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Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases

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Abstract

Protein-tyrosine phosphatases (PTPases) have been implicated in the physiological regulation of the insulin signalling pathway. In cellular and molecular studies, the transmembrane, receptor-type PTPase LAR and the intracellular, non-receptor enzyme PTP1B have been shown to have a direct impact on insulin action in intact cell models. Since insulin signalling can be enhanced by reducing the abundance or activity of specific PTPases, pharmaceutical agents directed at blocking the interaction between individual PTPases and the insulin receptor may have potential clinical relevance to the treatment of insulin-resistant states such as obesity and Type II diabetes mellitus.

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References

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

    Google Scholar 

  2. Ebina Y, Ellis L, Jamagin K et al.: Human insulin receptor cDNA: The structural basis for hormone activated transmembrane signalling. Cell 40: 747–758, 1985

    PubMed  Google Scholar 

  3. White MF, Shoelson SE, Keutmann H, Kahn CR: A cascade of tyrosine autophosphorylation in the β-subunit activates the phosphotransferase of the insulin receptor. J Biol Chem 263: 2969–2980, 1988

    PubMed  Google Scholar 

  4. Flores-Riveros JR, Sibley E, Kastelic T, Lane MD: Substrate phosphorylation catalyzed by the insulin receptor tyrosine kinase. Kinetic correlation to autophosphorylation of specific sites in the beta subunit. J Biol Chem 264: 21557–21572, 1989

    PubMed  Google Scholar 

  5. White W, Kahn CR: The cascade of autophosphorylation in the β-subunit of the insulin receptor. J Cell Biochem 39: 429–441, 1989

    PubMed  Google Scholar 

  6. King MJ, Sharma RP, Sale GJ: Site-specific dephosphorylation and deactivation of the human insulin receptor tyrosine kinase by particulate and soluble phosphotyrosyl protein phosphatases. Biochem J 275: 413–418, 1991

    PubMed  Google Scholar 

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

    Google Scholar 

  8. Yan PF, Li SL, Liang SJ, Giannini S, Fujita-Yamaguchi Y: The Role of COOH-terminal and acidic domains in the activity and stability of human insulin receptor protein tyrosine kinase studied by purified deletion mutants of the beta-subunit domain. J Biol Chem 268: 22444–22449, 1993

    PubMed  Google Scholar 

  9. Tavaré JM, Siddle K: Mutational analysis of insulin receptor function – consensus and controversy. Biochim Biophys Acta 1178: 21–39, 1993

    PubMed  Google Scholar 

  10. Haring HU, Kasuga M, White MF, Crettaz M, Kahn CR: Phosphorylation and dephosphorylation of the insulin receptor: Evidence against an intrinsic phosphatase activity. Biochemistry 23: 3298–3306, 1984

    PubMed  Google Scholar 

  11. Kowalski A, Gazzano H, Fehlmann M, Van Obberghen E: Dephosphorylation of the hepatic insulin receptor: Absence of intrinsic phosphatase activity in purified receptors. Biochem Biophys Res Comm 117: 885–893, 1983

    PubMed  Google Scholar 

  12. Mooney RA, Anderson DL: Phosphorylation of the insulin receptor in permeabilized adipocytes is coupled to a rapid dephosphorylation reaction. J Biol Chem 264: 6850–6857, 1989

    PubMed  Google Scholar 

  13. Bernier M, Liotta AS, Kole HK, Shock DD, Roth J: Dynamic regulation of intact and C-terminal truncated insulin receptor phosphorylation in permeabilized cells. Biochemistry 33: 4343–4351, 1994

    PubMed  Google Scholar 

  14. Goldstein BJ: Regulation of insulin receptor signalling by proteintyrosine dephosphorylation. Receptor 3: 1–15, 1993

    PubMed  Google Scholar 

  15. Backer JM, Kahn CR, White MF: Tyrosine phosphorylation of the insulin receptor during insulin-stimulated internalization in rat hepatoma cells. J Biol Chem 264: 1694–1701, 1989

    PubMed  Google Scholar 

  16. Kublaoui B, Lee J, Pilch PF: Dynamics of signalling during insulinstimulated endocytosis of its receptor in adipocytes. J Biol Chem 270: 59–65, 1995

    PubMed  Google Scholar 

  17. Klein HH, Freidenberg GR, Matthaei S, Olefsky JM: Insulin receptor kinase following internalization in isolated rat adipocytes. J Biol Chem 262: 10557–10564, 1987

    PubMed  Google Scholar 

  18. Bevan AP, Drake PG, Bergeron JJM, Posner BI: Intracellular signal transduction: The role of endosomes. Trends Endocrinol Metab 7: 13–21, 1996

    Google Scholar 

  19. Bevan AP, Burgess JW, Drake PG, Shaver A, Bergeron JJ, Posner BI: Selective activation of the rat hepatic endosomal insulin receptor kinase. Role for the endosome in insulin signalling. J Biol Chem 270: 10784–10791, 1995

    PubMed  Google Scholar 

  20. Burgess JW, Wada I, Ling N, Khan MN, Bergeron JJM, Posner BI: Decrease in β-subunit phosphotyrosine correlates with internalization and activation of the endosomal insulin receptor kinase. J Biol Chem 267: 10077–10086, 1992

    PubMed  Google Scholar 

  21. Khan MN, Baquiran G, Brule C et al.: Internalization and activation of the rat liver insulin receptor kinase in vivo. J Biol Chem 264: 12931–12940, 1989

    PubMed  Google Scholar 

  22. Faure R, Baquiran G, Bergeron JJM, Posner BI: The dephosphorylation of insulin and epidermal growth factor receptors. Role of endosomeassociated phosphotyrosine phosphatase(s). J Biol Chem 267: 11215–11221, 1992

    PubMed  Google Scholar 

  23. Walton KM, Dixon JE: Protein tyrosine phosphatases. Ann Rev Biochem 62: 101–120, 1993

    PubMed  Google Scholar 

  24. Fischer EH, Charbonneau H, Tonks NK: Protein tyrosine phosphatases – A diverse family of intracellular and transmembrane enzymes. Science. 253: 401–406, 1991

    PubMed  Google Scholar 

  25. Goldstein BJ: Phospho-protein phosphatases 1: Tyrosine phosphatases. In: P Sheterline (ed). Protein Profile. Academic Press, London, 1995, pp 1425–1585

    Google Scholar 

  26. Goldstein BJ, Meyerovitch J, Zhang WR et al.: Hepatic protein-tyrosine phosphatases and their regulation in diabetes. Adv Prot Phosphatases 6: 1–17, 1991

    Google Scholar 

  27. Zhang WR, Hashimoto N, Ahmad F, Ding W, Goldstein BJ: Molecular cloning and expression of a unique receptor-like protein-tyrosine phosphatase in the leukocyte common-antigen-related phosphatase family. Biochem J 302: 39–47, 1994

    PubMed  Google Scholar 

  28. DeFronzo RA, Bonadonna RC, Ferrannini E: Pathogenesis of NIDDM. A balanced overview. Diabetes Care 15: 318–368, 1992

    PubMed  Google Scholar 

  29. Zhang WR, Goldstein BJ: Identification of skeletal muscle proteintyrosine phosphatases by amplification of conserved cDNA sequences. Biochem Biophys Res Commun 178: 1291–1297, 1991

    PubMed  Google Scholar 

  30. Hashimoto N, Zhang WP, Goldstein BJ: Insulin receptor and epidermal growth factor receptor dephosphorylation by three major rat liver protein-tyrosine phosphatases expressed in a recombinant bacterial system. Biochem J 284: 569–576, 1992

    PubMed  Google Scholar 

  31. Freeman RM, Plutzky J, Neel BG: Identification of a human src homology 2-containing protein-tyrosine-phosphatase – A putative homolog of drosophila corkscrew. Proc Natl Acad Sci USA 89: 11239–11243, 1992

    PubMed  Google Scholar 

  32. Ahmad F, Goldstein BJ: Purification, identification and subcellular distribution of three predominant protein-tyrosine phosphatase enzymes in skeletal muscle tissue. Biochim Biophys Acta 1248: 57–69, 1995

    PubMed  Google Scholar 

  33. Ding W, Zhang WR, Sullivan K, Hashimoto N, Goldstein BJ: Identification of protein-tyrosine phosphatases prevalent in adipocytes by molecular cloning. Biochem Biophys Res Commun 202: 902–907, 1994

    PubMed  Google Scholar 

  34. Mei L, Doherty CA, Huganir RL: RNA splicing regulates the activity of a SH2 domain-containing protein tyrosine phosphatase. J Biol Chem 269: 12254–12262, 1994

    PubMed  Google Scholar 

  35. Frangioni JV, Beahm PH, Shifiin V, Jost CA, Neel BG: The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence. Cell 68: 545–560, 1992

    PubMed  Google Scholar 

  36. Goldstein BJ: Protein-tyrosine phosphatases and the regulation of insulin action. In: D LeRoith, JM Olefsky, SI Taylor (eds). Diabetes Mellitus: A Fundamental and Clinical Text. Lippincott, Philadelphia, 1996, pp 174–186

    Google Scholar 

  37. Ahmad F, Goldstein BJ: Increased abundance of specific skeletal muscle protein tyrosine phosphatases in a genetic model of obesity and insulin resistance. Metabolism 44: 1175–1184, 1995

    PubMed  Google Scholar 

  38. Ahmad F, Goldstein BJ: Alterations in specific protein-tyrosine phosphatases accompany the insulin resistance of streptozotocindiabetes. Am J Physiol 268: E932–E940, 1995

    PubMed  Google Scholar 

  39. Hashimoto N, Feener EP, Zhang WR, Goldstein BJ: Insulin receptor protein tyrosine phosphatases – Leukocyte common antigen-related phosphatase rapidly deactivates the insulin receptor kinase by preferential dephosphorylation of the receptor regulatory domain. J Biol Chem 267: 13811–13814, 1992

    PubMed  Google Scholar 

  40. Streuli M, Krueger NY, Ariniello PD et al.: Expression of the receptorlinked protein tyrosine phosphatase LAR: Proteolytic cleavage and shedding of the CAM-like extracellular region. EMBO J 11: 897–907, 1992

    PubMed  Google Scholar 

  41. Serra-Pages C, Saito H, Streuli M: Mutational analysis of proprotein processing, subunit association, and shedding of the LAR transmembrane protein tyrosine phosphatase. J Biol Chem 269: 23632–23641, 1994

    PubMed  Google Scholar 

  42. Pot DA, Woodford TA, Remboutsika E, Haun RS, Dixon JE: Cloning, bacterial expression, purification, and characterization of the cytoplasmic domain of rat LAP, a receptor-like protein tyrosine phosphatase. J Biol Chem 266: 19688–19696, 1991

    PubMed  Google Scholar 

  43. Streuli M, Krueger NX, Thai T, Tang M, Saito H: Distinct functional roles of the two intracellular phosphatase like domains of the receptor-linked protein tyrosine phosphatases LCA and LAR. EMBO J 9: 2399–2407, 1990.

    PubMed  Google Scholar 

  44. Longo FM, Martignetti JA, Le Beau JM, Zhang JS, Bames JP, Brosius J: Leukocyte common antigen-related receptor-linked tyrosine phosphatase. Regulation of mRNA expression. J Biol Chem 268: 26503–26511, 1993

    PubMed  Google Scholar 

  45. Kulas DT, Zhang WR, Goldstein BJ, Furlanetto RW, Mooney RA: Insulin receptor signalling is augmented by antisense inhibition of the protein-tyrosine phosphatase LAR. J Biol Chem 270: 2435–2438, 1995

    PubMed  Google Scholar 

  46. Kulas DT, Goldstein BJ, Mooney RA: The transmembrane proteintyrosine phosphatase LAR modulates signalling by multiple receptor tyrosine kinases. J Biol Chem 271: 748–754, 1996

    PubMed  Google Scholar 

  47. Zhang WR, Li PM, Oswald MA, Goldstein BJ: Modulation of insulin signal transduction by eutopic overexpression of the receptor-type protein-tyrosine phosphatase LAR. Mol Endocrinol 10: 575–584, 1996

    PubMed  Google Scholar 

  48. Li PM, Zhang WR, Goldstein BJ: Suppression of insulin receptor activation by overexpression of the protein-tyrosine phosphatase LAR in hepatoma cells. Cell Signal 1996

  49. Ahmad F, Goldstein BJ: Functional association between the insulin receptor and the transmembrane protein-tyrosine phosphatase LAR in intact cells. J Biol Chem 1996

  50. Baass PC, Diguglielmo GM, Authier F, Posner BI, Bergeron JJM: Compartmentalized signal transduction by receptor tyrosine kinases. Trends Cell Biol 5: 465–470, 1995

    PubMed  Google Scholar 

  51. Charbonneau H, Tonks NK, Kumar S et al.: Human placenta proteintyrosine phosphatase: Amino acid sequence and relationship to a family of receptor-like proteins. Proc Natl Acad Sci USA 86: 5252–5256, 1989

    PubMed  Google Scholar 

  52. Ide R, Maegawa H, Kikkawa R, Shigeta Y, Kashiwagi A: High glucose condition activates protein tyrosine phosphatases and deactivates insulin receptor function in insulin sensitive rat 1 fibroblasts. Biochem Biophys Res Commun 201: 71–77, 1994

    PubMed  Google Scholar 

  53. Cicirelli MF, Tonks NK, Diltz CD, Weiel JE, Fischer EH, Krebs EG: Microinjection of a protein-tyrosine-phosphatase inhibits insulin action in Xenopus oocytes. Proc Natl Acad Sci USA 87: 5514–5518, 1990

    PubMed  Google Scholar 

  54. Tonks NK, Cicirelli MF, Diltz CD, Krebs EG, Fischer EH: Effect of microinjection of a low-Mr human placenta protein tyrosine phosphatase on induction of meiotic cell division in Xenopus oocytes. Mol Cell Biol 10: 458–463, 1990

    PubMed  Google Scholar 

  55. Lammers R, Bossenrnaier B, Cool DE et al.: Differential activities of protein tyrosine phosphatases in intact cells. J Biol Chem 268: 22456–22462, 1993

    PubMed  Google Scholar 

  56. Ahmad F, Li PM, Meyerovitch J, Goldstein BJ: Osmotic loading of neutralizing antibodies defines a role for protein-tyrosine phosphatase 1B in negative regulation of the insulin action pathway. J Biol Chem 270: 20503–20508, 1995

    PubMed  Google Scholar 

  57. Kenner KA, Anyanwu E, Olefsky JM, Kusari J: Protein-tyrosine phosphatase 1B is a negative regulator of insulin-and insulin-like growth factor-1 stimulated signalling. J Biol Chem 271: 19810–19816, 1996

    PubMed  Google Scholar 

  58. Seely BL, Staubs PA, Reichart DR et al.: Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. Diabetes. 45: 1379–1385, 1996

    PubMed  Google Scholar 

  59. Moxham CM, Malbon CC. Insulin action impaired by deficiency of the g-protein subunit g(i-alpha-2). Nature 379: 840–844, 1996

    PubMed  Google Scholar 

  60. Kuhné MP, Pawson T, Lienhard GE, Feng GS: The insulin receptor substrate-1 associates with the SH2-containing phosphotyrosine phosphatase Syp. J Biol Chem 268: 11479–11481, 1993

    PubMed  Google Scholar 

  61. Case RD, Piccione E, Wolf G et al.: SH-PTP2/Syp SH2 domain binding specificity is defined by direct interactions with platelet-derived growth factor beta-receptor, epidermal growth factor receptor, and insulin receptor substrate-1-derived phosphopeptides. J Biol Chem 269: 10467–10474, 1994

    PubMed  Google Scholar 

  62. Sugimoto S, Wandless TJ, Shoelson SE, Neel BG, Walsh CT: Activation of the SH2-containing protein tyrosine phosphatase, SH-PTP2, by phosphotyrosine-containing peptides derived from insulin receptor substrate-1. J Biol Chem 269: 13614–13622, 1994

    PubMed  Google Scholar 

  63. Kuhné MR, Zhao ZZ, Rowles J et al.: Dephosphorylation of insulin receptor substrate 1 by the tyrosine phosphatase PTP2C. J Biol Chem 269: 15833–15837, 1994

    PubMed  Google Scholar 

  64. Xiao S, Rose DW, Sasaoka T et al.: Syp (SH-PTP2) is a positive mediator of growth factor-stimulated mitogenic signal transduction. J Biol Chem 269: 21244–21248, 1994

    PubMed  Google Scholar 

  65. Maegawa H, Ugi S, Ishibashi O et al.: Src homology-2 domains of protein tyrosine phosphatase are phosphorylated by insulin receptor kinase and bind to the COOH-terminus of insulin receptors in vitro. Biochem Biophys Res Commun 194: 208–214, 1993

    PubMed  Google Scholar 

  66. Ugi S, Maegawa H, Olefsky JM, Shigeta Y, Kashiwagi A: Src homology 2 domains of protein tyrosine phosphatase are associated in vitro with both the insulin receptor and insulin receptor substrate-1 via different phosphotyrosine motifs. FEBS Lett 340: 216–220, 1994

    PubMed  Google Scholar 

  67. Vogel W, Lammers R, Huang JT, Ulrich A: Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Science 259: 1611–1614, 1993

    PubMed  Google Scholar 

  68. Miarski KL, Saltiel AR: Expression of catalytically inactive Syp phosphatase in 3T3 cells blocks stimulation of mitogen-activated protein kinase by insulin. J Biol Chem 269: 21239–21243, 1994

    PubMed  Google Scholar 

  69. Yamaguchi K, Miarski KL, Saltiel AR, Pessin JE: Protein-tyrosinephosphatase SHPTP2 is a required positive effector for insulin downstream signalling. Proc Natl Acad Sci USA 92: 664–668, 1995

    PubMed  Google Scholar 

  70. Perkins LA, Larsen I, Perrimon N: corkscrew encodes a putative protein tyrosine phosphatase that functions to transduce the terminal signal from the receptor tyrosine kinase torso. Cell 70: 225–236, 1992

    PubMed  Google Scholar 

  71. Moller NPH, Moller KB, Lammers R et al.: Selective down-regulation of the insulin receptor signal by protein-tyrosine phosphatases alpha and epsilon. J Biol Chem 270: 23126–23131, 1995

    PubMed  Google Scholar 

  72. Zheng XM, Wang Y, Pallen CJ: Cell transformation and activation of pp60c-src by overexpression and activation of a protein tyrosine phosphatase. Nature 359: 336–339, 1992

    PubMed  Google Scholar 

  73. den Hertog J, Pals CEGM, Peppelenbosch MP, Tertoolen LGJ, Delaat SW, Kruijer W: Receptor protein tyrosine phosphatase-α activates pp60(c-src) and is involved in neuronal differentiation. EMBO J 12: 3789–3798, 1993

    PubMed  Google Scholar 

  74. den Hertog J, Tracy S, Hunter T: Phosphorylation of receptor protein-tyrosine phosphatase α on Tyr789, a binding site for the SH3-SH2-SH3 adaptor protein GRB-2 in vivo. EMBO J 13: 3020–3032, 1994

    PubMed  Google Scholar 

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Goldstein, B.J., Ahmad, F., Ding, W. et al. Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases. Mol Cell Biochem 182, 91–99 (1998). https://doi.org/10.1023/A:1006812218502

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