  PubMed  Article  Google Scholar 

  134. Lobie, P. E., Wood, T. J., Chen, C. M., Waters, M. J. & Norstedt, G. Nuclear translocation and anchorage of the growth hormone receptor. J. Biol. Chem. 269, 31735–31746 (1994).

    CAS  PubMed  Google Scholar 

  135. Denson, L. A. Growth hormone therapy in children and adolescents: pharmacokinetic/pharmacodynamic considerations and emerging indications. Expert Opin. Drug Metab. Toxicol. 4, 1569–1580 (2008).

    CAS  PubMed  Article  Google Scholar 

  136. Fuqua, J. S. Growth after organ transplantation. Semin. Pediatr. Surg. 15, 162–169 (2006).

    PubMed  Article  Google Scholar 

  137. Cuatrecasas, G. Fibromyalgic syndromes: could growth hormone therapy be beneficial? Pediatr. Endocrinol. Rev. 6 (Suppl. 4), 529–533 (2009).

    PubMed  Google Scholar 

  138. Abdel-Rahman, E. & Holley, J. L. A review of the effects of growth hormone changes on symptoms of frailty in the elderly with chronic kidney disease. Semin. Dial. 22, 532–538 (2009).

    PubMed  Article  Google Scholar 

  139. Flores-Morales, A., Greenhalgh, C. J., Norstedt, G. & Rico-Bautista, E. Negative regulation of growth hormone receptor signaling. Mol. Endocrinol. 20, 241–253 (2006).

    CAS  PubMed  Article  Google Scholar 

  140. Maamra, M. et al. A 36 residues insertion in the dimerization domain of the growth hormone receptor results in defective trafficking rather than impaired signaling. J. Endocrinol. 188, 251–261 (2006).

    CAS  PubMed  Article  Google Scholar 

  141. Brooks, A. et al. Activation of growth hormone receptor by subunit realignment. ENDO 09; The US Endocrine Society Annual Meeting, June 10–13, Washington DC, USA (2009).

Download references

Acknowledgements

M. J. Waters is supported by grants from the Australian National Health and Medical Research Council.

Author information

Authors and Affiliations

Authors

Contributions

A. J. Brooks and M. J. Waters researched the data for the article and both provided a substantial contribution to discussions of the content. A. J. Brooks and M. J. Waters contributed equally to writing the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Andrew J. Brooks.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Brooks, A., Waters, M. The growth hormone receptor: mechanism of activation and clinical implications. Nat Rev Endocrinol 6, 515–525 (2010). https://doi.org/10.1038/nrendo.2010.123

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2010.123

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing