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Insulin regulation of the Ras activation/inactivation cycle

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Abstract

In addition to mediating a number of metabolic functions, insulin also uses mitogenic pathways to maintain cellular homeostasis. Many of these mitogenic responses are mediated by signals through the small molecular weight guanine nucleotide binding protein, Ras. In the last decade, great progress has been made in understanding the molecular mechanisms which regulate the insulin mediated conversion of Ras from its inactive, GDP-bound state, to the activated GTP-bound form. More recently, it has been appreciated that insulin also regulates the inactivation of this pathway, namely by uncoupling the protein complexes whose formation is required for Ras activation. This review addresses molecular mechanism which both positively and negatively regulate this mitogenic signalling pathway.

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References

  1. Saltiel AR: Diverse signalling pathways in the cellular actions of insulin. Am J Physiol 270: E375–E385, 1996

    PubMed  Google Scholar 

  2. Cheatham B, Kahn CR: Insulin action and the insulin signalling network. Endo Rev 16: 117–142, 1995

    Google Scholar 

  3. Satoh T, Nakafuku M, Kaziro Y: Function of Ras as a molecular switch in signal transduction. J Biol Chem 267: 24149–24152, 1992

    PubMed  Google Scholar 

  4. Barbacid M: Ras genes. Ann Rev Biochem 56: 779–827, 1987

    PubMed  Google Scholar 

  5. Medema RH, Wubbolts R, Bos JL: Two dominant inhibitory mutants of p21ras interfere with insulin induced gene expression. Mol Cell Biol 11: 5963–5967, 1991

    PubMed  Google Scholar 

  6. Burgering BM, Medema RH, Maassen JA, Wetering ML, van der Eb AJ, McCormick F, Bos J L: Insulin mediated gene expression mediated by p21ras activation. EMBO J 10: 1103–1109, 1991

    PubMed  Google Scholar 

  7. Downward J: Regulatory mechanisms for Ras proteins. BioEssays 14: 177–184, 1992

    PubMed  Google Scholar 

  8. Marshall MS: Ras target proteins in eukaryotic cells. FASEB J 9: 1311–1318, 1995

    PubMed  Google Scholar 

  9. Boni-Schnetzler M, Kaligian A, DelVecchio R, Pilch P: Ligand-dependent intersubunit association within the insulin receptor complex activates its intrinsic activity. J Biol Chem 263: 6822–6828, 1988

    PubMed  Google Scholar 

  10. Czech M: The nature and regulation of the insulin receptor: Structure and function. Ann Rev Physiol 47: 357–381, 1985

    Google Scholar 

  11. Sun XJ, Wang LM, Zhang Y, Yenush L, Myers MG Jr, Glasheen E, Lane WS, Pierce JH, White MF: Role of IRS-2 in insulin and cytokine signalling. Nature 377: 173–177, 1995

    PubMed  Google Scholar 

  12. Pronk GJ, McGlade I, Pelicci G, Pawson T, Bos JL: Insulin-induced phosphorylation of the 46 and 52 kDA Shc Proteins. J Biol Chem 268: 5748–5753, 1993

    PubMed  Google Scholar 

  13. White MF, Maron R, Kahn CR: Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells. Nature 318: 183–186, 1985

    PubMed  Google Scholar 

  14. Sasaoka T, Draznin B, Leitner JW, Langlois WJ, Olefsky JM: Shc is the predominant signalling molecule coupling insulin receptors to activation of guanine nucleotide releasing factor and p21ras-GTP formation. J Biol Chem 269: 10734–10738, 1994

    PubMed  Google Scholar 

  15. Ouwens DM, van der Zon GCM, Pronk GJ, Bos JL, Moller W, Cheatham B, Kahn CR, Maassen JAT: A mutant insulin receptor induces formation of a Shc-growth factor receptor bound protein 2 (Grb2) complex and p21ras-GTP without detectable interaction of insulin receptor substrate 1 (IRS1) with Grb2. J Biol Chem 269: 33116–33123, 1994

    PubMed  Google Scholar 

  16. Pelicci G, Lanfrancone L, Grignani F, McGlade I, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci PG: A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 70: 93–104, 1992

    PubMed  Google Scholar 

  17. Migliaccio E, Mele S, Salcini AE, Pelicci G, Lai KV, Superti-Furga G, Pawson T, Fiore PPD, Pelicci PG: Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor-MAP kinase-fos signalling pathway. EMBO J 16: 706–716, 1997

    PubMed  Google Scholar 

  18. Okada S, Yamauchi K, Pessin JE: Shc isoform-specific tyrosine phosphorylation by the insulin and epidermal growth factor receptors. J Biol Chem 270: 20737–20741, 1995

    PubMed  Google Scholar 

  19. Waters SB, Chen D, Kao AW, Okada S, Holt KH, Pessin JE: Insulin and epidermal growth factor receptors regulate distinct pools of Grb2-SOS in the control of Ras activation. J Biol Chem 271: 18224–18230, 1996

    PubMed  Google Scholar 

  20. Kao AW, Waters SB, Okada S, Pessin JE: Insulin stimulates the phosphorylation of the 66 and 52 kDa Shc isoforms by distinct mechanisms. Endocrinology 138: 2474–2480, 1997

    PubMed  Google Scholar 

  21. Skolnik EY, Lee C-H, Batzer A, Vicentini LM, Zhou M, Daly R, Meyers MJJ, Backer JM, Ullrich A, White MF, Schlessinger J: The SH2/Sh3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: Implications for insulin control of Ras signalling. EMBO J 12: 1929–1936, 1993

    PubMed  Google Scholar 

  22. Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J: The SH2 and SH3 domain-containing protein Grb2 links receptor tyrosine kinases to Ras signalling. Cell 70: 431–442, 1992

    PubMed  Google Scholar 

  23. Rozakis-Adcock M, Fernley R, Wade J, Pawson T, Bowtell D: The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSOS1. Nature 363: 83–85, 1993

    PubMed  Google Scholar 

  24. Egan SE, Giddings BW, Brooks MW, Buday L, Sizeland AM, Weinberg RA: Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 363: 45–51, 1993

    PubMed  Google Scholar 

  25. Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J: Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 363: 85–88, 1993

    PubMed  Google Scholar 

  26. Simon MA, Bowtell DDL, Dodson GS, Laverty TR, Rubin GM: Ras l and a putative guanine nucleotide exchange factor perform crucial steps in signalling by the sevenless proteins tyrosine kinase. Cell 87: 701–718, 1991

    Google Scholar 

  27. Bowtell D, Fu P, Simon M, Senior P: Identification of murine homologues of the Drosophila son of sevenless gene: Potential activators of Ras. Proc Natl Acad Sci USA 89: 6511–6515, 1992

    PubMed  Google Scholar 

  28. Myers MG Jr, White MF: Insulin signal transduction and the IRS proteins. Ann Rev Pharm Toxicol 36: 615–658, 1996

    PubMed  Google Scholar 

  29. Waters SB, Pessin JE: Insulin receptor substrate 1 and 2 (IRS1 and IRS2): What a tangled web we weave. Trends Cell Biol 6: 1–4, 1996

    PubMed  Google Scholar 

  30. Myers MG Jr, Wang L-M, Sun XJ, Zhang Y, Yenush L, Schlessinger J, Pierce JH, White MF: Role of IRS-1-GRB-2 complexes in insulin signalling. Mol Cell Biol 14: 3577–3587, 1994

    PubMed  Google Scholar 

  31. Yamauchi K, Pessin JE: Insulin receptor substrate-1 (IRS1) and Shc compete for a limited pool of Grb2 in mediating insulin downstream signalling. J Biol Chem 269: 31107–31114, 1994

    PubMed  Google Scholar 

  32. Yoneszawa K, Ando A, Kaburagi Y, Yamamoto-Honda R, Kitamura T, Hara K, Nakafuku M, Okabayashi Y, Kadowaki T, Kaziro Y, Kasuga M: Signal transduction pathways from insulin receptors to Ras. J Biol Chem 269: 4634–4640, 1994

    PubMed  Google Scholar 

  33. Keegan AD, Nelms K, White M, Wang LM, Pierce JH, Paul WE: An IL-4 receptor region containing an insulin receptor motif is important for IL-4-mediated IRS-1 phosphorylation and cell growth. Cell 76: 811–820, 1994

    PubMed  Google Scholar 

  34. Yin T, Tsang ML, Yang YC: JAK1 kinase forms complexes with interleukin-4 receptor and 4PS/insulin receptor substrate-l-like protein and is activated by interleukin-4 and interleukin-9 in T lymphocytes. J Biol Chem 269: 26614–26617, 1994

    PubMed  Google Scholar 

  35. Pruett W, Yuan Y, Rose E, Batzer AG, Harada N, Skolnik EY: Association between Grb2/SOS and insulin receptor substrate 1 is not sufficient for activation of extracellular signal-regulated kinases by interleukin-4: Implications for Ras activation by insulin. Mol Cell Biol 15: 1778–1785, 1995

    PubMed  Google Scholar 

  36. Koide H, Satoh T, Nakafuku M, Kaziro Y: GTP-dependent association of Raf-1 with Ha-Ras: Identification of Raf as a target downstream of Ras in mammalian cells. Proc Natl Acad Sci USA 90: 8683–8686, 1993

    PubMed  Google Scholar 

  37. Moodie SA, Willumsen BM, Weber MJ, Wolfman A: Complexes of Ras GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 260: 1658–1661, 1993

    PubMed  Google Scholar 

  38. Zhang XF, Settleman J, Kyriakis JM, Takeuchisuzuki E, Elledge SJ, Marshall MS, Bruder JT, Rapp UR, Avruch J: Normal and oncogenic p21(ras) proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature 364: 308–313, 1993

    PubMed  Google Scholar 

  39. Warne PH, Viciana PR, Downward J: Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature 364: 352–354, 1993

    PubMed  Google Scholar 

  40. Van Aelst L, Barr M, Marcus S, Polverino A, Wigler M: Complex formation between RAS and RAF and other protein kinases. Proc Natl Acad Sci USA 90: 6213–6217, 1993

    PubMed  Google Scholar 

  41. Vojtek AB, Hollenberg SM, Cooper JA: Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 74: 205–214, 1993

    PubMed  Google Scholar 

  42. Zheng CF, Guan KL: Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2. J Biol Chem 268: 11435–11439, 1993

    PubMed  Google Scholar 

  43. Huang WD, Alessandrini A, Crews CM, Erikson RL: Raf-1 forms a stable complex with Mek1 and activates Mek1 by serine phosphorylation. Proc Natl Acad Sci USA 90: 10947–10951, 1993

    PubMed  Google Scholar 

  44. Crews CM, Alessandrini A, Erikson RL: The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science 258: 478–480, 1992

    PubMed  Google Scholar 

  45. Boulton TG, Yancopoulos GD, Gregory JS, Slaughter C, Moomaw C, Hsu J, Cobb MH: An insulin stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science 249: 64–65, 1990

    PubMed  Google Scholar 

  46. Anderson D, Koch CA, Grey L, Ellis C, Morgan MF, Pawson T: Binding of SH2 domains of phospholipase Cyl, GAP, and Src to activated growth factor receptors. Science 250: 979–982, 1990

    PubMed  Google Scholar 

  47. Haystead TAJ, Haystead CMM, Hu C, Lin TA, Lawrence JC: Phosphorylation of PHAS-I by mitogen-activated protein (MAP) kinase. Identification of a site phosphorylated by MAP kinase in vitro and in response to insulin in rat adipocytes. J Biol Chem 269: 23185–23191, 1994

    PubMed  Google Scholar 

  48. Chuang CF, Ng SY: Functional divergence of the MAP kinase pathway. ERK1 and ERK2 activate specific transcription factors. FEBS Lett 346: 229–234, 1994

    PubMed  Google Scholar 

  49. Gille H, Sharrocks AD, Shaw PE: Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature 358: 414–417, 1992

    PubMed  Google Scholar 

  50. Gille H, Korteniann M, Thomae O, Moomaw C, Slaughter C, Cobb MH, Shaw PE: ERK phosphorylation potentiates Elk-l-mediated ternary complex formation and transactivation. EMBO J 14: 951–962, 1995

    PubMed  Google Scholar 

  51. Janknecht R, Ernst WH, Pingoud V, Nordheim A: Activation of ternary complex factor Elk-1 by MAP kinase. EMBO J 12: 5097–5104, 1993

    PubMed  Google Scholar 

  52. Lin TA, Kong X, Haystead TAJ, Pause A, Belsham G, Sonenberg N, Lawrence JC: PHAS-I as a link between mitogen-activated protein kinase and translation initiation. Science 266: 653–656, 1994

    PubMed  Google Scholar 

  53. Nakajima T, Kinoshita S, Sasagawa T, Sasaki K, Naruto M, Kishimoto T, Akira S: Phosphorylation at threonine-235 by a Ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. Proc Natl Acad Sci USA 90: 2207–2211, 1993

    PubMed  Google Scholar 

  54. Whitmarsh AJ, Shore P, Sharrocks AD, Davis RJ: Integration of MAP kinase signal transduction pathways at the serum response element. Science 269: 403–407, 1995

    PubMed  Google Scholar 

  55. Manchester J, Kong X, Lowry LH, Lawrence JCJ: Ras signalling in the activation of glucose transport by insulin. Proc Natl Acad Sci USA 91: 4644–4648, 1994

    PubMed  Google Scholar 

  56. Kozma L, Baltensperger K, Klarlund J, Parras A, Santos E, Czech MP: The Ras signalling pathway mimics insulin action on glucose transporter translocation. Proc Natl Acad Sci USA 90: 4460–4464, 1993

    PubMed  Google Scholar 

  57. Berghe NVD, Ouwens DM, Maassen JA, Mackelenbergh MGH, Sips HCM, Krans HMJ: Activation of the Ras/mitogen-activated protein kinase signalling pathway alone is not sufficient to induce glucose uptake in 3T3-L1 adipocytes. Mol Cell Biol 14: 2372–2377, 1994

    PubMed  Google Scholar 

  58. Hausdorff SF, Frangioni JV, Birnbaum MJ: Role of p21ras in insulinstimulated glucose transport in 3T3-L1 adipocytes. J Biol Chem 269: 21391–21394, 1994

    PubMed  Google Scholar 

  59. Reusch JE-B, Bhuripanyo P, Carel K, Leitner JW, Hsieh P, DePaolo D, Draznin B: Differential requirement for p21ras activation in the metabolic signalling by insulin. J Biol Chem 270: 2036–2040, 1995

    PubMed  Google Scholar 

  60. Weise RJ, Mastick CC, Lazar DF, Saltiel AR: Activation of mitogenactivated protein kinase and phosphatidylinositol 3′-kinase is not sufficient for the hormonal stimulation of glucose uptake, lipogenesis, or glycogen synthesis in 3T3-L1 adipocytes. J Biol Chem 270: 3442–3446, 1995

    PubMed  Google Scholar 

  61. Figar DC, Birnbaum MJ: Characterization of the mitogen-activated protein kinase/90 kilodalton ribosomal protein S6 kinase signalling pathway in 3T3-L1 adipocytes and its role in insulin-stimulated glucose transport. Endocrinology 134: 728–735, 1994

    PubMed  Google Scholar 

  62. Sakaue M, Bowtell D, Kasuga M: A dominant-negative mutant of mSOS1 inhibits insulin-induced Ras activation and reveals Ras-dependent and-independent insulin signalling pathways. Mol Cell Biology 15: 379–388, 1995

    Google Scholar 

  63. Gabbay RA, Sutherland C, Gnudi L, Kahn BB, O'Brien RM, Granner DK, Flier JS: Insulin regulation of phosphorenolpyruvate carboxykinase gene expression does not require activation of the Ras/mitogen-activated protein kinase signalling pathway. J Biol Chem 271: 1890–1897, 1996

    PubMed  Google Scholar 

  64. Taha C, Mitsumoto Y, Liu Z, Skolnik EY, Klip A: The insulin-dependent biosynthesis of GLUT1 and GLUT3 glucose transporters in L6 muscle cells is mediated by distinct pathways. J Biol Chem 270: 24678–24681, 1995

    PubMed  Google Scholar 

  65. Medema RH, Vries-Smits AMMD, Zon GCMVD, Maassen JA, Bos HL: Ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides on p21 ras. Mol Cell Biol 13: 155–162, 1993

    PubMed  Google Scholar 

  66. Drazin B, Chang L, Leitner JW, Takata Y, Olefsky J: Insulin activates p21 Ras and guanine nucleotide releasing factor in cells expressing wild type and mutant insulin receptors. J Biol Chem 268: 19998–20001, 1993

    PubMed  Google Scholar 

  67. Shou C, Farnsworth CL, Neel BG, Feig LA: Molecular cloning of cDNAs encoding a guanine-nucleotide-releasing factor for Ras p21. Nature 358: 351–354, 1992

    PubMed  Google Scholar 

  68. Langlois WJ, Sasaoka T, Saltiel AR, Olefsky JM: Negative feedback regulation and desensitization of insulin and epidermal growth factor-stimulated p21ras activation. J Biol Chem 270: 25320–25323, 1995

    PubMed  Google Scholar 

  69. Skolnik EY, Batzer A, Li N, Lee C-H, Lowenstein E, Mohammadi M, Margolis B, Schlessinger J: The function of GRB2 in linking the insulin receptor to Ras signalling pathways. Science 260: 1953–1955, 1993

    PubMed  Google Scholar 

  70. Waters SB, Yamauchi K, Pessin JE: Insulin stimulated disassociation of the SOS-Grb2 complex. Mol Cell Biol 15: 2791–2799, 1995

    PubMed  Google Scholar 

  71. Waters SB, Holt KH, Ross SE, Syu L-J, Guan K-L, Saltiel AR, Koretzky GA, Pessin JE: Desensitization of Ras activation by a feedback disassociation of the SOS-Grb2 complex. J Biol Chem 270: 20883–20886, 1995

    PubMed  Google Scholar 

  72. Cherniack AD, Klarlund JK, Conway BR, Czech MP: Disassembly of son-of-sevenless proteins from Grb2 during p21 Ras desensitization by insulin. J Biol Chem 269: 1485–1488, 1995

    Google Scholar 

  73. Holt KH, Kasson BG, Pessin JE: Insulin stimulation of MEK-dependent but ERK-independent SOS protein kinase. Mol Cell Biol 16: 577–583, 1996

    PubMed  Google Scholar 

  74. Klarlund JK, Cherniack AD, Czech MP: Divergent mechanisms for homologous desensitization of p21Ras by insulin and growth factors. J Biol Chem 270: 23421–23428, 1995

    PubMed  Google Scholar 

  75. Rozakis-Adcock M, Geer PVD, Mbamalu G, Pawson T: MAP kinase phosphorylation of mSos1 promotes dissociation of mSos1-Shc and mSos1-EGF receptor complexes. Oncogene 11: 1417–1427, 1995

    PubMed  Google Scholar 

  76. Buday L, Warne PH, Downward J: Downregulation of the Ras activation pathway by MAP kinase phosphorylation of SOS. Oncogene 11: 1327–1331, 1995

    PubMed  Google Scholar 

  77. Holt KH, Waters SB, Yamauchi K, Decker SJ, Saltiel AR, Motto DG, Koretzky GA, Pessin JE: Epidermal growth factor receptor targeting prevents uncoupling of the Grb2-SOS complex. J Biol Chem 271: 8300–8306, 1995

    Google Scholar 

  78. Zhao H, Okada S, Pessin JE, Koretzky G: 1997, (Manuscript in preparation)

  79. Corbalan-Garcia S, Yang S-S, Degenhardt KR, Bar-Sagi D: Identification of the mitogen-activated protein kinase phosphorylation sites on human SOS1 that regulate interaction with Grb2. Mol Cell Biol 16: 5674–5682, 1996

    PubMed  Google Scholar 

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Ceresa, B.P., Pessin, J.E. Insulin regulation of the Ras activation/inactivation cycle. Mol Cell Biochem 182, 23–29 (1998). https://doi.org/10.1023/A:1006819008507

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