Signal Transduction Through the Growth Hormone Receptor

  • Peter E. Lobie
Part of the Endocrine Updates book series (ENDO, volume 4)


The importance of the cloned growth hormone (GH) receptor in the regulation of postnatal somatic growth is evidenced by the demonstration of point mutations and deletions in the gene encoding the GH receptor in Laron type dwarfism (1,2) and sex linked dwarfism in the chicken (3,4). Further, GH receptor gene deletion in mice results in a growth retarded phenotype (5). The mechanism by which the GH receptor mediates the general pleiotropic and specific somatic responses to its ligand have only recently begun to be understood. This review provides a brief discourse on the signal transduction pathways which have been demonstrated to be utilized by GH. The identification of such pathways, at least, provides a basis for understanding the pleiotropic actions of GH.


Growth Hormone Focal Adhesion Kinase Tyrosine Phosphorylation Growth Hormone Receptor Growth Hormone Stimulation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Godowski PJ, Leung DW, Meachem LR, Galgani JP, Helmiss R, Keret R, Rotwein P, Parks JS, Laron Z, Wood WI (1989) Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron type dwarfism. Proc. Natl. Acad. Sci. USA 86: 8083–8087PubMedCrossRefGoogle Scholar
  2. 2.
    Amselem S, Duquesnoy P, Attree O, Novelli G, Bousnina S, Postel-Vinay MC, Goosens M (1989) Laron dwarfism and mutations of the growth hormone receptor gene. N. Engl. J. Med. 321: 989–995PubMedCrossRefGoogle Scholar
  3. 3.
    Duriez B, Sobrier ML, Duquesnoy P, Tixier-Boichard M, Decuypere E, Coquerelle C, Zeman M, Goosens M, Amselem S (1993) A naturally occurring growth hormone receptor mutation: in vivo and in vitro evidence for the functional importance of the WS motif common to all members of the cytokine receptor superfamily. Mol. Endocrinol. 7: 806–814PubMedCrossRefGoogle Scholar
  4. 4.
    Huang N, Cogburn LA, Agarwal SK, Marks HL, Burnside J (1993) Overexpression of a truncated growth hormone receptor in the sex linked dwarf chicken. Mol. Endocrinol 7: 1391–1398PubMedCrossRefGoogle Scholar
  5. 5.
    Zhou Y, Xu BC, Maheshwari H, He L, Reed M, Lozykowski M, Chen N, Knapp JR, Cataldo LA, Okada S, Wagner TE, Baumann G, Kopchick JJ (1997) A mouse model for Laron syndrome produced by targeted disruption of the growth hormone receptor/binding protein gene. Proc 79th Ann. Meeting Endo. Soc. (Abstract p341)Google Scholar
  6. 6.
    Cosman D., Lyman SD., Idzerda RL., Beckmann MR, Park LS., Goodwin RG., March CJ (1990) A new cytokine receptor superfamily. TIBS 15: 265–270PubMedGoogle Scholar
  7. 7.
    Kitamura T, Ogorochi T, Miyajima A (1994) Multimeric cytokine receptors. TEM. 5: 8–13PubMedGoogle Scholar
  8. 8.
    Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Silvennoinen O (1995) Signalling through the haemopoietic cytokine receptors. Ann. Rev. Immunol. 13:369–398CrossRefGoogle Scholar
  9. 9.
    Bazan Jf (1989) A novel family of growth factor receptors. Biochem. biophys. Res. commun. 164: 788–795PubMedCrossRefGoogle Scholar
  10. 10.
    Patthy L (1990) Homology of a domain of the growth hormone/prolactin receptor family with type III modules of fibronectin. Cell 61: 13–14PubMedCrossRefGoogle Scholar
  11. 11.
    Waters MJ (1997) “The Growth Hormone Receptor” Handbook of PhysiologyGoogle Scholar
  12. 12.
    vol5 ch14; editor JL Kostyo; Oxford University Press.Google Scholar
  13. 13.
    Frank SJ, Yi W, Zhao Y, Goldsmith JF, Gilliland G, Jiang J, Sakai I, Kraft AS (1995) Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor. J. Biol. Chem. 270: 14776–14785PubMedCrossRefGoogle Scholar
  14. 14.
    Goujon L, Allevato G, Simonin G, Paquereau L, Le Cam A, Clark J, Nielsen JH, Djiane J, Postel-Vinay M-C, Edery M, Kelly PA (1994) Cytoplasmic sequences of the growth hormone receptor necessary for signal transduction. Proc. Natl. Acad. USA 91: 957–961CrossRefGoogle Scholar
  15. 15.
    VanderKuur J, Wang X, Zhang L-Y, Campbell G, Billestrup N, Norstedt G, Carter-Su C (1994) Critical cytoplasmic domains of the growth hormone receptor for JAK2 activation, MAP kinase activation and tyrosine phosphorylation of cellular proteins. J. Biol. Chem. 269: 21709–21717PubMedGoogle Scholar
  16. 16.
    Wang YD, Wong K, Wood WI (1995) Intracellular tyrosine residues of the human growth hormone receptor are not required for the signalling of proliferation or JAK-STAT activation. J. Biol. Chem 270: 7021–7024PubMedCrossRefGoogle Scholar
  17. 17.
    Tanner JW, Chen W, Young RL, Longmore GD, Shaw AS (1995) The conserved box 1 motif of cytokine receptors is required for association with JAK kinases. I biol. Chem. 270:6523–6530Google Scholar
  18. 18.
    Wells JA, Cunningham BC, Fuh G, Lowman HB, Bass SH, Mulkerrin MG, Ultsch M, Devos AM (1993) The molecular basis for growth hormone — receptor interactions. Rec. Prog. Horm. Res. 48: 253–275PubMedGoogle Scholar
  19. 19.
    De Vos A. M., Ultsch M. and Kossiakoff A. A. (1992) Human growth hormone and extracellular domain of its receptor: Crystal structure of the complex. Science 255:306–312.PubMedCrossRefGoogle Scholar
  20. 20.
    Cunningham BC, Ultsch M, DeVos AM, Mulkerrin MG, Clauser KR, Wells JA (1991) Dimerization of the extracellular domain of the hGH receptor by a single hormone molecule. Science 254: 821–825PubMedCrossRefGoogle Scholar
  21. 21.
    Fuh G, Cunningham BC, Fukunaga R, Nagata S, Goeddel DV, Wells JA 1992 Rational design of potent antagonists to the human growth hormone receptor. Science 256: 1677–1680PubMedCrossRefGoogle Scholar
  22. 22.
    Cunningham BC, Wells JA (1993) Comparison of a structural and functional epitope. J. Mol. Biol. 234: 554–563PubMedCrossRefGoogle Scholar
  23. 23.
    Chen WY, Wight DC, Wagner TE, Kopcnick JJ (1990) Expression of a mutated bovine GH gene suppresses growth of transgenic mice. Proc. Natl. Acad. Sci. USA87: 5061–5065CrossRefGoogle Scholar
  24. 24.
    Ross RJ, Esposito N, Shen XY, Von Laue S, Chew SL, Dobson PR, Postel-Vinay MC, Finidori J (1997) A short isoform of the human growth hormone receptor functions as a dominant negative inhibitor of the full length receptor and generates large amounts of binding protein. Mol. Endocrinol. 11:265–273PubMedCrossRefGoogle Scholar
  25. 25.
    Waters MJ, Rowlinson SW, Clarkson RW et al., Signal transduction by the growth hormone receptor. Proc. Soc. Exp. Biol. Med. 206: 216–220Google Scholar
  26. 26.
    Kishimoto T, Taga T, Akira S (1994) Cytokine signal transduction. Cell 76: 253–262PubMedCrossRefGoogle Scholar
  27. 27.
    Livnah O, Stura EA, Johnson DL, Middleton SA, Mulcahy LS, Wrighton NC, Dower WJ, Jolliffe LK, Wilson IA (1996) Functional mimicry of a protein hormone by a peptide agonist. Science 273: 464–471PubMedCrossRefGoogle Scholar
  28. 28.
    Argetsinger LS, Campbell GS, Yang X, Witthun BA, Silvennoinen O, Ihle JN, Carter-Su C. (1993) Identification of JAK2 as a growth hormone receptor associated kinase. Cell 74:1–20CrossRefGoogle Scholar
  29. 29.
    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. (1988) Growth hormone promoted tyrosyl phosphorylation of growth hormone receptors in murine 3T3-F442A fibroblasts and adipocytes. Biochemistry 27:326–334.PubMedCrossRefGoogle Scholar
  30. 30.
    Silva CM, Day RN, Weber MJ, Thoraer MO (1993) Human growth hormone receptor is characterized as the 134 kDa tyrosine phosphorylated protein activated by GH treatment in IM-9 cells. Endocrinology 133: 2307–2312PubMedCrossRefGoogle Scholar
  31. 31.
    Carter-Su C, King AP, Argetsinger LS, Smit LS, Vanderkuur J, Campbell GS (1996) Signalling pathway of GH. Endocrin. J. 43Suppl:S65–70CrossRefGoogle Scholar
  32. 32.
    Smit LS, Meyer DJ, Billestrup N, Norstedt G, Schwartz J, Carter-Su C (1996) The role of the growth hormone receptor and JAK1 and JAK2 kinases in the activation of STATsl,3 and 5 by growth hormone. Mol. Endocrinol. 10: 519–533PubMedCrossRefGoogle Scholar
  33. 33.
    Johnston JA, Kawamura AM, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O’Shea JJ (1994) Phosphorylation and activation of Janus kinase 3 in response to interleukin 2. Nature 370: 151–153PubMedCrossRefGoogle Scholar
  34. 34.
    Klingmuller U, Lorenz U, Cantley LC, Neel BG, Lodish HF (1995) Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of the proliferative signals. Cell 80: 729–738PubMedCrossRefGoogle Scholar
  35. 35.
    Kim SO, Jiang J, Yi WS, Feng GS, Frank SJ (1997) Interaction of the SH2 containing protein tyrosine Phosphatase SHP-1 and SHP-2 with the GH receptor-JAK2 complex. Proc. 79th Ann. Meet. Endocrine Society (Abstract 205)Google Scholar
  36. 36.
    Hackett RH, Wang YD, Sweitzer S, Feldman G, Wood WI, Lamer AC (1997) Mapping of a cytoplasmic domain of the human growth hormone receptor that regulates rates of inactivation of JAK2 and STAT proteins. J. Biol. Chem. 272: 11128–11132PubMedCrossRefGoogle Scholar
  37. 37.
    Yin T, Shen R, Feng GS, Yang YC (1997) Molecular characterization of specific interactions between SHP-2 Phosphatase and JAK tyrosine kinases. J. Biol. Chem. 272: 1032–1037PubMedCrossRefGoogle Scholar
  38. 38.
    Vanderkuur JA, Allevato G, Billestrup N, Norstedt G, Carter-Su C (1995) Growth hormone promoted tyrosyl phosphorylation of shc proteins and shc association with Grb2. J. Biol. Chem. 270: 7587–7593PubMedCrossRefGoogle Scholar
  39. 39.
    He TC, Jiang N, Zhuang H, Wojchowski DM (1995) Eryhtropoietin induced recruitment of shc via a receptor phosphotyrsoine independent JAK2 associated pathway. J. Biol. Chem. 270: 11055–11061PubMedCrossRefGoogle Scholar
  40. 40.
    Giordano V, DeFalco G, Chiari R, Quinto I, Pelicci PG, Bartholomew L, Delmastro P, Gadina M (1997) Shc mediates IL-6 signalling by interacting with gpl30 and JAK2 kinase. J. Immunol. 158: 4097–4103PubMedGoogle Scholar
  41. 41.
    Takahashi-Tezuka M, Hibi M, Fujitani Y, Fukuda T, Yamaguchi T, Hirano T (1997) Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK. Oncogene 14: 2273–2282PubMedCrossRefGoogle Scholar
  42. 42.
    Uddin S, Sher DA, Alsayed Y, Pons S, Colamonici OR, Fish EN, White MF, Platanias LC (1997) Interaction of p59 fyn with interferon activated JAK kinases. Biochem. Biophys. Res. Commun. 235: 83–88PubMedCrossRefGoogle Scholar
  43. 43.
    Sotiropoulos A, Moutoussamy S, Renaudie F, Clauss M, Kayser C, Gouilleux F, Kelly PA, Finidori J (1996) Differential activation of STAT3 and STAT5 by distinct regions of the growth hormone receptor. Mol. Endocrinol. 10: 998–1009PubMedCrossRefGoogle Scholar
  44. 44.
    Yi W, Kim SO, Jiang J, Park SH, Kraft AS, Waxman DJ, Frank SJ (1996) Growth hormone receptor cytoplasmic domain differentially promotes tyrosine phosphorylation of signal transducers and activators of transcription 5b and 3 by activated JAK2 kinase. Mol. Endocrinol. 10: 1425–1443PubMedCrossRefGoogle Scholar
  45. 45.
    Wood TJJ, Sliva D, Lobie PE, Gouilleux F, Mui AL, Groner B, Norstedt G, Haldosen LA (1997) Specificity of transcriptiona enhancement via the STAT responsive element in the serine protease inhibitor 2.1 promoter. Mol. Cell. Endocrinol. 130:69–81PubMedCrossRefGoogle Scholar
  46. 46.
    Moldrup A, Nielsen JH, Billestrup N (1995) Association of p59 fyn with the intracellular domain of the GH receptor. 77th Endocrine Soc. Meet. (Abstract)Google Scholar
  47. 47.
    Yu CL, Burakoff SJ (1997) Involvement of proteasomes in regulating JAK-STAT pathways upon interleukin-2 stimulation. J. Biol. Chem. 272: 14017–14020PubMedCrossRefGoogle Scholar
  48. 48.
    Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A (1997) A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387: 921–924PubMedCrossRefGoogle Scholar
  49. 49.
    Wiedermann CJ, Reinisch N, Braunsteiner H 1993 Stimulation of monocyte Chemotaxis by human growth hormone and its deactivation by somatostatin. Blood 82: 954–960PubMedGoogle Scholar
  50. 50.
    Goh ELK, Pircher TJ, Wood TJJ, Norstedt G, Graichen R, Lobie PE (1997) Growth hormone induced reorganization of the actin cytoskeleton is not required for STAT5 mediated transcription. Endocrinology 138: 3207–3215PubMedCrossRefGoogle Scholar
  51. 51.
    Guan JL, Chen HC (1996) Signal transduction in cell matrix interactions. Int. Rev.Cytol. 168:81–121PubMedCrossRefGoogle Scholar
  52. 52.
    Ilic D, Damsky CH, Yamamoto T (1997) Focal adhesion kinase: at the crossroads of signal transduction. J. Cell. Sci. 110: 401–407PubMedGoogle Scholar
  53. 53.
    Chen HC, Guan JL (1994) Stimulation of phosphatidylinositol 3 kinase association with focal adhesion adhesion kinase by platelet derived growth factor. J. Biol. Chem. 269: 31229–31233PubMedGoogle Scholar
  54. 54.
    Schlaepfer DD, Hunter T (1997) Focal adhesion kinase overexpression enhances ras dependent integrin signalling to ERK2/mitogen activated protein kinase through interactions with and activation of c-src. J. Biol. Chem. 272:13189–13195PubMedCrossRefGoogle Scholar
  55. 55.
    Ridderstrale M, Tornqvist H (1994) PI-3 kinase inhibitor wortmannin blocks the insulin like effects of growth hormone in isolated rat adipocytes. Biochem. Biophys. Res. Commun. 203: 306–310PubMedCrossRefGoogle Scholar
  56. 56.
    Winston LA, Hunter T (1995) JAK2, Ras, Raf are reuired for activation of ERK/ mitogen activated protein kinase by growth homrone. J. Biol. Chem. 270: 30837–30840PubMedCrossRefGoogle Scholar
  57. 57.
    Hanks SK, Polte TR (1997) Signalling through focal adhesion kinase. Bioessays 19: 137–145PubMedCrossRefGoogle Scholar
  58. 58.
    Treisman R (1996) Regulation of transcription by MAP kinase cascades. Curr. Opin. Cell. Biol. 8: 205–215PubMedCrossRefGoogle Scholar
  59. 59.
    Campbell GS, Pang L, Miyasaka T, Saltiel AR, Carter-Su C (1992) Stimulation by growth hormone of MAP kinase activity in 3T3-F442A fibroblasts. J. Biol. Chem. 267: 6074–6080PubMedGoogle Scholar
  60. 60.
    Möller C, Hansson A, Enberg B, Lobie PE, Norstedt G (1992) Growth hormone induction of tyrosine phosphorylation and activation of mitogen activated protein kinases in cells transfected with rat GH receptor cDNA. J. Biol. Chem. 267: 23403–23408PubMedGoogle Scholar
  61. 61.
    Winston LA, Bertics PJ (1992) Growth hormone stimulates the tyrosine phosphorylation of 42-kDa and 45 K-Da ERK related proteins. J. Biol. Chem. 267:4747–4751PubMedGoogle Scholar
  62. 62.
    Tanaka S, Ouchi T, Hanafusa H (1997) Downstream of crk adaptor signalling pathway: activation of jun kinase by v-crk through the guanine nucleotide exchange protein C3G. Proc. Natl. Acad. Sci. USA. 94: 2356–2361PubMedCrossRefGoogle Scholar
  63. 63.
    Han Y, Leaman DW, Watling D, Rogers NC, Groner B, Kerr IM, Wood WI, Stark GR (1996) Participation of JAK and STAT proteins in growth hormone induced signalling. J. Biol. Chem. 271: 5947–5952PubMedCrossRefGoogle Scholar
  64. 64.
    Vanderkuur JA, Butch ER, Waters SB, Pessin JE, Guan KL, Carter-Su C (1997) Signalling molecules involved in cuopling growth hormone receptor to mitogen activated protain kinase activation. Endocrinology 138: 4301–4307PubMedCrossRefGoogle Scholar
  65. 65.
    Kilgour E, Gout I, Anderson NG (1996) Requirement for phosphoinositide 3-OH kinase in growth hormone signalling to the mitogen activated protein kinase and p70 s6k pathways. Biochem. J. 315:517–522PubMedGoogle Scholar
  66. 66.
    Davis RJ (1993) The mitogen activated protein kinase signal transduction pathway. J. Biol. Chem. 268: 14553–14556PubMedGoogle Scholar
  67. 67.
    Pircher TJ, Flores-Morales A, Mui AL, Saltiel AR, Norstedt G, Gustafsson JA, Haldosen LA (1997) Mitogen activated protein kinase kinase inhibition decreases growth hormone stimulated transcription mediated by STAT5. Mol. Cell. Endocrinol., in press.Google Scholar
  68. 68.
    Anderson NG (1993) Similtaneous activation of p90rsk and p70s6k by growth hormone in 3T3-F442A pre-aadipocytes. Biochem. Biophys. Res. Commun. 193: 284–290PubMedCrossRefGoogle Scholar
  69. 69.
    Tollet P, Hamberg M, Gustafsson JA, Mode A (1995) Growth hormone signalling leading to CYP2C12 gene expression in rat hepatocytes involves phospholipase A2. J. Biol. Chem. 270: 12569–12577PubMedCrossRefGoogle Scholar
  70. 70.
    Gurland G, Ashcom G, Cochran BH, Schwartz J (1990) Rapid events in growth hormone action. Induction of c-fos and c-jun transcription in 3T3-F442A preadipocytes. Endocrinology 127: 3187–3195Google Scholar
  71. 71.
    Hodge CL, Liao JF, Ho PF, Schwartz J (1997) GH stimulated phosphorylation of ELK-1 or related protein contributes to c-fos transcription through the SRE. Proc. 79th Meet. Endo. Soc. (Abstract p73)Google Scholar
  72. 72.
    Meyer DJ, Campbell GS, Cochran BH, Argetsinger LS, Larner AC, Finbloom DS, Carter-Su C 1994 Growth hormone induces a DNA binding factor related to Interferon stimulated 91 KDa transcription factor. J. Biol. Chem. 269: 4701–4704PubMedGoogle Scholar
  73. 73.
    Campbell GS, Meyer DJ, Raz R, Levy DE, Schwartz J, Carter-Su C (1995) Activation of acute phase response factor (APRF) / STAT3 transcription factor by growth hormone. J. Biol. Chem. 270: 3974–3979PubMedCrossRefGoogle Scholar
  74. 74.
    Sotiropoulos A, Moutoussamy S, Binart N, Kelly PA (1995) The membrane proximal region of the cytoplasmic domain of the growth hormone receptor is involved in the activation of STAT3. FEBS Letters 369: 169–172PubMedCrossRefGoogle Scholar
  75. 75.
    Wood TJJ, Sliva D, Lobie PE, Pircher TJ, Gouilleux F, Wakao H, Gustafsson J-Â, Groner B, Norstedt G, Haidosen L-A 1995 Mediation of growth hormone-dependent transcriptional activation by mammary gland factor/stat5. J Biol Chem 270:9448–9453PubMedCrossRefGoogle Scholar
  76. 76.
    Waxman DJ, Ram PA, Park SH, Choi HK (1995) Intermittent plasma growth hormone triggers tyrosine phosphorylation and nuclear translocation of a liver expressed, Stat5 related DNA binding protein. Proposed role as a regulator of male specific gene transcription. J. Biol. Chem. 270: 13262–13270PubMedCrossRefGoogle Scholar
  77. 77.
    Bergard PL, Shih HM, Towle HC, Schwarzenberg SJ, Berry SA 1995 Growth hormone induction of hepatic serine protease inhibitor 2.1 transcription is mediated by a STAT5 related factor binding synergistically to two gamma activated sites. J. Biol. Chem. 270: 24903–24910CrossRefGoogle Scholar
  78. 78.
    Rivera RM, Miranti CK, Misra RP, Ginty DD, Chen RH, Blenis J, Greenberg ME (1993) A growth factor induced kinase phosphorylates the serum response factor at a site that regulates its DNA binding activity. Mol. Cell. Biol. 13: 6260–6273PubMedGoogle Scholar
  79. 79.
    Meyer DJ, Stephenson EW, Johnson L, Cochran BH, Schwartz J (1993) The serum response element can mediate the induction of c-fos by growth hormone. Proc. Natl. Acad. Sci. USA 90: 6721–6725PubMedCrossRefGoogle Scholar
  80. 80.
    Horvath CM, Darnell JE (1997) The state of the STATs. Curr. Opin. Cell. biol. 9: 233–239PubMedCrossRefGoogle Scholar
  81. 81.
    Okazaki K, Sagata N (1995) The mos/map kinase pathway stabilizes c-fos by phosphorylation and augments its transforming activity in NIH 3T# cells. EMBO. J. 14: 5048–5059PubMedGoogle Scholar
  82. 82.
    Davidson MB (1987) Effect of growth hormone on carbohydrate and lipid metabolism. Endocrine Rev. 8: 115–131CrossRefGoogle Scholar
  83. 83.
    Eisenhauser KM, Chun SY, Billig H, Hseuh AJ (1995) Growth hormone suppression of apoptosis in preovulatory rat follicles and partial neutralization by insulin like growth factor binding protein. Biol. Reprod. 53: 13–20CrossRefGoogle Scholar
  84. 84.
    Argetsinger LS, Hsu GW, Myers MG, Billestrup N, White MF, Carter-Su C (1995) Growth hormone, interferon gamma and leukaemia inhibitory factor promoted tyrosyl phosphorylation of insulin receptor substrate-1. J. Biol. Chem. 270: 14685–14692PubMedCrossRefGoogle Scholar
  85. 85.
    Argetsinger LS, Norstedt G, Billestrup N, White MF, Carter-Su C (1996) Growth hormone, interferon gamma and leukaemia inhibitory factor utilize insulin receptor substrate 2 in intracellular signalling. J. Biol. Chem. 271: 29415–29421PubMedCrossRefGoogle Scholar
  86. 86.
    Ridderstrale M, Degerman E, Tornqvist H (1995) Growth hormone stimulates the tyrosine phosphorylation of the insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase in primary adipocytes. J. Biol. Chem. 279: 3471–3474Google Scholar
  87. 87.
    Souza SC, Frick GP, Yip R, Lobo RB, Tai LR, Goodman HM (1994) Growth hormone activation of insulin receptor substrate-1. J. Biol. Chem. 269: 30085–30088PubMedGoogle Scholar
  88. 88.
    Lavan BE, Fantin VR, Chang ET, Lane WS, Keller SR, Lienhard GE (1997) A novel 160 kDa phosphotyrosine protein in insulin treated embryonic kidney cells is a new member of the insulin receptor substrate family. J. Biol. Chem. 272:21403–21407PubMedCrossRefGoogle Scholar
  89. 89.
    Yenush L, White MF (1997) The IRS-signalling system during insulin and cytokine action. BioEssays 19: 491–500PubMedCrossRefGoogle Scholar
  90. 90.
    Yamauchi K, Holt K, Pessin JE (1993) Phosphatidylinositol 3-kinase functions upstream of ras and raf in mediating insulin stimulation of c-fos transcription. J. biol. Chem. 268: 14597–14600PubMedGoogle Scholar
  91. 91.
    Lam K, Carpenter CL, Ruderman NB, Friel JC, Kelly KL (1994) The phosphatidlyinositol 3 kinase serine phosphorylates IRS-1; stimulation by insulin and inhibition by wortmannin. J. Biol. Chem. 269: 20648–20652PubMedGoogle Scholar
  92. 92.
    Pfeffer LM, Mullersman JE, Pfeffer SR, Murti A, Shi W, Yang CH (1997) STAT3 as an adaptor to couple phosphatidlyinositol 3 kinase to the IFNAR1 chain of the type 1 interferon receptor. Science 276: 1418–1420PubMedCrossRefGoogle Scholar
  93. 93.
    Beitner-Johnson D, Balkesley VA, Shen-Orr Z, Jiminez M, Stannard B, Wang LM, Pierce J, LeRoith D (1996) The proto oncogene product c-Crk associates with insulin receptor substrate 1 and 4PS. J. Biol. Chem. 271: 9287–9290PubMedCrossRefGoogle Scholar
  94. 94.
    Smal J, DeMeyts P (1987) Role of protein kinase C in the insulin like effects of growth hormone in rat adipocytes. Biochem. biophys. Res. Communic. 147: 1232–1240CrossRefGoogle Scholar
  95. 95.
    Slootweg MC, Degroot RP, Herrmann-Erlee MP, Koornneef I, Kruijer W, Kramer Ym (1991) Growth hormone induces expression of c-jun and jun B oncogenes and employs a protein kinase C signal transduction pathway for the induction of c-fos oncogene expression. J. Mol. Endocrinol. 6: 179–188PubMedCrossRefGoogle Scholar
  96. 96.
    Tollet P, Legraverand C, Gustafsson JA, Mode A (1991) A role for protein kinases in the growth hormone regulation of cytochrome P4502cl2 and insulin like growth factor-1 mRNA expression in primary rat heaptocytes. Mol. Endocrinol. 5: 1351–1358PubMedCrossRefGoogle Scholar
  97. 97.
    Gaur S, Yamaguchi H, Goodman HM (1996) Growth hormone increases calcium uptake in rat fat cells by a mechanism dependent on protein kinase C. Am. J. Physiol. 270:C1485–C1492PubMedGoogle Scholar
  98. 98.
    Clarkson RW, Chen CM, Harrison S, Wells C, Muscat GE, Waters MJ (1995) Early responses of transactivating factors to growth hormone in preadipocytes. Mol Endocrinol. 9: 108–120PubMedCrossRefGoogle Scholar
  99. 99.
    Dekker LV, Parker PJ (1994) Protein kinase C: a question of specificity. TIBS 19: 73–77PubMedGoogle Scholar
  100. 100.
    Okada S, Kopchick JJ (1997) Growth hormone and insulin stimulate different subsets of protein kinase C isotypes through different mechanisms. Proc. 79th Ann. Meet. Endocrine Soc. (Abstract p576)Google Scholar
  101. 101.
    l00.Doglio A, Dani C, Grimaldi P, Ailhaud G (1989) Growth hormone stimulates c-fos gene expression by means of protein kinase C without increasing inositol lipid turnover. Proc. Natl. Acad. Sci. USA 86: 1148–1152PubMedCrossRefGoogle Scholar
  102. 102.
    Johnson RM, Napier MA, Cronin MJ, King KL (1990) Growth hormone stimulates the formation of sn-l,2-diacylglycerol in rat heaptocytes. Endocrinology 127: 2099–2103PubMedCrossRefGoogle Scholar
  103. 103.
    Rogers SA, Hammerman MR (1989) Growth hormone activates phospholipase C in proximal tubular basolateral membranes from canine kidney. Proc. Natl. Acad. Sci. USA 86: 6363–6366PubMedCrossRefGoogle Scholar
  104. 104.
    Roupas P, Herington AC (1995) Signalling mechanisms involved in the production of diacylglycerol by growth hormone. Proc 77th Meet Endocrine Soc. (Abstract p345)Google Scholar
  105. 105.
    Argetsinger LS, Carter-Su C (1996) Mechanism of signalling by growth hormone receptor. Physiol. Rev. 76: 1089–1107PubMedGoogle Scholar
  106. 106.
    Hondo MM, DeMeyts P, Bouchelouche P (1994) Human growth hormone increases cytosolic free calcium in cultured human IM-9 lymphocytes: a novel mechanism mechanism of growth hormone transmembrane signalling. Biochem. Biophys. Res. communie. 202: 391–397CrossRefGoogle Scholar
  107. 107.
    Schwartz Y, Goodman HM (1990) Refractoriness to the insulin like effects of growth hormone depends upon calcium. Endocrinology 126: 170–176CrossRefGoogle Scholar
  108. 108.
    Schwartz Y, Yamaguchi H, Goodman HM (1992) Growth hormone increases intracellular free calcium in rat adipocytes: correlations with actions on carbohydrate metabolism. Endocrinology 131: 772–778PubMedCrossRefGoogle Scholar
  109. 109.
    Billestrup N, Bouchelouche P, Allevato G, Hondo M, Nielsen JH (1995) Growth hormone receptor C-terminal domains required for growth hormoneinduced intracellular free calcium oscillations and gene transcription. Proc. Natl. Acad. Sci. USA 92: 2725–2729PubMedCrossRefGoogle Scholar
  110. 110.
    Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ, Davey HW (1997) Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc. Natl. Acad. Sci. USA 94: 7239–7244PubMedCrossRefGoogle Scholar
  111. 111.
    Stahl N, Farruggella T, Boulton TG, Zhong Z, Darnell JE, Yancopoulos GD (1995) Modular tyrosine based motifs in cytokine receptors specify choice of STATs and other substrates. Science 267: 1349–1353PubMedCrossRefGoogle Scholar
  112. 112.
    Smit LS, Vanderkuur JA, Stimage A, Han Y, Luo G, Yu-Lee LY, Schwartz J, Carter-Su C (1997) Growth hormone induced tyrosyl phosphorylation and DNA binding activity of STAT5a and STAT5b. Endocrinology 138: 3426–3434PubMedCrossRefGoogle Scholar
  113. 113.
    Lobie PE, Allevato G, Nielsen JH, Norstedt G, Billestrup N (1995) Requirement of tyrosine residues 333 and 338 of the growth hormone receptor for selected GH stimulated function. J. Biol. Chem. 270: 21745–21750PubMedCrossRefGoogle Scholar
  114. 114.
    Hansen LH, Wang X, Kopchick JJ, Bouchelouche P, Nielsen JH, Galsgaard ED, Billestrup N (1996) Identification of tyrosine residues in the intracellular domain of the growth hormone receptor required for transcriptional signalling and STAT5 activation. J. Biol. Chem. 27: 12669–12673Google Scholar
  115. 115.
    Finbloom DS, Petricoin EF, Hackett RH, David M, Feldman GM, Igarashi KI, Fibach E, Weber MJ, Thorner MO, Silva CM, Larner AC (1994) Growth hormone and erythropoietin differentially activate DNA-binding proteins by tyrosine phosphorylation. Mol. Cell. Biol. 14: 2113–2118PubMedGoogle Scholar
  116. 116.
    Silva CM, Lu H, Weber MJ, Thorner MO (1994) Differential tyrosine phosphorylation of JAK1, JAK2 and STAT1 by growth hormone and interferon gamma in IM-9 cells. J. Biol. Chem. 269: 27532–27539PubMedGoogle Scholar
  117. 117.
    Luo G, Yu-Lee LY (1997) Differential activities of STAT5 at growth related versus differentiation specific promoters. Proc 79 Meet. Endocr. Soc. (Abstract p571)Google Scholar
  118. 118.
    Stocklin E, Wissler M, Gouilleux F, Groner B (1996) Functional interactions between STAT5 and the glucocorticoid receptor. Nature 383: 726–728PubMedCrossRefGoogle Scholar
  119. 119.
    Lisanti MP, Scherer PE, Vidugiriene J, Tang ZL, Hermanowski-Vosatka A, Tu YH, Cook RF, Sargiacomo M (1994) Characterization of caveolin rich membrane domains isolated from an endothelial-rich source: Implications for human disease. J Cell Biol 126: 111–126PubMedCrossRefGoogle Scholar
  120. 120.
    Lobie PE, Mertani H, Morel G, Morales-Bustos O, Norstedt G, Waters MJ (1994) Receptor mediated nuclear translocation of growth hormone. J Biol Chem 269:21330–21339PubMedGoogle Scholar
  121. 121.
    Lobie PE, Wood TJJ, Chen CM, Waters MJ, Norstedt G (1994) Nuclear translocation and anchorage of the growth hormone receptor. J. Biol. Chem. 269:31375–31746Google Scholar
  122. 122.
    Stout LE, Svensson AM, Sorenson RL (1997) Prolactin regulation of islet derived INS-1 cells: characteristics and immunocytochemical analysis of STAT5 translocation. Endocrinology 138: 1592–1603PubMedCrossRefGoogle Scholar
  123. 123.
    Lobie PE, Ronsin B, Silvennoinen O, Haldosen LA, Norstedt G, Morel G (1996) Constitutive nuclear localization of Janus kinases 1 and 2. Endocrinology 137: 4037–4045PubMedCrossRefGoogle Scholar
  124. 124.
    Wang Y, Yu-Lee L (1996) Multiple STAT complexes nteract at the interferon regulatory factor-1 interferon gamma activation sequence in prolactin stimulated Nb2 T cells. Mol. Cell. Endocrinol. 121: 19–28PubMedCrossRefGoogle Scholar
  125. 125.
    Ram PA, Waxman DJ (1997) Interaction of growth hormone activated STATs with SH2 containing phosphotyrosine Phosphatase SHP-1 and nuclear JAK2 tyrosine kinase. J. Biol. Chem. 272: 17694–17702PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Peter E. Lobie
    • 1
  1. 1.Institute of Molecular and Cell Biology and Defence Medical Research InstituteNational University of SingaporeSingaporeRepublic of Singapore

Personalised recommendations