Insulin Action pp 31-48

Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 24) | Cite as

Insulin signal transduction through protein kinase cascades

  • Joseph Avruch

Abstract

This review summarizes the evolution of ideas concerning insulin signal transduction, the current information on protein ser/thr kinase cascades as signalling intermediates, and their status as participants in insulin regulation of energy metabolism. Best characterized is the Ras-MAPK pathway, whose input is crucial to cell fate decisions, but relatively dispensable in metabolic regulation. By contrast the effectors downstream of PI-3 kinase, although less well elucidated, include elements indispensable for the insulin regulation of glucose transport, glycogen and cAMP metabolism. Considerable information has accrued on PKB/cAkt, a protein kinase that interacts directly with Ptd Ins 3′OH phosphorylated lipids, as well as some of the elements further downstream, such as glycogen synthase kinase-3 and the p70 S6 kinase. Finally, some information implicates other erk pathways (e.g. such as the SAPK/JNK pathway) and Nck/cdc42-regulated PAKs (homologs of the yeast Ste 20) as participants in the cellular response to insulin. Thus insulin recruits a broad array of protein (ser/thr) kinases in its target cells to effectuate its characteristic anabolic and anticatabolic programs. (Mol Cell Biochem 182: 31-48, 1998)

Key words

insulin action protein serine/threonine kinase Ras-Raf MAP kinase ribosomal S6 protein kinase (RSKs) phosphatidyl inositol-3 kinase 

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References

  1. 1.
    Cahill GF, Steiner DF (eds).: Endocrinology 1 Handbook of Physiology. American Physiological Society, 1972Google Scholar
  2. 2.
    White MW, Kahn CR: The insulin signalling system. J Biol Chem 269: 1–4, 1994PubMedGoogle Scholar
  3. 3.
    Avruch J: Small GTPases and (serine/threonine) protein kinase cascades in insulin signal transduction. In: D LeRoith, J Olefsky, S Taylor (eds). Diabetes Mellitus: A Fundamental and Clinical Text. J.P. Lippincott Co., PA, USA, 1996Google Scholar
  4. 4.
    Bliss R: The discovery of insulin. University of Chicago Press, 1982Google Scholar
  5. 5.
    Larner J: Insulin-signalling mechanisms. Lessons from the old testament of glycogen metabolism and the new testament of molecular biology. Diabetes 37: 262–275, 1988PubMedGoogle Scholar
  6. 6.
    Cuatrecasas P: Interaction of insulin with the cell membrane: The primary action of insulin. Proc Natl Acad Sci 63: 450–457, 1969PubMedCrossRefGoogle Scholar
  7. 7.
    Robison GA, Butcher RW, Sutherland EW: Cyclic AMP, Academic Press, New York, 1971, pp 1–23Google Scholar
  8. 8.
    Krebs EG: Protein kinases. Curr Top Cell Reg 5: 99–133, 1972Google Scholar
  9. 9.
    Butcher RW, Sneyd S, Park CR, Sutherland EW: Effect of insulin on adenosine 3′ 5′ monophosphate in raf epidydimal fat pads. J Biol Chem 242: 1651–1656, 1996Google Scholar
  10. 10.
    Ullrich A, Schlessinger J: Signal transduction by receptors with tyr kinase activity. Cell 61: 203–206, 1990PubMedCrossRefGoogle Scholar
  11. 11.
    Fantl WJ, Johnson DE, Williams LT: Signalling by receptor tyrosine kinases. Ann Rev Biochem 62: 453–481, 1993PubMedCrossRefGoogle Scholar
  12. 12.
    Koch CA, Anderson D, Moran MF, Ellis C, Pawson T: SH2 and SH3 domains: Elements that control interactions of cytoplasmic signalling proteins. Science 252: 668–674, 1991PubMedCrossRefGoogle Scholar
  13. 13.
    Kavanaugh WM, Williams LT: An alternative to SH2 domains for binding tyrosine-phosphorylated proteins. Science 266: 18627–18655, 1994CrossRefGoogle Scholar
  14. 14.
    Bork P, Margolis B: A phosphotyrosine interaction domain Cell. 80: 693–694, 1995PubMedCrossRefGoogle Scholar
  15. 15.
    Matsuda M, Mayer BJ, Fukui Y, Hanafusa H: Binding of transforming protein, P47gag-crk, to a broad range of phosphotyrosine-containing proteins. Science 248(4962): 1537–1539, 1990PubMedCrossRefGoogle Scholar
  16. 16.
    Tornqvist HE, Avruch J: Relationship of site-specific β subunit tyrosine autophosphorylation to insulin activation of the insulin receptor (tyrosine) kinase activity. J Biol Chem 263: 4593–4601, 1988PubMedGoogle Scholar
  17. 17.
    Avruch J, Nemenoff RA, Pierce M, Kwok YC, Blackshear PJ: Protein phosphorylations as a mode of insulin action. In: MP Czech (ed). Molecular Basis for Insulin Action. Plenum Press, New York, 1985, pp 263–296CrossRefGoogle Scholar
  18. 18.
    Kyriakis JM, Avruch J: S6 kinases and MAP kinases: Sequential intermediates in insulin/mitogen-activated protein kinase cascades. In: JR Woodgett (ed). Protein Kinases: Frontiers in Molecular Biology. Oxford University Press, Oxford, 1994, pp 85–148Google Scholar
  19. 19.
    Avruch J, Zhang XF, Kyriakis JM: Raf meets Ras: Closing a frontier in signal transduction. TIBS 19: 274–283, 1994Google Scholar
  20. 20.
    Lowy DR, Willumsen BM: Function and regulation of Ras. Ann Rev Biochem 62: 851–891, 1993PubMedCrossRefGoogle Scholar
  21. 21.
    Avruch J, Kyriakis JM, Zhang XF: Raf-1 kinase. In: B Draznin, D Leroith (eds). Molecular Biology of Diabetes. Humana Press Inc., New Jersey, USA, 1994, pp 179–207Google Scholar
  22. 22.
    Ahn NG, Seger R, Krebs EC: The mitogen-activated protein kinase activator. Curr Opin Cell Biol 4: 992–999, 1992PubMedCrossRefGoogle Scholar
  23. 23.
    Cobb MH, Goldsmith EJ: How MAP kinases are regulated. J Biol Chem 270: 14843–14846, 1995PubMedCrossRefGoogle Scholar
  24. 24.
    Denton RM, Tavare JM: Does mitogen-activated-protein kinase have a role in insulin action? The cases for and against. Eur J Biochem 227: 597–611, 1995PubMedCrossRefGoogle Scholar
  25. 25.
    Valencia A, Chardin P, Wittinghofer A, Sander C: The Ras protein family: Evolutionary tree and role of conserved amino acids. Biochem 30: 4637–4648, 1991CrossRefGoogle Scholar
  26. 26.
    Zhang FL, Casey PJ: Protein prenylation: Molecular mechanisms and functional consequences. Ann Rev Biochem 65: 241–269, 1996PubMedCrossRefGoogle Scholar
  27. 27.
    Schlessinger J: How receptor tyrosine kinases activate Ras. TIBS 18: 273–275, 1993PubMedGoogle Scholar
  28. 28.
    Boguski MS, McCormick F: Proteins regulating Ras and its relatives. Nature 366: 643–654, 1993PubMedCrossRefGoogle Scholar
  29. 29.
    Marshall MS: The effector interactions of p21Ras. TIBS 18: 250–254, 1993PubMedGoogle Scholar
  30. 30.
    Zhang XF, Settleman J, Kyriakis JM, Takeuchi-Suzuki E, Elledge SJ, Marshall MS, Bruder JT, Rapp UR, Avruch J: Normal and oncogenic p21Ras binds to the amino-terminal regulatory domain of c-Raf-1. Nature 364: 308–313, 1993PubMedCrossRefGoogle Scholar
  31. 31.
    Satoh T, Nakafuku M, Kaziro Y: Function of Ras as a molecular switch in signal transduction: J Biol Chem 267: 24149–24152, 1992PubMedGoogle Scholar
  32. 32.
    Marshall CJ: Ras effectors. Curr Opin Cell Biol 8: 197–204, 1996PubMedCrossRefGoogle Scholar
  33. 33.
    Rapp UR, Heidecker C, Huleihel M et al.: Raf family serine/threonine protein kinases in mitogen signal transduction. Cold Spring Harbor, Symp Quant Biol 53: 173–184, 1988CrossRefGoogle Scholar
  34. 34.
    Chuang E, Barnard D, Hettich L, Zhang XF, Avruch J, Marshall MS: Critical binding and regulatory interactions between Ras and Raf occur through a small, stable N-terminal domain of Raf and specific Ras effector residues. Mol Cell Biol 14: 5318–5325, 1994PubMedGoogle Scholar
  35. 35.
    Barnard D, Diaz B, Hettich L, Chuang E, Zhang XF, Avruch J, Marshall M: Identification of the sites of interaction between c-Raf-1 and Ras-GTP. Oncogene 10: 1283–1290, 1995PubMedGoogle Scholar
  36. 36.
    Herrmann C, Martin GA, Wittinghoefer A: Quantitative analysis of the complex between p21Ras and the Ras-binding domain of the human raf-1 protein kinase. J Cell Biol 272: 2901–2905, 1995Google Scholar
  37. 37.
    Hu CD, Kariya K, Tamada M, Akasaka K, Shirouzu M, Yokoyama S, Kataoka T: Cysteine-rich region of Raf-1 interacts with activator domain of post-translationally modified Ha-Ras. J Biol Chem 270: 30274–30277, 1995PubMedCrossRefGoogle Scholar
  38. 38.
    Luo Z, Diaz B, Marshall MS, Avruch J: An intact raf zinc finger is required for optimal binding to processed Ras and for Ras-dependent raf activation in situ. Mol Cell Biol 17: 46–53, 1997PubMedGoogle Scholar
  39. 39.
    Leevers SJ, Paterson HF, Marshall CJ: Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 369: 411–414, 1994PubMedCrossRefGoogle Scholar
  40. 40.
    Stokoe D, Macdonald SC, Cadwallader K, Symons M, Hancock JF: Activation of Raf as a result of recruitment to the plasma. Science 264: 1463–1467, 1994PubMedCrossRefGoogle Scholar
  41. 41.
    Mineo C, Anderson RG, White M: Physical association with Ras enhances activation of membrane-bound Raf (Raf CAAX). J Biol Chem 272: 10345–10348, 1997PubMedCrossRefGoogle Scholar
  42. 42.
    Luo Z, Zhang X-f, Rapp U, Avruch J: Identification of the 14.3.3 zeta domains important for self association and Raf binding. J Biol Chem 270: 23681–23687, 1995Google Scholar
  43. 43.
    Fantl WJ, Muslin AJ, Kikuchi A, Martin JA, MacNicol AM, Gross RW, Williams LT: Activation of Raf-1 by 14-3-3 proteins. Nature 371: 612–614, 1994PubMedCrossRefGoogle Scholar
  44. 44.
    Muslin AJ, Tanner JW, Allen PM, Shaw AS: Interaction of 14-3-3 with signalling proteins is mediated by the recognition of phosphoserine. Cell 84: 889–897, 1996PubMedCrossRefGoogle Scholar
  45. 45.
    Morrison DK, Heidecker C, Rapp UR, Copeland TD: Identification of the major phosphorylation sites of the Raf-1 kinase. J Biol Chem 268: 17309–17316, 1993PubMedGoogle Scholar
  46. 46.
    Luo Z, Tzivion C, Belshaw PJ, Marshall M, Avruch J: Oligomerization activates c-Raf-1 through a Ras-dependent mechanism. Nature 383: 181–185, 1996PubMedCrossRefGoogle Scholar
  47. 47.
    Farrar MA, Alberol-Ila, Perlmutter RM: Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization. Nature 383: 178–181, 1996PubMedCrossRefGoogle Scholar
  48. 48.
    Kornfeld K, Horn DB, Horvitz HR: The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signalling in C. elegans Cell 83: 903–913, 1995PubMedCrossRefGoogle Scholar
  49. 49.
    Therrien M, Chang HC, Solomon NM, Karim FD, Wassarman DA, Rubin CM: KSR, a novel protein kinase required for RAS signal transduction. Cell 83: 879–888, 1995PubMedCrossRefGoogle Scholar
  50. 50.
    Zhang Y, Yao B, Delikat S, Bayoumy S, Lin XH, Basu S, McCinley M, Chan-Hui PY, Lichenstein H, Kolesnick R: Kinase suppressor of Ras is ceramide-activated protein kinase. Cell 89: 63–72, 1997PubMedCrossRefGoogle Scholar
  51. 51.
    Kolch W, Heidecker G, Kochs G: Protein kinase Ca activates RAF-1 by direct phosphorylation. Nature 364: 249–252, 1993PubMedCrossRefGoogle Scholar
  52. 52.
    Marais R, Light Y, Paterson HF, Marshall CJ: Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J 14: 3136–3145, 1995PubMedGoogle Scholar
  53. 53.
    Kyriakis JM, Force TL, Rapp UR, Bonventre JV, Avruch J: Mitogen regulation of c-Raf-1 protein kinase activity toward mitogen-activated protein kinase-kinase. J Biol Chem 268: 16009–16019, 1993PubMedGoogle Scholar
  54. 54.
    Wu J, Dent P, Jelinek T, Wolfman A, Weber MJ, Sturgill TJ: Inhibition of the EGF-activated MAP kinase signalling pathway by adenosine S′, 5′-monophosphate. Science 262: 1065–1069, 1993PubMedCrossRefGoogle Scholar
  55. 55.
    Altschuler DL, Peterson SN, Ostrowski MC, Lapetina EG: Cyclic AMP-dependent activation of Raplb. J Cell Biol 270: 10373–10376, 1995Google Scholar
  56. 56.
    Cook SJ, Rubinfeld B, Albert I, McCormick F: RapV12 antagonizes Ras-dependent activation of ERK1 and ERK2 by LPA and EGF in Rat-1 fibroblasts: EMBO J 12: 3475–3485, 1993PubMedGoogle Scholar
  57. 57.
    Vossler NM, Yao H, York RD, Pan MC, Rim CS, Stork PJ: cAMP activates MAP kinase and Elk-1 through a B-Raf-and Rap1-dependent pathway. Cell 89: 73–82, 1997PubMedCrossRefGoogle Scholar
  58. 58.
    Yamamori B, Kuroda S, Shimizu K, Fukui K, Ohtsuka T, Takai Y: Purification of a Ras-dependent mitogen-activated protein kinase kinase kinase from bovine brain cytosol and its identification as a complex of B-Raf and 14-3-3 proteins. J Biol Chem 270: 11723–11726, 1995PubMedCrossRefGoogle Scholar
  59. 59.
    Okada T, Masuda T, Shinkai M, Kariya K, Kataoka T: Post-translational modification of H-Ras is required for activation of, but not for association with, B-Raf. J Biol Chem 271: 4671–4678, 1996PubMedCrossRefGoogle Scholar
  60. 60.
    Kyriakis JM, App H, Zhang X-F, Banerjee P, Brautigan DL, Rapp UR, Avruch J: Raf-1 activates MAP kinase-kinase. Nature 358: 417–421, 1992PubMedCrossRefGoogle Scholar
  61. 61.
    Galaktino K, Jessus C, Beach D: Raf-1 interaction with Cdc25 Phosphatase ties mitogenic signal transduction to cell cycle activation. Genes Devel 9: 1046–1052, 1995CrossRefGoogle Scholar
  62. 62.
    Posada J, Yew N, Ahn NG, Vandewoude CF, Cooper JA: Mos stimulates MAP kinase in Xenopus oocytes and activates a MAP kinase kinase in vitro. Mol Cell Biol: 132546–132553, 1993Google Scholar
  63. 63.
    Lange-Carter CA, Pleiman CM, Cardner AM, Blumer KJ, Johnson CL: A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science 260: 315–319, 1993PubMedCrossRefGoogle Scholar
  64. 64.
    Sturgill TW, Ray LB, Erikson E, Mailer JL: Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II. Nature 334: 715–718, 1988PubMedCrossRefGoogle Scholar
  65. 65.
    Waskiewicz AJ, Flynn A, Proud CC, Cooper JA: Mitogen-activated protein kinases activate the serine/threonine kinases Mnkl and Mnk2. EMBO J 16: 1909–1929, 1997PubMedCrossRefGoogle Scholar
  66. 66.
    Mukhopadhyay NK, Price DJ, Kyriakis JM, Pelech S. Sanghera J, Avruch J: An array of insulin-activated, proline-directed (Ser/Thr) protein kinases phosphorylate the p70 S6 kinase. J Biol Chem 267: 3325–3335, 1992PubMedGoogle Scholar
  67. 67.
    Hsiao KM, Chou SY, Shih SJ, Ferrell JE Jr: Evidence that inactive p42 mitogen-activated protein kinase and inactive Rsk exist as a heterodimer in vivo. Proc Natl Acad Sci 91: 5480–5484, 1994PubMedCrossRefGoogle Scholar
  68. 68.
    Dai T, Rubie E, Franklin CC, Kraft A, Gillespie DA, Avruch J, Kyriakis JM, Woodgett JR: Stress-activated protein kinases bind directly to the delta domain of c-jun in resting cells: Implications for repression of c-jun function. Oncogene 10: 849–855, 1995PubMedGoogle Scholar
  69. 69.
    Kallunki T, Deng T, Hibi M, Karin M: c-jun can recruit JNK to phosphorylate dimerization partners via specific docking interactions. Cell 87: 929–939, 1996PubMedCrossRefGoogle Scholar
  70. 70.
    Erikson E, Mailer JL: Purification and characterization of a protein kinase from Xenopus eggs highly specific for ribosomal protein S6. J Biol Chem 261: 350–355, 1986PubMedGoogle Scholar
  71. 71.
    Alcorta DA, Crews CM, Sweet LJ, Bankston L, Jones SW, Erikson RL: Sequence and expression of chicken and mouse rsk: Homologs of Xenopus laevis ribosomal S6 kinase. Mol Cell Biol 9: 3850–3859, 1989PubMedGoogle Scholar
  72. 72.
    Zhao Y, Bjorbaek C, Weremowicz S, Morton CC, Moller DE: RSK3 encodes a novel pp90rsk isoform with a unique N-terrmnal sequence: Growth factor-stimulated kinase function and nuclear translocation. Mol Cell Biol 15: 4353–41363, 1995PubMedGoogle Scholar
  73. 73.
    Sutherland C, Campbell DG, Cohen P: Identification of insulin-stimulated protein kinase-1 as the rabbit equivalent of rskmo-2; identification of two threonines phosphorylated during activation by MAP kinases. Eur JBiochem 212: 581–588, 1993CrossRefGoogle Scholar
  74. 78.
    Price DJ, Grove, JR, Calvo V, Avruch J, Bierer BE: Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science 257: 973–977, 1992PubMedCrossRefGoogle Scholar
  75. 79.
    Erikson E, Mailer JL: Substrate specificity of ribosomal protein S6 kinase H from Xenopus eggs. Second Mess and Phosphoprotein 12: 135–143, 1988Google Scholar
  76. 80.
    Blenis J: Signal transduction via the MAP kinases: Proceed at your own risk. Proc Natl Acad Sci USA 90: 5889–5992, 1993PubMedCrossRefGoogle Scholar
  77. 81.
    Dent P, Lavoinne A, Nakielny S, Caudwell FB, Watt P, Cohen P: The molecular mechanism by which insulin stimulates glycogen synthesis in mammalian skeletal muscle. Nature 348: 302–308, 1990PubMedCrossRefGoogle Scholar
  78. 82.
    Sutherland C, Leighton I, Cohen P: Inactivation of glycogen synthase kinase-3b by MAP kinase-activated protein kinase-1 (RSK-2) and p70 S6 kinase; new kinase connections in insulin and growth factor signalling. Biochem J 296: 15–19, 1993PubMedGoogle Scholar
  79. 83.
    Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA: Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378: 785–789, 1995PubMedCrossRefGoogle Scholar
  80. 84.
    Eldar-Finkelman H, Seger R, Vandenheede JR, Krebs EG: Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signalling pathway in NIH/3T3 cells. J Biol Chem 270: 987–990, 1995PubMedCrossRefGoogle Scholar
  81. 85.
    Benito M, Porras A, Nebreda AR, Santos E: Differentiation of 3T3 fibroblasts to adipocytes induced by transfection of Ras oncogenes. Science 253: 565–568, 1991PubMedCrossRefGoogle Scholar
  82. 86.
    Porras A, Maszynski K, Rapp UR, Santos E: Dissociation between activation of Raf-1 and the 42-kDa mitogen-activated protein kinase/ 90-kDa S6 kinase (MAPK/RSK) cascade in the insulin/Ras pathway of adipocytic differentiation of 3T3 L1 cells. J Biol Chem 269: 12741–12748, 1994PubMedGoogle Scholar
  83. 90.
    Yano H, Nakanishi S, Kimura K et al.: Inhibition of histamine secretion by wortmannin through the blockade of phosphatidylinositol 3-kinase in RBL-2H3 cells. J Biol Chem 268: 25846–25856, 1993PubMedGoogle Scholar
  84. 91.
    Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR: Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol 14: 4902–4911, 1994PubMedGoogle Scholar
  85. 92.
    Hara K, Yonezawa K, Sakave H, Ando A, Kotani K, Kitamura T, Kitamura Y, Ueda H, Stephens L, Jackson TR et al.: 1-Phosphatidylinositol 3-kinase activity is required for insulin stimulated glucose transport but not for RAS activation in CHO cells. Proc Natl Acad Sci 91: 7415–7419, 1994PubMedCrossRefGoogle Scholar
  86. 93.
    Robinson LA, Razzack ZF, Lawrence JCJ, James DE: Mitogen-activated protein kinase activation is not sufficient for stimulation of glucose transport or glycogen synthase in 3T3-L1 adipocytes. J Biol Chem 268: 26422–26427, 1993PubMedGoogle Scholar
  87. 94.
    Lin TA, Lawrence JC: Activation of ribosomal protein S6 kinases does not increase glycogen synthesis or glucose transport in rat adipocytes. JBiol Chem 269: 21255–21261, 1994Google Scholar
  88. 95.
    Carpenter CL, Cantley LC: Phosphoinositide kinases. Curr Opin Cell Biol 8: 153–158, 1996PubMedCrossRefGoogle Scholar
  89. 96.
    Toker A, Meyer M, Reddy K et al.: Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3, 4-P2 and PtdIns-3, 4, 5-P3. J Biol Chem 269: 32358–32367, 1994PubMedGoogle Scholar
  90. 97.
    Nakanishi H, Brewer KA, Exton JH: Activation of the z isozyme of protein kinase C by phosphatidylinositol 3, 4, 5-triphosphate. J Biol Chem 268: 13–16, 1993PubMedGoogle Scholar
  91. 98.
    Franke TF, Kaplan DR, Cantley LC: P13K: Downstream AKTion blocks apoptosis. Cell 88: 435–437, 1997PubMedCrossRefGoogle Scholar
  92. 99.
    Farese RV: In: D LeRoith, J Olefsky, S Taylor (eds). Diabetes Mellitus: A Fundamental and Clinical Text. J.P. Lippincott Co., PA, USA, 1996Google Scholar
  93. 100.
    Blackshear PJ: In: B Draznin, D Leroith (eds). The Role (or Lack Thereof) of Protein Kinase C in Insulin Action. Humana Press Inc., New Jersey, USA, 1994, pp 229–244Google Scholar
  94. 101.
    Rameh LE, Chen CS, Cantley LC: Phosphatidylinositol (3, 4, 5)P3 interacts with SH2 domains and modulates PI 3-kinase association with tyrosine-phosphorylated proteins. Cell 83: 821–830, 1995PubMedCrossRefGoogle Scholar
  95. 102.
    Jones PF, Jakubowicz T, Pitossi FJ, Maurer F, Hemmings BA: Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. Proc Natl Acad Sci 88: 4171–4175, 1991PubMedCrossRefGoogle Scholar
  96. 103.
    Coffer PJ, Woodgett JR: Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Euro J Biochem 201: 475–481, 1991CrossRefGoogle Scholar
  97. 10k.
    Bellacosa A, Testa JR, Staal SP, Tsichlis PN: A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 254: 214–217, 1991CrossRefGoogle Scholar
  98. 105.
    Staal SP, Hartley JW, Rowe WP: Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma. Proc Natl Acad Sci 74: 3065–3067, 1977PubMedCrossRefGoogle Scholar
  99. 106.
    Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR, Tsichlis PN: The protein kinase encoded by the Akt protooncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81: 727–736, 1995PubMedCrossRefGoogle Scholar
  100. 107.
    Kohn AD, Kovacina KS, Roth RA: Insulin stimulates the kinase activity of RAC-PK, a pleckstrin homology domain containing ser/thr kinase. EMBOJ 14: 4288–4295, 1995Google Scholar
  101. 108.
    Burgering BM, Coffer PJ: Protein kinase B (c-Akt) in phosphatidyl-inositol-3-OH kinase signal transduction. Nature 376: 599–602, 1995PubMedCrossRefGoogle Scholar
  102. 109.
    Klippel A, Reinhard C, Kavanaugh WM, Apell G, Escobedo MA, Williams LT: Membrane localization of phosphatidylinositol 3-kinase is sufficient to activate multiple signal-transducing kinase pathways. Mol Cell Biol 16: 4117–4127, 1996PubMedGoogle Scholar
  103. 110.
    Marte BM, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J: R-Ras can activate the phosphoinositide 3-kinase but not the MAP kinase arm of the Ras effector pathways. Curr Biol 7: 63–70, 1997PubMedCrossRefGoogle Scholar
  104. 111.
    Franke TF, Kaplan DR, Cantley LC, Toker A: Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3, 4-bisphosphate Science 275: 665–668, 1997PubMedCrossRefGoogle Scholar
  105. 112.
    Klippel A, Kavanaugh WM, Pot D, Williams LT: A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mol Cell Biol 17: 338–344, 1997PubMedGoogle Scholar
  106. 113.
    Andjelkovic M, Jakubowicz T, Cron P, Ming XF, Han JW, Hemmings BA: Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein Phosphatase inhibitors. Proc Natl Acad Sci 93: 5699–5704, 1996PubMedCrossRefGoogle Scholar
  107. 114.
    Konishi H, Matsuzaki H, Tanaka M, Ono Y, Tokunaga C, Kuroda S, Kikkawa U: Activation of RAC-protein kinase by heat shock and hyperosmolarity stress through a pathway independent of phosphatidylinositol 3-kinase. Proc Natl Acad Sci 93: 7639–7643, 1996PubMedCrossRefGoogle Scholar
  108. 115.
    Kohn AD, Takeuchi F, Roth RA: Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem 271: 21920–21926, 1996PubMedCrossRefGoogle Scholar
  109. 116.
    Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA: Mechanism of activation of protein kinase B by insulin and IGF-1. EMBOJ 15: 6541–6551, 1996Google Scholar
  110. 117.
    Keranen LM, Dutil EM, Newton AC: Protein kinase C is regulated in vivo by three functionally distinct phosphorylations. Curr Biol 5: 1394–1403, 1995PubMedCrossRefGoogle Scholar
  111. 118.
    Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, Wettenhall RE, Thomas C: The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. EMBO J 14: 5279–5287, 1995PubMedGoogle Scholar
  112. 119.
    Alessi DR, james SR, Downes CP, Holmes AB, Gafrey PRJ, Reese CB, Cohen P: Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Ba. Curr Biol 7: 261–269, 1997PubMedCrossRefGoogle Scholar
  113. 120.
    Frevert EU, Kahn BB: Differential effects of constitutively active phosphatidylinositol 3-kinase on glucose transport, glycogen synthase activity, and DNA synthesis in 3T3-L1 adipocytes. Mol Cell Biol 17: 190–198, 1997PubMedGoogle Scholar
  114. 121.
    Kohn AD, Summers SA, Birnbaum MJ, Roth RA: Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem 271: 31372–31378, 1996PubMedCrossRefGoogle Scholar
  115. 122.
    Embi N, Rylatt DB, Cohen P: Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and Phosphorylase kinase. Eur JBiochem 107: 519–527, 1980CrossRefGoogle Scholar
  116. 123.
    Parker PJ, Embi N, Caudwell FB, Cohen P: Glycogen synthase from rabbit skeletal muscle. State of phosphorylation of the seven phosphoserine residues in vivo in the presence and absence of adrenaline. Eur J Biochem 124: 47–55, 1982PubMedCrossRefGoogle Scholar
  117. 124.
    Roach PJ: Multisite and hierarchal protein phosphorylation. J Biol Chem 266: 14139–14142, 1991PubMedGoogle Scholar
  118. 125.
    Cohen P: In: PD Boyer, EG Krebs (eds). The Enzymes. Academic Press, London, 1996, p 462Google Scholar
  119. 126.
    Poulter L, Ang SC, Gibson BW, Williams DH, Holmes CF, Caudwell FB, Pitcher J, Cohen P: Analysis of the in vivo phosphorylation state of rabbit skeletal muscle glycogen synthase by fast-atom-bombardment mass spectrometry. Eur J Biochem 175: 497–510, 1988PubMedCrossRefGoogle Scholar
  120. 127.
    Sheorain VS, Juhl H, Bass M, Soderling TR: Effects of epinephrine, diabetes, and insulin on rabbit skeletal muscle glycogen synthase. Phosphorylation site occupancies. J Biol Chem 259: 7024–7030, 1984PubMedGoogle Scholar
  121. 128.
    Lawrence JC, Hiken JF, DePaoli Roach AA, Roach PJ: Hormonal control of glycogen synthase in rat hemidiaphragms. Effects of two cyanogen bromide fragments. Biol Chem 258: 10710–10719, 1983Google Scholar
  122. 129.
    Woodgett JR: Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J 9: 2431–2438, 1990PubMedGoogle Scholar
  123. 130.
    Hughes K, Nikolakaki E, E PS, Totty NF, Woodgett JR: Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBOJ 12: 803–808, 1993Google Scholar
  124. 131.
    Ramakrishna S, Benjamin WB: Insulin action rapidly decreases multifunctional protein kinase activity in rat adipose tissue. J Biol Chem 263: 12677–12681, 1988PubMedGoogle Scholar
  125. 132.
    Hughes K, Ramakrishna SB, Benjamin WB, Woodgett JR: Identification of multifunction ATP-citrate lyase kinase as the alpha-isoform of glycogen synthase kinase-3. Biochem J 288: 309–314, 1992.PubMedGoogle Scholar
  126. 133.
    Welsh GI, Proud CG: Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor EIF-2B. Biochem J 294: 625–629, 1993PubMedGoogle Scholar
  127. 134.
    Stambolic V, Woodgett JR: Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem J 303: 701–704, 1994PubMedGoogle Scholar
  128. 135.
    Sutherland C, Cohen P: The alpha-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p70 S6 kinase or MAP kinase-activated protein kinase-1 in vitro. FEBS Lett 338: 37–42, 1994PubMedCrossRefGoogle Scholar
  129. 136.
    Lawrence JC, Roach PJ: New insights into the role and mechanism of glycogen synthase activation by insulin. Diabetes 46: 541–547, 1997PubMedCrossRefGoogle Scholar
  130. 137.
    Smith CJ/ Rubin CS, Rosen OM: Insulin-treated 3T3-L1 adipocytes and cell-free extracts derived from them incorporated 32P into ribosomal protein S6. Proc Natl Acad Sci USA 77: 2641–2645, 1980PubMedCrossRefGoogle Scholar
  131. 138.
    Price DJ, Nemenoff RA, Avruch J: Purification of a hepatic S6 kinase from cycloheximide-treated rats. J Biol Chem 264: 13825–13833, 1989PubMedGoogle Scholar
  132. 139.
    Kozma SC, Lane HA, Ferrari S, Luther H, Siegmaun M, Thomas G: A stimulated S6 kinase from rat liver: Identity with the mitogen activated S6 kinase of 3T3 cells. EMBO J 8: 4125–4132, 1989PubMedGoogle Scholar
  133. 140.
    Kozma SC, Ferrari S, Bassand P, Siegmann M, Totty N, Thomas G: Cloning of the mitogen-activated S6 kinase from rat liver reveals an enzyme of the second messenger subfamily. Proc Natl Acad Sci USA 87: 7365–7369, 1990PubMedCrossRefGoogle Scholar
  134. 141.
    Banerjee P, Ahmad MF, Grove JR, Kozlosky C, Price DJ, Avruch J: Molecular structure of a major insulin/mitogen-activated 70 kDa S6 protein kinase. Proc Natl Acad Sci USA 87: 8550–8554, 1990PubMedCrossRefGoogle Scholar
  135. 142.
    Calvo V, Crews CM, Vik TA, Bierer BE: Interleukin 2 stimulation of p70 S6 kinase activity is inhibited by the immunosuppressant rapamycin. Proc Natl Acad Sci USA 89: 7571–7575, 1992PubMedCrossRefGoogle Scholar
  136. 143.
    Chung J, Kuo CJ, Crabtree CR, Blenis J: Rapamycin-FKBP specifically blocks growth-dependent activation of a signalling by the 70 kd S6 protein kinases. Cell 69: 1227–1236, 1992PubMedCrossRefGoogle Scholar
  137. 144.
    Brown EJ, Beal PA, Keith CT, Chen J, Shin TB, Schreiber SL: Control of p70 s6 kinase bykinase activity of FRAP in vivo. Nature 377: 441–446, 1995PubMedCrossRefGoogle Scholar
  138. 145.
    Dumont FJ, Su Q: Mechanism of action of the immunosuppressant rapamycin. Life Sciences 58(5): 373–395, 1996PubMedCrossRefGoogle Scholar
  139. 146.
    Lane HA, Fernandez A, Lamb NJC, Thomas G: p70s6k function is essential for Gl progression. Nature 363: 170–172, 1993PubMedCrossRefGoogle Scholar
  140. 147.
    Reinhard C, Fernandez A, Lamb NJ, Thomas G: Nuclear localization of p85s6k: Functional requirement for entry into S phase. EMBO J 13: 1557–1565, 1994PubMedGoogle Scholar
  141. 148.
    Jefferies HB, Reinhard C, Kozma SC, Thomas G: Rapamycin selectively represses translation of the ‘polypyrimidine tract’ MRNA family. Proc Natl Acad Sci USA 91: 4441–4445, 1994PubMedCrossRefGoogle Scholar
  142. 149.
    Meyuhas D, Avri P, Shama S: In: JWB Hershey, MB Mathews, N Sonenberg (eds). Translational Control. Cold Spring Harbor Laboratory Press, 1996, p 363Google Scholar
  143. 150.
    DePhilip RM, Rudert WA, Lieberman I: Preferential stimulation of ribosomal protein synthesis by insulin and in the absence of ribosomal and messenger ribonucleic acid formation. Biochem 19: 1662–1669, 1980CrossRefGoogle Scholar
  144. 151.
    Shepherd PR, Nave BT, Siddle K: Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3-L1 adipocytes: Evidence for the involvement of phosphoinositide 3-kinase and p70 ribosomal protein-S6 kinase. Biochem J 305: 25–28, 1995PubMedGoogle Scholar
  145. 152.
    Azpiazu I, Saltiel AR, DePaoli-Roach AA, Lawrence JC: Regulation of both glycogen synthase and PHAS-I by insulin in rat skeletal muscle involves mitogen-activated protein kinase-independent and rapamycin-sensitive pathways. J Biol Chem 271: 5033–5039, 1996PubMedCrossRefGoogle Scholar
  146. 153.
    Sommercorn J, Fields R, Raz I, Maeda R: Abnormal regulation of ribosomal protein S6 kinase by insulin in skeletal muscle of insulinresistant humans. J Clin Invest 91: 509–514, 1993PubMedCrossRefGoogle Scholar
  147. 154.
    Grove JR, Banerjee P, Balasubramanyam A et al.: Cloning and expression of two human p70 S6 kinase Polypeptides differing only at their amino termini. Mol Cell Biol 11: 5541–5550, 1991PubMedGoogle Scholar
  148. 155.
    Reinhard C, Thomas G, Kozma SC: A single gene encodes two isoforms of the p70 S6 kinase: activation upon mitogenic stimulation. Proc Natl Acad Sci USA 89: 4052–4056, 1992PubMedCrossRefGoogle Scholar
  149. 156.
    Coffer PJ, Woodgett JR: Differential subcellular localisation of two isoforms of p70 S6 protein kinase. Biochem Biophys Res Comm 198: 7806, 1994CrossRefGoogle Scholar
  150. 157.
    Price DJ, Mukhopadhyay NK, Avruch J: Insulin-activated protein kinases phosphorylate a pseudosubstrate synthetic peptide inhibitor ofthe p70S6 kinase. J Biol Chem 266: 16281–16284, 1991PubMedGoogle Scholar
  151. 158.
    Ferrari S, Bannwarth W, Morley SJ, Totty NF, Thomas G: Activation of p70s6k is associated with phosphorylation of four clustered sites displaying Ser/Thr-Pro motifs. Proc Natl Acad Sci USA 89: 7282–7286, 1992PubMedCrossRefGoogle Scholar
  152. 159.
    Weng Q-P, Andrabi K, Kozlowski MT, Grove JR, Avruch J: Multiple independent inputs are required for activation of the p70 S6 kinase. Mol Cell Biol 15: 2333–2340, 1995PubMedGoogle Scholar
  153. 160.
    Cheatham L, Monfar M, Chou MM, Blenis J: Structural and functional analysis of pp70S6k. Proc Natl Acad Sci USA 92: 11696–11700, 1995PubMedCrossRefGoogle Scholar
  154. 161.
    Weng Q-P, Andrabi K, Klippel A, Kozlowski MT, Williams LT, Avruch J: Phosphatidylinositol-3 kinase signals activation of p70 S6 kinase in situ through site-specific p70 phosphorylation. Proc Natl Acad Sci USA 15: 5744–5748, 1995CrossRefGoogle Scholar
  155. 162.
    Han J-W, Pearson RB, Dennis PB, Thomas G: Rapamycin, wortmannin, and the methylxanthine SQ20006 inactivate p70S6K by inducing dephosphorylation of the same subset of sites. J Biol Chem 270: 21396–21403, 1995PubMedCrossRefGoogle Scholar
  156. 163.
    Chung J, Grammer TC, Lemon KP, Kazlauskas A, Blenis J: PDGF-and insulin-dependent pp70S6k activation mediated by phosphatidyl-inositol-3-OH kinase. Nature 370: 71–75, 1994PubMedCrossRefGoogle Scholar
  157. 164.
    Chou MM, Blenis J: The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Racl. Cell 85: 573–583, 1996PubMedCrossRefGoogle Scholar
  158. 165.
    Dennis PB, Pullen N, Kozma SC, Thomas G: The principal rapamycinsensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases. Mol CellBiol 16: 6242–6251, 1996Google Scholar
  159. 166.
    Whitehead IP, Campbell S, Rossman KL, Der CJ: Dbl family proteins. Biochim Biophys Acta 133: 1–23, 1997Google Scholar
  160. 167.
    Levin DE, Errede B: The proliferation of MAP kinase signalling pathways in yeast. Curr Opin Cell Biol 7: 197–202, 1995PubMedCrossRefGoogle Scholar
  161. 168.
    Kyriakis JM, Avruch J: Protein kinase cascades activated by stress and inflammatory cytokines. BioEssays 18: 567–577, 1996PubMedCrossRefGoogle Scholar
  162. 169.
    Kyriakis JM, Avruch J: Sounding the alarm: Protein kinase cascades activated by stress and inflammation. 271: 24313-24316, 1996Google Scholar
  163. 170.
    Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J, Woodgett JR: The stress-activated protein kinase subfamily ofc-jun kinases. Nature 369: 156–160, 1994PubMedCrossRefGoogle Scholar
  164. 171.
    Kyriakis JM, Woodgett JR, Avruch J: The stress-activated protein kinases; A novel ERK subfamily responsive to cellular stress inflammatory cytokines. NY Acad Sci 766: 303–319, 1995CrossRefGoogle Scholar
  165. 172.
    Westwick JK, Weitzel C, Leffert HL, Brenner DA: Activation of Jun kinase is an early event in hepatic regeneration. J Clin Invest 95: 803–810, 1995PubMedCrossRefGoogle Scholar
  166. 173.
    I. Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ: FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J 15: 4629–4642, 1996PubMedGoogle Scholar
  167. 174.
    Tsakiridis T, Taha C, Crinstein S, Klip A: Insulin activates a p21-activated kinase in muscle cells via phosphatidylinositol 3-kinase. J Biol Chem 271(33): 19664–19667, 1996PubMedCrossRefGoogle Scholar
  168. 175.
    Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T, Nebreda AR: A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 78: 1027–1037, 1994PubMedCrossRefGoogle Scholar
  169. 176.
    McLaughlin MM, Kumar S, McDonnell PC, Van Horn S, Lee JC, Livi CP, Young PR: Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J Biol Chem 271: 8488–8492, 1996PubMedCrossRefGoogle Scholar
  170. 177.
    Fukunaga R, Hunter T: MAKl, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J 16: 1921–1933, 1977CrossRefGoogle Scholar
  171. 178.
    Chfton AD, Young PR, Cohen P: A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress. FEBS Lett 392: 209–214, 1996CrossRefGoogle Scholar
  172. 179.
    Spiegelman BM, Hotamisligil GS: Through thick and thin: Wasting, obesity, and TNF alpha. Cell 73: 625–627, 1993PubMedCrossRefGoogle Scholar
  173. 180.
    Hotamisligil CS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM: IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha-and obesity-induced insulin resistance. Science 271: 665–668, 1996PubMedCrossRefGoogle Scholar
  174. 181.
    Kanety H, Hemi R, Papa MZ, Karasik A: Sphingomyelinase and ceramide suppress insulin-induced tyrosine phosphorylation of the insulin receptor substrate-l. J Biol Chem 271: 9895–9897, 1996PubMedCrossRefGoogle Scholar
  175. 182.
    Dong Chen, Waters SB, Holt KH, Pessin JE: SOS phosphorylation and disassociation of the Grb2-SOS complex by the ERK and JNK signalling pathways. J Biol Chem 271: 6328–6332, 1996CrossRefGoogle Scholar
  176. 183.
    Chu Y, Solski PA, Khosravi-Far R, Der CJ, Kelly K: The mitogen-activated protein kinase phosphatases PAC1, MKP-1, and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation. J Biol Chem 271: 6497–6591, 1996PubMedCrossRefGoogle Scholar
  177. 184.
    Vojtek AB, Cooper JA: Rho family members: activators of MAP kinase cascades. Cell 82: 527–529, 1995PubMedCrossRefGoogle Scholar
  178. 185.
    Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T, Gutkind JS: The small GTP-binding proteins Racl and Cdc42 regulate the activity of the JNK/SAPK signalling pathway. Cell 81: 1137–1146, 1995PubMedCrossRefGoogle Scholar
  179. 186.
    Minden A, Lin A, Claret FX, Abo A, Karin M: Selective activation of the JNK signalling cascade and c-jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell 81: 1147–1157, 1995PubMedCrossRefGoogle Scholar
  180. 187.
    Kotani K, Yonezawa K, Hara K, Ueda H, Kitamura Y, Sakaue H, Ando A, Chavanieu A, Calas B, Grigorescu F et al.: Involvement of phosphoinositide 3-kinase in insulin-or IGF-1-induced membrane ruffling. EMBO J 13: 2313–2321, 1994PubMedGoogle Scholar
  181. 188.
    Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A: The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70: 401–410, 1992PubMedCrossRefGoogle Scholar
  182. 189.
    Hu Q, Klippel A, Muslin AJ, Fantl WJ, Williams LT: Ras-dependent induction of cellular responses by constitutively active phosphatidyl-inositol-3 kinase. Science 268: 100–102, 1995PubMedCrossRefGoogle Scholar
  183. 190.
    Reif K, Nobes CD, Thomas G, Hall A, Cantrell DA: Phosphatidylinositol 3-kinase signals activate a selective subset of Rac/Rho-dependent effector pathways. Curr Biol 6: 1445–1455, 1996PubMedCrossRefGoogle Scholar
  184. 191.
    Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry NU, Waterfield MD, Downward J: Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370: 527–532, 1994PubMedCrossRefGoogle Scholar
  185. 192.
    Leberer E, Dignard D, Harcus D, Thomas DY, Whiteway M: The protein kinase homologue Ste20p is required to link the yeast pheromone response G-protein beta gamma subunits to downstream signalling components. EMBO J 11: 4815–4824, 1992PubMedGoogle Scholar
  186. 193.
    Simon MN, De Virgilio C, Souza B, Pringle JR, Abo A, Reed SI: Role for the Rho-family GTPase Cdc42 in yeast mating-pheromone signal pathway. Nature 376: 702–705, 1995PubMedCrossRefGoogle Scholar
  187. 194.
    Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L: A brain serine/ threonine protein kinase activated by Cdc42 and Racl. Nature 367: 40–46, 1994PubMedCrossRefGoogle Scholar
  188. 195.
    Zhang S, Han J, Sells MA, Chernoff J, Knaus UG, Ulevitch RJ, Bokoch GM: Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pakl. J Biol Chem 270: 23934–23936, 1995PubMedCrossRefGoogle Scholar
  189. 196.
    Polverino A, Frost J, Yang P, Hutchison M, Neiman AM, Cobb MH, Marcus S: Activation of mitogen-activated protein kinase cascades by p21-activated protein kinases in cell-free extracts of Xenopus oocytes. J Biol Chem 270: 26067–26070, 1995PubMedCrossRefGoogle Scholar
  190. 197.
    Galisteo ML, Chernoff J, Su YC, Skolnik EY, Schlessinger J: The adaptor protein Nck links receptor tyrosine kinases with the serine-threonine kinase Pakl. J Biol Chem 271: 20997–21000, 1996PubMedCrossRefGoogle Scholar
  191. 198.
    Bokoch GM, Wang Y, Bohl BP, Sells MA, Quilliam LA, Knaus UG: Interaction of the Nck adapter protein with p21-activated kinase (PAK1). J Biol Chem 271(42): 25746–25749, 1996PubMedCrossRefGoogle Scholar
  192. 199.
    Lu W, Katz S, Cupta R, Mayer BJ: Activation of Pak by membrane localization mediated by an SH3 domain from the adaptor protein Nck. Curr Biol 7: 85–94, 1997PubMedCrossRefGoogle Scholar
  193. 200.
    Nonaka H, Tanaka K, Hirano H, Fujiwara T, Kohno H, Umikawa M, Mino A, Takai Y: A downstream target of RHO1 small GTP-binding protein is PKC1, a homolog of protein kinase C, which leads to activation of the MAP kinase cascade in Saccharomyces cerevisiae. EMBO J 14: 5931–5938, 1PubMedGoogle Scholar
  194. 201.
    Watanabe G, Saito Y, Madaule P, Ishizaki T, Fujisawa K, Morii N, Mukai H, Ono Y, Kakizuka A, Narumiya S: Protein kinase N (PKN) and PKN-related protein rhophilin as targets of small GTPase Rho. Science 271: 645–648, 1996PubMedCrossRefGoogle Scholar
  195. 202.
    Amano M, Mukai H, Ono Y, Chihara K, Matsui T, Hamajima Y, Okawa K, lwamatsu A, Kaibuchi K: Identification of a putative target for Rho as the serine-threonine kinase protein kinase N. Science 271: 648–650, 1996PubMedCrossRefGoogle Scholar
  196. 203.
    Vincent S, Settleman J: The PRK2 kinase is a potential effector target of both Rho and Rac GTPases and regulates actin cytoskeletal organization. Mol Cell Biol 17: 2247–2256, 1997PubMedGoogle Scholar
  197. 204.
    Hill CS, Wynne J, Treisman R: The Rho family GTPases RhoA, Rac1, and CDC42HS regulate transcriptional activation by SRF. Cell 81: 1159–1170, 1995PubMedCrossRefGoogle Scholar
  198. 205.
    Quilliam LA, Lambert QT, Mickelson-Young LA, Westwick JK, Sparks AB, Kay BK, Jenkins NA, Gilbert DJ, Copeland NG, Der CJ: Isolation of a NCK-associated kinase, PRK2, an SH3-binding protein and potential effector of Rho protein signalling. J Biol Chem 271: 28772–28776, 1996PubMedCrossRefGoogle Scholar
  199. 206.
    Pombo CM, Kehrl JH, Sanchez I, Katz P, Avruch J, Zon LI, Woodgett JR, Force T, Kyriakis JM: Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase. Nature 377: 750–754, 1995PubMedCrossRefGoogle Scholar
  200. 207.
    Avruch J, Tornqvist HE, Gunsalus JR, Yurkow EJ, Kyriakis JM, Price DJ: Insulin regulation of protein phosphorylation. In: P. Cuatrecasas, S Jacob (eds). Handbook of Experimental Pharmacology. Vol. 92, Chapter 15, Berlin: Springer-Verlag, 1990, pp 313–366Google Scholar
  201. 208.
    Czech MP, Klarlund JK, Yagaloff KA, Bradford AP, Lewis RE: Insulin receptor signalling. Activation of multiple serine kinases. J Biol Chem 263: 1017–11020, 1988Google Scholar
  202. 209.
    Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P: Characterization of a 3-phosphoinositide-dependent protein kinase which phosphoylates and activates PKBα. Curr Biol 7: 261–269, 1997PubMedCrossRefGoogle Scholar
  203. 210.
    Alessi DR, Kozlowski MT, Weng QP, Morrice N, Avruch J: 3-phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the P70 Sb kinase in vivo and in vitro. Curr Biol 8: 69–81, 1997CrossRefGoogle Scholar
  204. 211.
    Dalby KN, Morrice N, Caudwell FB, Avruch J, Cohen P: Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase 2a/P90 rsk that are inducible by MAPK. J Biol Chem 273: 1496–1502, 1998PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1998

Authors and Affiliations

  • Joseph Avruch
    • 1
  1. 1.Diabetes Unit, Medical Services and the Department of Molecular Biology, Massachusetts General Hospital, and the Department of MedicineHarvard Medical SchoolBostonUSA

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