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Growth hormone signal transduction

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Abstract

Growth hormone (GH) promotes animal growth by stimulating bone and cartilage cell proliferation, and influences carbohydrate and lipid metabolism. Some of these effects are brought about indirectly via somatomedin induction in hepatocytes, others by acting directly on the target cells. In either case, GH first binds to specific receptors on cells to trigger a sequence of biochemical events culminating in a biological response. Recently much has been learnt about the molecular structure of GH receptor, its binding to ligand, and the ensuing signal transduction events.

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References

  1. Abdel-Meguid, S., Sheih, H. S., Smith, W. W., Dayringer, H. E., Violand, B. N., and Bentle, L. A., Three-dimensional structure of a genetically engineered variant of porcine growth hormone. Proc. natl Acad. Sci. USA84 (1987) 6434–6437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Asakawa, K., Grunberger, G., McElduff, A., and Gorden, P., Polypeptide hormone receptor phosphorylation: is there a role in receptor-mediated endocytosis of human growth hormone? Endocrinology117 (1985) 631–637.

    Article  CAS  PubMed  Google Scholar 

  3. Asakawa, K., Hedo, J. A., McElduff, A., Rouiller, D. G., Waters, M. J., and Gordon, P., The human growth hormone receptor of cultured human lymphocytes. Biochem. J.238 (1986) 379–386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Aston, R., Holder, A. T., Ivanyi, J., and Bomford, R., Enhancement of bovine growth hormone activity in vivo. Mol. Immun.24 (1987) 143–150.

    Article  CAS  Google Scholar 

  5. Barnard, R., Bundesen, P. G., Rylatt, D. B., and Waters, M. J., Evidence from the use of monoclonal antibody probes for structural heterogeneity of the growth hormone receptor. Biochem. J.231 (1985) 459–468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bazan, J. F., Structural design and molecular evolution of a cytokine receptor superfamily. Proc. natl Acad. Sci. USA87 (1990) 6934–6938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Berczi, I., Nagy, E., de Toledo, S. M., Matusik, R. J., and Friesen, H. G., Pituitary hormones regulatec-myc and DNA synthesis in lymphoid tissue. J. Immun.146 (1991) 2201–2206.

    Article  CAS  PubMed  Google Scholar 

  8. Berridge, M. J., and Irvine, R. F., Inositol triphosphate, a novel second messenger in cellular signal transduction. Nature312 (1984) 315–321.

    Article  CAS  PubMed  Google Scholar 

  9. Besterman, J. M., Duronio, V., and Cuatrecasas, P., Rapid formation of diacylglycerol from phosphatidylcholine. A pathway for generation of second messenger. Proc. natl Acad. Sci. USA83 (1986) 6785–6789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bollag, G. E., Roth, R. A., Beaudoin, J., Mochly Rosen, D., and Koshland Jr. D. E., Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its proteintyrosine kinase activity. Proc. natl Acad. Sci. USA83 (1986) 5822–5824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Boutin, J. M., Jolicoeur, C., Okamura, H., Gagnon, J., Edery, M., Shirota, M., Banville, D., Dusanter, I., Djiane, J., and Kelly, P. A., Cloning and expression of the rat prolactin receptor, a member of the growth hormone/prolactin receptor gene family. Cell53 (1988) 69–77.

    Article  CAS  PubMed  Google Scholar 

  12. Carter-Su, C., Schwartz, J., and Kikuchi, G., Identification of a high affinity GH receptor in rat adipocyte membrane. J. biol. Chem.259 (1984) 1099–1104.

    Article  CAS  PubMed  Google Scholar 

  13. Carter-Su, C., Stubbart, J. R., Wang, X., Stred, S. E., Argetsinger, L. S., and Shafer, J. A., Phosphorylation of highly purified growth hormone receptors by a growth hormone receptor-associated tyrosine kinase. J. biol. chem.264 (1989) 18654–18661.

    Article  CAS  PubMed  Google Scholar 

  14. Cochet, C., Kachles, O., Chombaz, E. M., Borrello, I., King, C. R., and Schlessinger, J., Demonstration of epidermal growth factor-induced receptor dimerization in living cells using a chemical covalent cross-linking agent. J. biol. Chem.263 (1988) 3290–3295.

    Article  CAS  PubMed  Google Scholar 

  15. Cosman, D., Lyman, S. D., Idzerda, R. L., Beckman, M. P., Park, L. S., Goodwin, R. G., and March, C. J., A new cytokine receptor superfamily. Trends. biochem. Sci.15 (1990) 265–270.

    Article  CAS  PubMed  Google Scholar 

  16. Coussens, L., Van Beveren, C., Smith, D., Chen, E., Mitchell, L., Isacke, C. M., Verma, I. M., and Ullrich, A., Structural alteration of viral homologue of receptor proto-oncogenefms at carboxyl terminus. Nature320 (1986) 277–280.

    Article  CAS  PubMed  Google Scholar 

  17. Cunningham, B. C., Ultsch, M., DeVos, A. M., Mulkerrin, M. G., Clauser, K. R., and Wells, J. A., Dimerization of the extracellular domain of the human growth hormone recceptor by a single hormone molecule. Science254 (1991) 821–825.

    Article  CAS  PubMed  Google Scholar 

  18. Cunningham, B. C., and Wells, J. A., High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science244 (1989) 1081–1085.

    Article  CAS  PubMed  Google Scholar 

  19. Curran, T., and Franza, Jr., B. R., Fos and Jun: the AP-1 Connection. Cell55 (1988) 395–397.

    Article  CAS  PubMed  Google Scholar 

  20. Davis, S., Aldrich, T. H., Valenzuela, D. M., Wong, V., Furth, M. E., Squinto, S. P., and Yancopoulos, G. D., The receptor for ciliary neurotrophic factor. Science253 (1991) 59–63.

    Article  CAS  PubMed  Google Scholar 

  21. De Meyts, P., Structure of growth hormone and its receptor: an unexpected stoichiometry. Trends. biochem. Sci.17 (1992) 169–170.

    Article  PubMed  Google Scholar 

  22. De Vos, A., Ultsch, M., and Kosslakoff, A. A., Human growth hormone and extracellular domain of its receptor: Crystal structure of the complex. Science255 (1992) 306–312.

    Article  PubMed  Google Scholar 

  23. Doglio, A., Dani, C., Grimaldi, P., and Ailhaud, G., Growth hormone stimulatesc-fos gene expression by means of protein kinase C without increasing inositol lipid turnover. Proc. natl Acad. Sci. USA86 (1989) 1148–1152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Donner, D. B., Covalent coupling of human GH to its receptor on rat hepatocytes. J. biol. Chem.258 (1983) 2736–2743.

    Article  CAS  PubMed  Google Scholar 

  25. Elbein, A. D., Inhibitors of the biosynthesis and processing of N-linked oligosaccharide chains. A. Rev. Biochem.56 (1987) 497–534.

    Article  CAS  Google Scholar 

  26. Elberg, G., Kelly, P. A., Djiane, J., Blinder, L., and Gertler, A., Mitogenic and binding properties of monoclonal antibodies to the prolactin receptor in Nb2 rat lymphoma cells. J. biol. Chem.265 (1990) 14770–14776.

    Article  CAS  PubMed  Google Scholar 

  27. Edery, M., Jolicoeur, C., Levy-Meyrueis, C., Dusanter-Fourt, J., Petridou, B., Boutin, J. M., Lesueur, L., Kelly, P. A., and Djiane, J.. Identification and sequence analysis of a second form of prolactin receptor by molecular cloning of complementary DNA from rabbit mammary gland. Proc. natl Acad. Sci. USA86 (1989) 2112–2116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Foster, C. M., Shafer, J. A., Rozsa, F. W., Wang, X., Lewis, S. D., Renken, D. A., Natale, J. E., Schwartz, J., and Carter-Su, C., Growth hormone promoted tyrosyl phosphorylation of growth hormone receptors in murine 3T3-F442A fibroblasts and adipocytes. Biochemistry27 (1988) 326–334.

    Article  CAS  PubMed  Google Scholar 

  29. Fuh, G., Cunningham, B. C., Fukunaga, R., Nagata, S., Goeddel, D. V., and Wells, J. A., Rational design of potent antagonists to the human growth hormone. Science256 (1992) 1677–1680.

    Article  CAS  PubMed  Google Scholar 

  30. Goodman, H. M., and Kostyo, J. L., Altered profiles of biological activity of growth hormone fragments on adipocytes metabolism. Endocrinology108 (1981) 553–558.

    Article  CAS  PubMed  Google Scholar 

  31. Gurland, G., Ashcom, G., Cochran, B. H., and Schwartz, J., Rapid events in growth hormone action. Induction ofc-fos andc-jun transcription in 3T3-F442A preadipocytes. Endocrinology127 (1990) 3187–3195.

    Article  CAS  PubMed  Google Scholar 

  32. Hall, A. K., and Rao, M. S., Cytokines and neurokines: related ligands and related receptors. Trends. Neurosci.15 (1992) 35–37.

    Article  CAS  PubMed  Google Scholar 

  33. Hendrickson, W. A., Modes of transduction. Curr. Biol.2 (1992) 57–59.

    Article  CAS  PubMed  Google Scholar 

  34. Herrera, R., Ro, H. S., and Robinson, G. S., A direct role for C/EBP and the AP-1 binding site in the gene expression linked to adipocyte differentiation. Mol. cell. Biol.9 (1989) 5331–5339.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Herschman, H. R., Primary response genes induced by growth factors and tumor promoters. A. Rev. Biochem.60 (1991) 281–319.

    Article  CAS  Google Scholar 

  36. Hidaka, H., Inagaki, M., Kawamoto, S., and Sadsaki, Y., Isoquinoline-sulfonamides, novel and potent inhibitors of cyclic nucleotide-dependent protein kinase and protein kinase C. Biochemistry23 (1984) 5036–5041.

    Article  CAS  PubMed  Google Scholar 

  37. Hughes, J. P., Simpson, J. S. A., and Friesen, H. G., Analysis of growth hormone and lactogenic sites cross linked to iodinated human growth hormone. Endocrinology112 (1983) 1980–1985.

    Article  CAS  PubMed  Google Scholar 

  38. Hughes, J. P., and Friesen, H. g., The nature and regulation of the receptors for pituitary growth hormone. A. Rev. Physiol.47 (1985) 469–482.

    Article  CAS  Google Scholar 

  39. Keating, M. T., Esobedo, J. A., and Williams, L. T., Ligand activation causes a phosphorylation-dependent change in platelet-derived growth factor receptor conformation. J. biol. Chem.263 (1988) 12805–12808.

    Article  CAS  PubMed  Google Scholar 

  40. Keefer, L. M., and DeMeyts, P., Glycosylation on cell surface receptors: tunicamycin treatment decreases insulin and growth hormone binding to different levels in cultured lymphocytes. Biochem. biophys. Res. Commun.101 (1981) 22–29.

    Article  CAS  PubMed  Google Scholar 

  41. Lacal, J. C., Moscat, J., and Aaronson, S. A., Novel source of 1,2-diacylglycerol elevated in cells transformed by Ha-ras oncogene. Nature330 (1987) 269–272.

    Article  CAS  PubMed  Google Scholar 

  42. Leung, D. W., Spencer, S. A., Cachianes, G., Hammonds, R. G., Collins, C., Henzel, W. J., Barnard, R., Waters, M. J., and Wood, W. I., Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature330 (1987) 537–543.

    Article  CAS  PubMed  Google Scholar 

  43. Lewis, U. J., Dunn, J. T., Bonewald, L. F., Seavey, B. K., and Vanderlaan, W. P., A naturally occurring structural variant of human growth hormone. J. biol. Chem.253 (1978) 2679–2687.

    Article  CAS  PubMed  Google Scholar 

  44. Maharajan, P., Ferrara, L., DiLuccia, A., Manniti, F., Paino, G., and Maharajan, V., Growth hormone: cellular and molecular aspects and its use in animal production—A review. Acta med. vet.35 (1989) 361–373.

    Google Scholar 

  45. Murphy, L. J., Bell, G. I., and Friesen, H. G., Growth hormone stimulates sequential induction ofc-myc and insulin-like growth factor I expression in vivo. Endocrinology120 (1987) 1806–1812.

    Article  CAS  PubMed  Google Scholar 

  46. Nakamura, Y., Komatsu, N., and Nakauchi, H., A truncated erythropoietin receptor that fails to prevent programmed cell death of erythroid cells. Science257 (1992) 1138–1141.

    Article  CAS  PubMed  Google Scholar 

  47. Pang, D. T., Sharma, B. R., Shafer, J. A.,White, M. F., and Kahn, C. R., Predominance of tyrosine phosphorylation of insulin receptors during the initial response of intact cells to insulin, J. biol. Chem.260 (1985) 7131–7136.

    Article  CAS  PubMed  Google Scholar 

  48. Pelech, S. L., and Vance, D. E., Signal transduction via phosphatidyl choline cycles. Trends. biochem. Sci.14 (1989) 28–30.

    Article  CAS  Google Scholar 

  49. Penn, L. J. Z., Laufer, E. M., and Land, H., C-MYC: Evidence for multiple regulatory functions. Seminar Cancer Biol.1 (1990) 69–80.

    CAS  Google Scholar 

  50. Reed, B. C., Ronnett, G. V., and Lane, M. D., Role of glycosylation and protein synthesis in insulin receptor metabolism by 343-L1 mouse adipocytes. Proc. natl Acad. Sci. USA78 (1981) 2908–2912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Saltiel, A. R., Sherline, P., and Fox, J. A., Insulin stimulated diacylglycerol production results from the hydrolyses of a novel phosphatidylinositol glycerol. J. biol. Chem.,262 (1987) 1116–1121.

    Article  CAS  PubMed  Google Scholar 

  52. Schlessinger, J., Signal transduction by allosteric receptor oligomerization. Trends. biochem. Sci.13 (1988) 443–447.

    Article  CAS  PubMed  Google Scholar 

  53. Seeburg, P. H., The human growth hormone gene family: nucleotide sequences show recent divergence and predict a new polypeptide, hormone. DNA1 (1982) 239–249.

    Article  CAS  PubMed  Google Scholar 

  54. Siegelman, M., Bond, M. W., Gallatin, W. M., John, T. S., Smith, H. T., Fried, V. A., and Weissman, I. L., Cell surface molecule associated with lymphocyte homing is a ubiquitinated branched-chain glycoprotein. Science231 (1986) 823–829.

    Article  CAS  PubMed  Google Scholar 

  55. Sims, J. E., March, C. J., Cosman, D., Widmer, M. B., McDonald, H. R., McMahan, C. J., Grubin, C. E., Wignall, J. M., Jackson, J. L., Call, S. M., Friend, D., Alpert A. R., Gillis, S., Urdal, D. L., and Dower, S. K., cDNA expression cloning, cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science241 (1988) 585–589.

    Article  CAS  PubMed  Google Scholar 

  56. Sleiker, L. J., and Lane, M. D., Post-translational processing of the epidermal growth factor receptor. J. biol. Chem.260 (1985) 687–690.

    Article  Google Scholar 

  57. Slootweg, M. C., Van Buul-Offers, S. C., Hoogerbrugge, C. M., Herrman-Erlee, M. P. M. Vander Eijnden-Van Raaij, A. J. M., Duursma, S. A., and Van Zoelen, E. J. J., Characterization of growth factor activity produced by fetal mouse osteoblasts. J. Endocrin.124 (1990a) 301–309.

    Article  CAS  Google Scholar 

  58. Slootweg, M. C., Van Genesen, S. T., Otte, A., Duursma, S. A., and Kruijer, W., Activation of mouse osteoblast growth hormone receptor:c-fos oncogene expression independent of phosphoinositide breakdown and cAMP. J. mol. Endocrin.4 (1990b) 265–274.

    Article  CAS  Google Scholar 

  59. Slootweg, M. C., de Groot, R. P., Herrman-Erlee, M. P. M., Koornneef, I., Kruijer, W., and Kramer, Y. M., Growth hormone induces expression ofc-jun andjun-B oncogenes and employs a protein kinase C signal transduction pathway for the induction ofc-fos oncogene expression. J. mol. Endocrin.6 (1991) 179–188.

    Article  CAS  Google Scholar 

  60. Smal, J., and DeMeyts, P., Role of kinase C in the insulin-like effects of human growth hormone in rat adipocytes. Biochem. biophys. Res. Commun.147 (1987) 1232–1240.

    Article  CAS  PubMed  Google Scholar 

  61. Sobel, A., Boutterin, M. C., Beretta, L., Chneiweiss, H., Doye, V., and Peyro-Saint-Paul, H., Intracellular substrates for extracellular signalling. J. biol. Chem.264 (1989) 3765–3772.

    Article  CAS  PubMed  Google Scholar 

  62. Szecowka, J., Tai, L. H. and Goodman, H. M., Effects of tunicamycin on growth hormone binding in rat adipocytes. Endocrinology126 (1990) 1834–1841.

    Article  CAS  PubMed  Google Scholar 

  63. Tager, H. S., and Steiner, D. F., Peptide hormones. A. Rev. Biochem.43 (1974) 509–537.

    Article  CAS  Google Scholar 

  64. Tamaoki, T., Nomoto, H., Takanasi, I., Kato, Y., Morimoto, M., and Tomita, F., Staurosporine, a protein inhibitor of phospholipid/Ca++-dependent protein kinase. Biochem. biophys. Res. Commun.135 (1986) 397–402.

    Article  CAS  PubMed  Google Scholar 

  65. Thomas, H., Green, I. C., Wallis, M., and Aston, R., Heterogeneity of growth-hormone receptors detected with monoclonal antibodies to human growth hormone. Biochem. J.243 (1987) 365–372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tsushima, T., Murakami, H., Wu-Kai, K., Isozaki, O., Sato, Y., and Shizume, K., Analysis of hepatic growth hormone binding sites of pregnant rabbit cross linked to125I-labelled human GH. FEBS Lett.147 (1982) 49–53.

    Article  CAS  PubMed  Google Scholar 

  67. Ullrich, A., and Schlessinger, J., Signal transduction by receptors with tyrosine kinase activity. Cell61 (1990) 203–212.

    Article  CAS  PubMed  Google Scholar 

  68. Wallis, M., Mechanisms of action of growth hormone, in: Hormones and their Actions, pp. 265–294. Eds B. A. cooke, R. J. B. King and H. J. van der Molen. Elsevier, Amsterdam 1988.

    Google Scholar 

  69. Wallis, M., Daniels, M., Ray, K. P., Cottingham, J. D., and Aston, R., Monoclonal antibodies to bovine growth hormone potentiate effects of the hormone on somatomedin C levels and growth of hypophysectomized rats. Biochem. biophys. Res. Commun.149 (1987) 187–193.

    Article  CAS  PubMed  Google Scholar 

  70. Waters, M. J., and Friesen, H. G., Purification and partial characterization of a non-primate GH-receptor. J. biol. Chem.254 (1979) 6815–6825.

    Article  CAS  PubMed  Google Scholar 

  71. Williams, L. T., Signal transduction by the platelet-derived growth factor receptor. Science243 (1989) 1564–1570.

    Article  CAS  PubMed  Google Scholar 

  72. Yarden, Y., Escobedo, J. A., Kuang, W. J., Yang-Feng, T. L., Daniel, T. O., Tremble, P. M., Cheng, E. Y., Ando, M. E., Harkins, R. N., Francke, U., Fried, V. A., Ullrich, A., and Williams, L. T., Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature323 (1986) 226–232.

    Article  CAS  PubMed  Google Scholar 

  73. Yarden, Y., and Ullrich, A., Growth factor receptor tyrosine kinases. A. Rev. Biochem.57 (1988) 443–478.

    Article  CAS  Google Scholar 

  74. Zon, L. I., Moreau, J. W., Koo, J. W., Mathey-Prevot, B., and D'Andrea, A. D., The erythropoietin receptor transmembrane region is necessary for activation by the Friend spleen focus-forming virus gp 55 glycoprotein. Mol. cell. Biol.12 (1992) 2949–2957.

    CAS  PubMed  PubMed Central  Google Scholar 

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  1. C.N.R. Institute for the Adaptation of Cattle and Buffalo to the Southern Italy Environment (IABBAM), Naples, Italy

    P. Maharajan

  2. Institute of Cybernetics, Consiglio Nazionale delle Ricerche, I-80072, Arco Felice, Naples, Italy

    V. Maharajan

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Maharajan, P., Maharajan, V. Growth hormone signal transduction. Experientia 49, 980–987 (1993). https://doi.org/10.1007/BF02125645

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