Insulin signal transduction through protein kinase cascades

Molecular and Cellular Biochemistry

Volumn 182, Issue 1-2, 1998, Pages 31-48

  Avruch, Joseph ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

Insulin action; MAP kinase; Phosphatidyl inositol 3 kinase; Protein serine threonine kinase; Ras Raf; Ribosomal S6 protein kinase (RSKs)

Indexed keywords

CYCLIC AMP; GLUCOSE; GLYCOGEN; GLYCOGEN SYNTHASE; INSULIN; INSULIN RECEPTOR; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE; PROTEIN SERINE THREONINE KINASE; RAF PROTEIN; RAS PROTEIN;

ENERGY METABOLISM; GLUCOSE TRANSPORT; GLYCOGEN METABOLISM; NUCLEOTIDE METABOLISM; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; HUMANS; INSULIN; MODELS, BIOLOGICAL; PROTEIN-SERINE-THREONINE KINASES; SIGNAL TRANSDUCTION;

EID: 0031919552     PISSN: 03008177     EISSN: None     Source Type: Journal    
DOI: 10.1023/A:1006823109415     Document Type: Review

References (204)

1. Cahill GF, Steiner DF (eds). : Endocrinology 1 Handbook of Physiology. American Physiological Society, 1972
2. White MW, Kahn CR: The insulin signalling system. J Biol Chem 269: 14, 1994
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, 1996
4. Bliss R: The discovery of insulin. University of Chicago Press, 1982
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, 1988
6. Cuatrecasas P: Interaction of insulin with the cell membrane: The primary action of insulin. Proc Natl Acad Sci 63: 450-457, 1969
7. Robison GA, Butcher RW, Sutherland EW: Cyclic AMP, Academic Press, New York, 1971, pp 1-23
8. Krebs EG: Protein kinases. Curr Top Cell Reg 5: 99-133, 1972
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, 1996
10. Ullrich A, Schlessinger J: Signal transduction by receptors with tyr kinase activity. Cell 61: 203-206, 1990
11. Fantl WJ, Johnson DE, Williams LT: Signalling by receptor tyrosine kinases. Ann Rev Biochem 62: 453-481, 1993
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, 1991
13. Kavanaugh WM, Williams LT: An alternative to SH2 domains for binding tyrosine-phosphorylated proteins. Science 266: 1862?-18655, 1994
14. Bork P, Margolis B: A phosphotyrosine interaction domain. Cell 80: 693-594, 1995
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, 1990
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, 1988
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 263-296
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 85-148
19. Avruch J, Zhang XF, Kyriakis JM: Raf meets Ras: Closing a frontier in signal transduction. TIBS 19: 274-283, 1994
20. Lowy DR, Willumsen BM: Function and regulation of Ras. Ann Rev Biochem 62: 851-891, 1993
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 179-207
22. Ahn NG, Seger R, Krebs EC: The mitogen-activated protein kinase activator. Curr Opin Cell Biol 4: 992-999, 1992
23. Cobb MH, Goldsmith EJ: How MAP kinases are regulated. J Biol Chem 270: 14843-14846, 1995
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, 1995
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, 1991
26. Zhang FL, Casey PJ: Protein prenylation: Molecular mechanisms and functional consequences. Ann Rev Biochem 65: 241-269, 1996
27. Schlessinger J: How receptor tyrosine kinases activate Ras. TIBS 18: 273-275, 1993
28. Boguski MS, McCormick F: Proteins regulating Ras and its relatives. Nature 366: 643-654, 1993
29. Marshall MS: The effector interactions of p21Ras. TIBS 18: 250-254, 1993
30. Ras binds to the amino-terminal egulatory domain of c-Raf-1. Nature 364: 308-313, 1993
31. Satoh T, Nakafuku M, Kaziro Y: Function of Ras as a molecular switch in signal transduction: J Biol Chem 267: 24149-24152, 1992
32. Marshall CJ: Ras effectors. Curr Opin Cell Biol 8: 197-204, 1996
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, 1988
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, 1994
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, 1995
36. Ras and the Ras-binding domain of the human raf-1 protein kinase. J Cell Biol 272: 2901-2905, 1995
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, 1995
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, 1997
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, 1994
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, 1994
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, 1997
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, 1995
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, 1994
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, 1996
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, 1993
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, 1996
47. Farrar MA, Alberol-Ila, Perlmutter RM: Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization. Nature 383: 178-181, 1996
48. Kornfeld K, Hom DB, Horvitz HR: The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signalling in C. elegans Cell 83: 903-913, 1995
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, 1995
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, 1997
51. Kolch W, Heidecker G, Kochs G: Protein kinase Ca activates RAF-1 by direct phosphorylation. Nature 364: 249-252, 1993
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, 1995
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, 1993
54. Wu J, Dent P, Jelinek T, Wolfman A, Weber MJ, Sturgill TJ: Inhibition of the EGF-activated MAP kinase signalling pathway by adenosine 3′,5′-monophosphate. Science 262: 1065-1069, 1993
55. Altschuler DL, Peterson SN, Ostrowski MC, Lapetina EG: Cyclic AMP-dependent activation of Rap1b. J Cell Biol 270: 10373-10376, 1995
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, 1993
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 Rap 1-dependent pathway. Cell 89: 73-82, 1997
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, 1995
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, 1996
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, 1992
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, 1995
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, 1993
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, 1993
64. Sturgill TW, Ray LB, Erikson E, Maller JL: Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II. Nature 334: 715-718, 1988
65. Waskiewicz AJ, Flynn A, Proud CC, Cooper JA: Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J 16: 1909-1929, 1997
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, 1992
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, 1994
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, 1995
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, 1996
70. Erikson E, Maller JL: Purification and characterization of a protein kinase from Xenopus eggs highly specific for ribosomal protein S6. J Biol Chem 261: 350-355, 1986
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, 1989
72. Zhao Y, Bjorbaek C, Weremowicz S, Morton CC, Moller DE: RSK3 encodes a novel pp90rsk isoform with a unique N-terminal sequence: Growth factor-stimulated kinase function and nuclear translocation. Mol Cell Biol 15: 4353-4363, 1995
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 J Biochem 212: 581-588, 1993
74. Price DJ, Grove, JR, Calvo V, Avruch J, Bierer BE: Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science 257: 973-977, 1992
75. Erikson E, Maller JL: Substrate specificity of ribosomal protein S6 kinase H from Xenopus eggs. Second Mess and Phosphoprotein 12: 135-143, 1988
76. Blenis J: Signal transduction via the MAP kinases: Proceed at your own risk. Proc Natl Acad Sci USA 90: 5889-5992, 1993
77. 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, 1990
78. 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, 1993
79. 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, 1995
80. 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, 1995
81. Benito M, Porras A, Nebreda AR, Santos E: Differentiation of 3T3 fibroblasts to adipocytes induced by transfection of Ras oncogenes. Science 253: 565-568, 1991
82. 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, 1994
83. 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, 1993
84. 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, 1994
85. 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, 1994
86. 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, 1993
87. Lin TA, Lawrence JC: Activation of ribosomal protein S6 kinases does not increase glycogen synthesis or glucose transport in rat adipocytes. J Biol Chem 269: 21255-21261, 1994
88. Carpenter CL, Cantley LC: Phosphoinositide kinases. Curr Opin Cell Biol 8: 153-158, 1996
89. 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, 1994
90. 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, 1993
91. Franke TF, Kaplan DR, Cantley LC: P13K: Downstream AKTion blocks apoptosis. Cell 88: 435-437, 1997
92. Farese RV: In: D LeRoith, J Olefsky, S Taylor (eds). Diabetes Mellitus: A Fundamental and Clinical Text. J.P. Lippincott Co., PA, USA, 1996
93. 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 229-244
94. 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, 1995
95. 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, 1991
96. 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, 1991
97. Bellacosa A, Testa JR, Staal SP, Tsichlis PN: A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 254: 274-277, 1991
98. 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, 1977
99. 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, 1995
100. Kohn AD, Kovacina KS, Roth RA: Insulin stimulates the kinase activity of RAC-PK, a pleckstrin homology domain containing ser/thr kinase. EMBO J 14: 4288-4295, 1995
101. Burgering BM, Coffer PJ: Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376: 599-602, 1995
102. 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, 1996
103. 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, 1997
104. 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, 1997
105. 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, 1997
106. 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, 1996
107. 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, 1996
108. Kohn AD, Takeuchi F, Roth RA: Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem 271: 21920-21926, 1996
109. 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. EMBO J 15: 6541-6551, 1996
110. Keranen LM, Dutil EM, Newton AC: Protein kinase C is regulated in vivo by three functionally distinct phosphorylations. Curr Biol 5: 1394-1403, 1995
111. 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, 1995
112. 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, 1997
113. 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, 1997
114. Kohn AD, Summers SA, Bimbaum 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, 1996
115. 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 J Biochem 107: 519-527, 1980
116. 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, 1982
117. Roach PJ: Multisite and hierarchal protein phosphorylation. J Biol Chem 266: 14139-14142, 1991
118. Cohen P: In: PD Boyer, EG Krebs (eds). The Enzymes. Academic Press, London, 1996, p 462
119. 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, 1988
120. 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, 1984
121. 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, 1983
122. Woodgett JR: Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J 9: 2431-2438, 1990
123. Hughes K, Nikolakaki E, E PS, Totty NF, Woodgett JR: Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J 12: 803-808, 1993
124. Ramakrishna S, Benjamin WB: Insulin action rapidly decreases multifunctional protein kinase activity in rat adipose tissue. J Biol Chem 263: 12677-12681, 1988
125. 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.
126. 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, 1993
127. Stambolic V, Woodgett JR: Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem J 303: 701-704, 1994
128. 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, 1994
129. Lawrence JC, Roach PJ: New insights into the role and mechanism of glycogen synthase activation by insulin. Diabetes 46: 541-547, 1997
130. 32P into ribosomal protein S6. Proc Natl Acad Sci USA 77: 2641-2645, 1980
131. Price DJ, Nemenoff RA, Avruch J: Purification of a hepatic S6 kinase from cycloheximide-treated rats. J Biol Chem 264: 13825-13833, 1989
132. 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, 1989
133. 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, 1990
134. 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, 1990
135. 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, 1992
136. 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, 1992
137. 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, 1995
138. Dumont FJ, Su Q: Mechanism of action of the immunosuppressant rapamycin. Life Sciences 58(5): 373-395, 1996
139. Lane HA, Fernandez A, Lamb NJC, Thomas G: p70s6k function is essential for G1 progression. Nature 363: 170-172, 1993
140. Reinhard C, Fernandez A, Lamb NJ, Thomas G: Nuclear localization of p85s6k: Functional requirement for entry into S phase. EMBO J 13: 1557-1565, 1994
141. 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, 1994
142. Meyuhas D, Avri P, Shama S: In: JWB Hershey, MB Mathews, N Sonenberg (eds). Translational Control. Cold Spring Harbor Laboratory Press, 1996, p 363
143. 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, 1980
144. 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, 1995
145. 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, 1996
146. Sommercorn J, Fields R, Raz I, Maeda R: Abnormal regulation of ribosomal protein S6 kinase by insulin in skeletal muscle of insulin-resistant humans. J Clin Invest 91: 509-514, 1993
147. 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, 1991
148. 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, 1992
149. Coffer PJ, Woodgett JR: Differential subcellular localisation of two isoforms of p70 S6 protein kinase. Biochem Biophys Res Comm 198: 7806, 1994
150. Price DJ, Mukhopadhyay NK, Avruch J: Insulin-activated protein kinases phosphorylate a pseudosubstrate synthetic peptide inhibitor of the p70 S6 kinase. J Biol Chem 266: 16281-16284, 1991
151. s6k is associated with phosphorylation of four clustered sites displaying Ser/Thr-Pro motifs. Proc Natl Acad Sci USA 89: 7282-7286, 1992
152. 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, 1995
153. Cheatham L, Monfar M, Chou MM, Blenis J: Structural and functional analysis of pp70S6k. Proc Natl Acad Sci USA 92: 11696-11700, 1995
154. 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, 1995
155. S6K by inducing dephosphorylation of the same subset of sites. J Biol Chem 270: 21396-21403, 1995
156. Chung J, Grammer TC, Lemon KP, Kazlauskas A, Blenis J: PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase. Nature 370: 71-75, 1994
157. Chou MM, Blenis J: The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Rac 1. Cell 85: 573-583, 1996
158. 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 Cell Biol 16: 6242-6251, 1996
159. Whitehead IP, Campbell S, Rossman KL, Der CJ: Dbl family proteins. Biochim Biophys Acta 133: 1-23, 1997
160. Levin DE, Errede B: The proliferation of MAP kinase signalling pathways in yeast. Curr Opin Cell Biol 7: 197-202, 1995
161. Kyriakis JM, Avruch J: Protein kinase cascades activated by stress and inflammatory cytokines. BioEssays 18: 567-577, 1996
162. Kyriakis JM, Avruch J: Sounding the alarm: Protein kinase cascades activated by stress and inflammation. 271: 24313-24316, 1996
163. Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J, Woodgett JR: The stress-activated protein kinase subfamily of c-jun kinases. Nature 369: 156-160, 1994
164. 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, 1995
165. 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, 1995
166. 1. Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ: FGF and stress regulate CREB and ATE-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J 15: 4629-4642, 1996
167. 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, 1996
168. 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, 1994
169. 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, 1996
170. Fukunaga R, Hunter T: MAKI, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J 16: 1921-1933, 1977
171. 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. FEES Lett 392: 209-214, 1996
172. Spiegelman BM, Hotamisligil GS: Through thick and thin: Wasting, obesity, and TNF alpha. Cell 73: 625-627, 1993
173. Hotamisligil CS, Peraldi P, Budavari A, Ellis R, White ME, Spiegelman BM: IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271: 665-668, 1996
174. Kanety H, Hemi R, Papa MZ, Karasik A: Sphingomyelinase and ceramide suppress insulin-induced tyrosine phosphorylation of the insulin receptor substrate-1. J Biol Chem 271: 9895-9897, 1996
175. 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, 1996
176. 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, 1996
177. Vojtek AB, Cooper JA: Rho family members: activators of MAP kinase cascades. Cell 82: 527-529, 1995
178. Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T, Gutkind JS: The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signalling pathway. Cell 81: 1137-1146, 1995
179. Minden A, Lin A, Claret EX, 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, 1995
180. 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 raffling. EMBO J 13: 2313-2321, 1994
181. 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, 1992
182. Hu Q, Klippel A, Muslin AJ, Fantl WJ, Williams LT: Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase. Science 268: 100-102, 1995
183. 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, 1996
184. 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, 1994
185. 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, 1992
186. 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, 1995
187. Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L: A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature 367: 40-46, 1994
188. 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 Pak1. J Biol Chem 270: 23934-23936, 1995
189. 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, 1995
190. Galisteo ML, Chernoff J, Su YC, Skolnik EY, Schlessinger J: The adaptor protein Nck links receptor tyrosine kinases with the serine-threonine kinase Pak1. J Biol Chem 271: 20997-21000, 1996
191. 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, 1996
192. 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, 1997
193. 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, 1995
194. 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, 1996
195. Amano M, Mukai H, Ono Y Chihara K, Matsui T, Hamajima Y Okawa K, Iwamatsu A, Kaibuchi K: Identification of a putative target for Rho as the serine-threonine kinase protein kinase N. Science 271: 648-650, 1996
196. 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, 1997
197. Hill CS, Wynne J, Treisman R: The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell 81: 1159-1170, 1995
198. 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, 1996
199. 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, 1995
200. 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 313-366
201. Czech MP, Klarlund JK, Yagaloff KA, Bradford AP, Lewis RE: Insulin receptor signalling. Activation of multiple serine kinases. J Biol Chem 263: 1017-11020, 1988
202. 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, 1997
203. 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, 1997
204. 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, 1998