The Role of Covalent and Non-Covalent Mechanisms in Insulin Receptor Action

  • Paul L. Rothenberg
  • C. Ronald Kahn
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)

Abstract

Diminished cellular responsiveness to the metabolic and growth promoting effects of insulin occurs in several pathophysiological conditions - - most commonly in insulin and non-insulin dependent diabetes mellitus, but also in obesity, uremia, glucocorticoid and growth hormone excess, and in certain rare syndromes such as lipoatrophic diabetes and leprechaunism (Kahn, 1985; Reaven, 1988). Although insulin action has been intensively investigated at the physiological and biochemical level for close to half a century, we are only beginning to obtain an in-depth understanding of the molecular mechanism of insulin signal transduction. A complete molecular analysis of this process will be necessary for a rational therapeutic approach to insulin-resistant disease states.

Keywords

Obesity Tyrosine Serine Oligomer Polypeptide 

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References

  1. Avruch, J., Nemenoff, R.A., Blackshear, P.J., Pierce, M.W., Osathanondh, R., 1982, Insulin-stimulated tyrosine phosphorylation of the insulin receptor in detergent extracts of placental membranes, J Biol Chem, 257:15162.PubMedGoogle Scholar
  2. Bernier, M., Laird, D.M., Lane, M.D., 1987, Insulin-activated tyrosine phosphorylation of a 15-kilodalton protein in intact 3T3-L1 adipocytes, Proc Natl Acad Sci USA, 84:1844.PubMedCrossRefGoogle Scholar
  3. Bollag, G.E., Roth, R.A., Beaudoir, J., Mochly-Rosen, D., Koshland, D.E., Jr., 1987, Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein kinase activity, Proc Natl Acad Sci USA, 83:5822.CrossRefGoogle Scholar
  4. Garo, J.F., Ittoop, O., Pories, W.J., Meelhein, D., Flickinger, E.G., Thomas, F., Jenquin, M., Silverman, J.F., Khazanie, P.G. and Sinha, M.K., 1986, Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure and kinase activity, J Clin Invest, 78:249.CrossRefGoogle Scholar
  5. Chou, C.K., Dull, T.J., Russell, D.S., Gherzi, R., Lebwohl, D., Ullrich, A., Rosen, O.M., 1987, Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin, J Biol Chem, 262:1842.PubMedGoogle Scholar
  6. Comi, R.J., Grunberger, G., Gordon, P., 1987, Relationship of insulin binding and insulin-stimulated tyrosine kinase activity is altered in type II diabetes, J Clin Invest, 79:453.PubMedCrossRefGoogle Scholar
  7. Deutch, P.J., Wan, C.F., Rosen, O.M., Rubin, C.S., 1983, Latent insulin receptors and possible receptor precursors in 3T3-LI adipocytes, Proc Natl Acad Sci USA, 80:133.CrossRefGoogle Scholar
  8. Ebina, Y., Ellis, L. Jarnagin, K., Edery, M., Graf, L., Clauser, E., Ou, J-H., Masiar, F., Kan, Y., Goldfine, I., Roth, R., Rutter, W., 1985, The human insulin receptor cDNA: The structural basis for hormone activated trans-membrane signalling, Cell 40:747.PubMedCrossRefGoogle Scholar
  9. Ebina, Y., Araki, E., Taira, M., Shimada, F., Mori, M., Craik, C.S., Siddle, K., Pierce, S.B., Roth, R.A., Rutter, W.J., 1987, Replacement of lysine residue 1030 in the putative ATP-binding region of the insulin receptor abolishes insulin- and antibody-stimulated glucose uptake and receptor kinase activity, Proc Natl Acad Sci USA, 84:704.PubMedCrossRefGoogle Scholar
  10. Freidenberg, G.R., Henry, R.R., Klein, H.H., Reichart, D.R., Olefsky, J.M., 1987, Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects, J Clin Invest, 79:240.PubMedCrossRefGoogle Scholar
  11. Freychet, P.J., Roth, J., Neville, D.M., Jr., 1971, Insulin receptors in the liver: Specific binding of [125I] insulin to the plasma membrane and its relation to insulin bioactivity, Proc Natl Acad Sci USA, 68:1833.PubMedCrossRefGoogle Scholar
  12. Fujita-Yamaguchi, Y., Cho, S., Sakamoto, Y., Itakura, K., 1983, Purification of insulin receptors with full binding activity, J Biol Chem, 258:5045.PubMedGoogle Scholar
  13. Gaulton, G., Kelly, K., Pawlowski, J., Mato, J.M., Jarett, L., 1988, Regulation and Functions of an Insulin-Sensitive Glycosyl-Phosphatidylinositol during T-lymphocyte activation, Cell 53:963.PubMedCrossRefGoogle Scholar
  14. Gautam, N., Baetscher, M., Aebersold, R., Simon, M.I., 1989, A G-protein gamma subunit shares homology with ras proteins, Science, 244:971.PubMedCrossRefGoogle Scholar
  15. Gibbs, E.M., Allard, W.J., Lienhard, G.E., 1986, The glucose transporter in 3T3-L1 adipocytes is phosphorylated in response to phorbol ester but not in respose to insulin, J Biol Chem, 261:16597.PubMedGoogle Scholar
  16. Goren, H.J., Northup, J.K., Hollenberg, M.D., 1985, Action of insulin modulated by pertussis toxin in rat adipocytes, Can J Physiol Pharmacol, 63:1017.PubMedCrossRefGoogle Scholar
  17. Haring, H.U., White, M.F., Machicao, F. Ermel, B., Schleicher, E., Obermaier, B., 1987, Insulin rapidly stimulates phosphorylation of a 46-kDa membrane protein on tyrosine residue as well as phosphorylation of several soluble proteins in intact fat cells, Proc Natl Acad Sci USA, 84:113.PubMedCrossRefGoogle Scholar
  18. Hawley, D.M. Maddox, B.A. Patel, R., Wong, K.Y., Mamula, P.W., Firestone, G.L., Brunetti, A., Verspohl, E., Goldfine, I., 1989, Insulin receptor monoclonal antibodies that mimic insulin action without activating tyrosine kinase, J Biol Chem, 264:2438.PubMedGoogle Scholar
  19. Hedo, J., Kahn, C.R., Hayoshi, M., Yamada, K.M., Kasuga, M., 1983, Biosynsthesis and glycosylation of the insulin receptor: Evidence for a single polypeptide precursor of the two major subunits, J Biol Chem, 258:10020.PubMedGoogle Scholar
  20. Herrera, R., Rosen, O.M., 1982, Autophosphorylation of the insulin receptor in vitro. Designation of phosphorylation sites and correlation with receptor kinase activation, J Biol Chem, 261:11989.Google Scholar
  21. Heyworth, C.M., Grey, A.M., Wilson, S.R., Hanski, E., Houslay, M.D., 1989, The action of isle 1 activating protein on insulin’s ability to inhibit adenylate cyclase and activate cyclic AMP phosphodiesterases in hepatocytes. Biochem J, 235:145.Google Scholar
  22. Kadowaki, T., Koyasu, S., Nishida, E., Tobe, K., Izumi, T., Takaku, F., Sakai, H., Yahara, I., Kasuga, M., 1987, Tyrosine phosphorylation of common and specific sets of cellular proteins induced by insulin, IGF-I and EGF in the intact cell, J Biol Chem, 262:7342.PubMedGoogle Scholar
  23. Kahn, C.R., 1975, Membrane Receptors for Polypeptide Hormones, in: Methods in Membrane Biology, Vol 3, E.D. Korn, ed., Plenum Press, New York.Google Scholar
  24. Kahn, C.R., 1985, The molecular mechanism of insulin action, Annual Rev Med, 36:429.CrossRefGoogle Scholar
  25. Kasuga, M., Hedo, J.A., Yamada, K.M., Kahn, C.R., 1982, Structure of the insulin receptors and its subunits, J Biol Chem 257:10392.PubMedGoogle Scholar
  26. Kasuga, M., Karlsson, F.A., Kahn, C.R., 1982a, Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor, Science, 215:185.PubMedCrossRefGoogle Scholar
  27. Kasuga, M., Zick, Y., Blithe, D.L., Karlsson, F.A., Haring, H.U., Kahn, C.R., 1982b, Insulin stimulation of phosphorylation of the β-subunit of the insulin receptor: Formation of both phosphoserine and phosphotyrosine, J Biol Chem, 257:9891.PubMedGoogle Scholar
  28. Korn, L.J., Siebel, C.W., McCormick, F., Roth, R.A., 1987, Ras p21 as a potential mediator of insulin action in Xenopus oocytes, Science, 236:840.PubMedCrossRefGoogle Scholar
  29. Luttrell, L.M., Hewlett, E., Romero, G., Rogol, A.D., 1988, Pertussis toxin treatment attenuates some effects of insulin in BC3H1 murine myocytes, J Biol Chem, 263:6134.PubMedGoogle Scholar
  30. Low, M.G., Saltiel, A.R., 1988, Structural and functional roles of glycosyl-phosphatidylinositol in membranes, Science 239:268.PubMedCrossRefGoogle Scholar
  31. Massague, J., Pilch, P.F., Czech, M.P., 1981, Electrophoretic resolution of three major insulin receptors with unique subunit stoichiometries, Proc Natl Acad Sci USA, 77:7137.CrossRefGoogle Scholar
  32. Morgan, D.O., Roth, R.A., 1987, Acute insulin action requires insulin receptor kinase activity: Introduction of an inhibitory monoclonal antibody into mammalian cells blocks the rapid effects of insulin, Proc Natl Acad Sci USA 84:41.PubMedCrossRefGoogle Scholar
  33. O’Brian, R.M., Houslay, M.D., Milligan, G., Siddle, K., 1987, The insulin receptor tyrosine kinase phosphorylates holomeric forms of the guanine nucleotide regulatory proteins Gi and Go, FEBS Letters, 212:281.CrossRefGoogle Scholar
  34. Petruzzelli, L., Herrera, R., Arrenas-Garcia, R., Fernandez, R., Birnbaum, M.J., Rosen, O.M., 1986, Isolation of a Drosphilia genomic sequence homologous to the kinase domain of the human insulin receptor and detection of the phosphorylated Drosphilia receptor with an anti-peptide antibody, Proc Natl Acad Sci USA 83:4710.PubMedCrossRefGoogle Scholar
  35. Petruzzelli, L.M., Gangaly, S., Smith, C.R., Cobb, M.H., Rubin, C.S., Rosen, O.M., 1982, Insulin activates a tyrosine-specific protein kinase in extracts of 3T3-L1 adipoytes and human placenta, Proc Natl Acad Sci USA 79:6792.PubMedCrossRefGoogle Scholar
  36. Perlman, R., Bottaro, D., White, M.F., Kahn, C.R., 1989, Conformational changes in the α and β-subunits of the insulin receptor identified by anti-peptide antibodies, J Biol Chem, 264:8946.PubMedGoogle Scholar
  37. Pilch, P.F., Czech, M.P., 1980, Purification of the adipocyte insulin receptor by immunoaffinty chromatography, J Biol Chem, 255:1722.PubMedGoogle Scholar
  38. Reaven, G.M., 1988, The role of insulin resistance in human disease, Diabetes 37:1595.PubMedCrossRefGoogle Scholar
  39. Reddy, S.K., Kahn, C.R., 1989, Insulin resistance: A look at the role of insulin receptor kinase, Diab Med, 5:621.CrossRefGoogle Scholar
  40. Ronnett, G.V., Knutson, V.P., Kohanski, R.A., Simpson, T.L., Lane, M.D., 1984, Role of glycosylation in processing of the newly translated insulin proreceptors in 3T3-L1 adipocytes, J Biol Chem, 259:4566.PubMedGoogle Scholar
  41. Rosen, O.M., 1987, After insulin binds, Science, 237:1452.PubMedCrossRefGoogle Scholar
  42. Takayama, S., White, M.F., Lauris, V., Kahn, C.R., 1984, Phorbol esters modulate insulin receptor phosphorylation and insulin action in cultured hepatoma cells, Proc Natl Acad Sci USA, 81:7797.PubMedCrossRefGoogle Scholar
  43. Tashiro-Hashimoto, Y., Tobe, K., Koshio, O., Izumi, T., Takaku, F., Akanuma, Y., Kasuga, M., 1989, Tyrosine phosphorylation of pp185 by insulin receptor kinase in a cell-free system, J Biol Chem, 264:6879.PubMedGoogle Scholar
  44. Ullrich, A., Bell, J., Chen, E., Herrera, R., Petruzzelli, L., Dull, T., Gray, A., Coussens, L., Liao, Y-C, Tsubokawa, M., Mason, A., Seeburg, P., Grunfeld, C., Rosen, O., Ramachandran, J., 1985, Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes, Nature 313:756.PubMedCrossRefGoogle Scholar
  45. White, M.F., Kahn, C.R., 1986, The insulin receptor and tyrosine phosphorylation, in: The Enzymes, Vol XVII, P.D. Boyer, E.G. Krebs, eds., Academic Press, Inc., Orlando.Google Scholar
  46. White, M.F., Haring, H.U., Kasuga, M., Kahn, C.R., 1984, Kinetic properties and sites of autophosphorylation of the partially purified insulin receptor from hepatoma cells, J Biol Chem 259:255.PubMedGoogle Scholar
  47. White, M.F., Maron, R., Kahn, C.R., 1985, Insulin rapidly stimulates tyrosine phosphorylation of a Mr 185,000 protein in intact cells, Nature, 318:183.PubMedCrossRefGoogle Scholar
  48. White. M.F., Shoelson, S.E., Keutmann, H., Kahn, C.R., 1988, Cascade of tyrosine autophosphorylation in the β-subunit activates the insulin receptor, J Biol Chem, 263:2969.PubMedGoogle Scholar
  49. White, M.F., Stegmann, E.W., Dull, T.J., Ullrich, A., Kahn, C.R., 1981, Characterization of an endogenous substrate of the insulin receptor in cultured cells, J Biol Chem, 262:9769.Google Scholar
  50. Yip, C.C., Yeung, C.W.T., Moule, M.L., 1980, Photoaffinty labelling of the insulin receptor proteins of liver plasma membrane, Biochemistry, 19:70.PubMedCrossRefGoogle Scholar
  51. Zick, Y., Sagit-Eisenberg, R., Pines, M., Gierschik, P., Spiegel, A., 1986, Muti-site phosphorylation of the α-subunit of transducin by insulin receptors and protein kinase C, Proc Natl Acad Sci USA, 83:9194.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Paul L. Rothenberg
    • 1
  • C. Ronald Kahn
    • 1
  1. 1.Departments of Pathology and Medicine, Brigham and Women’s HospitalHarvard Medical School and Joslin Diabetes CenterBostonUSA

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