Bastarrachea RA, Laviada-Molina H, Machado-Domínguez I, Kent JJ, López-Alvarenga JC, Comuzzie AG

Language: Spanish
References: 71
Page: 180-189
PDF size: 254.89 Kb.

ABSTRACT

The actions of insulin are initiated by its binding to the insulin receptor (IR), a disulfide-bonded heterotetrameric membrane protein. Insulin binds to two asymmetric sites on the extracellular a subunits and causes conformational changes that lead to autophosphorylation of the membrane-spanning b subunits and activation of the receptor’s intrinsic tyrosine kinase. Insulin receptors transphosphorylate several immediate substrates (on Tyr residues) including insulin receptor substrate (IRS) proteins. These events lead to the activation of downstream signaling molecules. The function of the receptor tyrosine kinase is essential for the biological effects of insulin. The pathogenesis of type 2 diabetes mellitus is complex, involving progressive development of insulin resistance and a defect in insulin secretion, which leads to overt hyperglycemia. The molecular basis for insulin resistance in type 2 diabetes remains poorly understood. However, the role of peripheral and hepatic insulin resistance in the pathogenesis of diabetes is undisputed. Insulin resistance can be due to multiple defects in signal transduction (such as impaired activation of insulin receptor-tyrosine kinase and reduced activation of insulin-stimulated phosphatidylinositol-3-OH kinase (PI-3K). A number of molecular targets are now being investigated as ways of enhancing insulin-mediated signal transduction. New approaches to targeting the insulin receptor itself would be to inhibit enzymes responsible for deactivation of the receptor or downstream targets in the signalling pathway (for example, IRS proteins). A number of specific protein tyrosine phosphatases (PTPs) have been identified as candidate targets, among others.

REFERENCES

1. Klip A, Paquet MR. Glucose transport and glucose transporters in muscle and their metabolic regulation. Diabetes Care 1990; 13: 228-243.

2. Bruning JC et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 1998; 2: 559-569.

3. Abel ED et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 2001; 409: 729-733.

4. Gavrilova O et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000; 105: 271-278.

5. Kulkarni RN et al. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 1999; 96: 329-339.

6. Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E, Ou JH, Masiarz F, Kan YW, Goldfine IW. The human IR cDNA: the structural basis for hormone-activated transmembrane signaling. Cell 1985; 40: 747-758.

7. Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M, Takai T, Noda M, Mishina M, Shimizu S, Furutani Y, Kayano T, Ikeda T, Kubo T, Takahashi H, Takahashi T: Human IR and its relationship to the tyrosine kinase family of oncogenes. Nature 1985; 313: 756-761.

8. Lee J, Pilch PF, Shoelson SE, Scarlata SF. Conformational changes of the IR upon insulin binding and activation as monitored by fluorescence spectroscopy. Biochemistry 1997; 36: 2701-2708.

9. Hubbard SR, Wei L, Ellis L, Hendrickson WA. Crystal structure of the tyrosine kinase domain of the human IR. Nature 1994; 372: 746-754.

10. Hubbard SR. Crystal structure of the activated IR tyrosine kinase in complex with peptide substrate and ATP analog. EMBO J 1997; 16: 5572-5581.

11. Haslam RJ, Koide HB, Hemmings BA. Pleckstrin domain homology. Nature 1993; 363: 309-310.

12. Voliovitch H, Schindler DG, Hadari YR, Taylor SI, Accili D, Zick Y. Tyrosine phosphorylation of IR substrate-1 in vivo depends upon the presence of its pleckstrin homology region. J Biol Chem 1995; 270: 18083-18087.

13. Pawson T. Protein modules and signaling networks. Nature 1995; 373: 573-580.

14. Sawka-Verhelle D, Tartare-Deckert S, White MF, Van Obberghen E. IR substrate-2 binds to the IR through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591-786. J Biol Chem 1996; 271: 5980-5983.

15. Wolf G, Trub T, Ottinger E, Groninga L, Lynch A, White MF, Miyazaki M, Lee J, Shoelson SE. PTB domains of IRS-1 and Shc have distinct but overlapping binding specificities. J Biol Chem 1995; 270: 27407-27410.

16. Eck MJ, Dhe-Paganon S, Trub T, Nolte RT, Shoelson SE. Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the IR. Cell 1996; 85: 695-705.

17. Cheatham B, Kahn CR. Insulin action and the insulin signaling network. Endocr Rev 1995; 16: 117-142.

18. Roy S, McPherson RA, Apolloni A, Yan J, Lane A, Clyde-Smith J, Hancock JF. 14-3-3 facilitates Ras-dependent Raf-1 activation in vitro and in vivo. Mol Cell Biol 1998; 18: 3947-3955.

19. Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 1995; 80: 179-185.

20. Czech MP, Corvera S. Signaling mechanisms that regulate glucose transport. J Biol Chem 1999; 274: 1865-1868.

21. Etgen GJ, Valasek KM, Broderick CL. In vivo adenoviral delivery of recombinant human protein kinase C-z stimulates glucose transport activity in rat skeletal muscle. J Biol Chem 1999; 274: 22139-22142.

22. Bandyopadhyay G, Standaert ML, Zhao L, Yu B, Avignon A, Galloway L, Karnam P, Moscat J, Farese RV. Activation of protein kinase C (a, b, and z) by insulin in 3T3/L1 cells: transfection studies suggest a role for PKC-z in glucose transport. J Biol Chem 1997; 272: 2551-2558.

23. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995; 378: 785-789.

24. Welsh GI, Proud CG. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J 1993; 294: 625-629.

25. Lawrence JC Jr, Abraham RT. PHAS/4E-BPs as regulators of mRNA translation and cell proliferation. Trends Biochem Sci 1997; 22: 345-349.

26. Patti ME, Kahn CR. The insulin receptor—a critical link in glucose homeostasis and insulin action. J Basic Clin Physiol Pharmacol 1998; 9: 89-109.

27. Butler AA, LeRoith D. Tissue-specific versus generalized gene targeting of the igf1 and igf1r genes and their roles in insulin-like growth factor physiology. Endocrinology 2001; 142: 1685-1688.

28. Skorokhod A et al. Origin of insulin receptor-like tyrosine kinases in marine sponges. Biol Bull 1999; 197: 198-206.

29. White MF. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem 1998; 182: 3-11.

30. Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest 2000; 106: 165-169.

31. Tamemoto H et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 1994; 372: 182-186.

32. Araki E et al. Alternative pathway of insulin signaling in mice with targeted disruption of the IRS-1 gene. Nature 1994; 372: 186-190.

33. Kido Y et al. Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Invest 2000; 105: 199-205.

34. Withers DJ et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998; 391: 900-904.

35. Fantin VR, Wang Q, Lienhard GE, Keller SR. Mice lacking insulin receptor substrate 4 exhibit mild defects in growth, reproduction, and glucose homeostasis. Am J Physiol Endocrinol Metab 2000; 278: E127-E133.

36. Fasshauer M et al. Essential role of insulin receptor substrate 1 in differentiation of brown adipocytes. Mol Cell Biol 2001; 21: 319-329.

37. Mendez R, Myers MG Jr, White MF, Rhoads RE. Stimulation of protein synthesis, eukaryotic translation initiation factor 4E phosphorylation, and PHAS-I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidylinositol 3-kinase. Mol Cell Biol 1996; 16: 2857-2864.

38. Tsuruzoe K, Emkey R, Kriauciunas KM, Ueki K, Kahn CR. Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. Mol Cell Biol 2001; 21: 26-38.

39. Hotamisligil GS et al. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 1996; 271: 665-668.

40. Craparo A, Freund R, Gustafson TA. 14-3-3 (£) interacts with the insulin-like growth factor I receptor and insulin receptor substrate I in a phosphoserine-dependent manner. J Biol Chem 1997; 272: 11663-11669.

41. Yuan M et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkb. Science 2001; 293: 1673-1677.

42. Kim JK et al. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 2001; 108: 437-446.

43. Elchebly M et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 1999; 283: 1544-1548.

44. 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 1995; 305: 25-28.

45. Myers MG Jr et al. IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. Proc Natl Acad Sci USA 1992; 89: 10350-10354.

46. Pons S et al. The structure and function of p55PIK reveal a new regulatory subunit for phosphatidylinositol 3-kinase. Mol Cell Biol 1995; 15: 4453-4465.

47. Antonetti DA, Algenstaedt P, Kahn CR. Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. Mol Cell Biol 1996; 16: 2195-2203.

48. Fruman DA, Cantley LC, Carpenter CL. Structural organization and alternative splicing of the murine phosphoinositide 3-kinase p85 alpha gene. Genomics 1996; 37: 113-121.

49. Peterson RT, Schreiber SL. Kinase phosphorylation: keeping it all in the family. Curr Biol 1999; 9: R521-R524.

50. Mackay DJ, Hall A. Rho GTPases. J Biol Chem 1998; 273: 20685-20688.

51. Ziegler SF, Bird TA, Schneringer JA, Schooley KA, Baum PR. Molecular cloning and characterization of a novel receptor protein tyrosine kinase from human placenta. Oncogene 1993; 8: 663-670.

52. Alessi DR et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997; 7: 261-269.

53. Cross DA et al. The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf. Biochem J 1994; 303: 21-26.

54. Nakae J, Park BC, Accili D. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J Biol Chem 1999; 274: 15982-15985.

55. Brady MJ, Bourbonais FJ, Saltiel AR. The activation of glycogen synthase by insulin switches from kinase inhibition to phosphatase activation during adipogenesis in 3T3-L1 cells. J Biol Chem 1998; 273: 14063-14066.

56. Cho H et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB ). Science 2001; 292: 1728-1731.

57. Standaert ML et al. Protein kinase C- as a downstream effector of phosphatidylinositol 3-kinase during insulin stimulation in rat adipocytes. Potential role in glucose transport. J Biol Chem 1997; 272: 30075-30082.

58. Boulton TG et al. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 1991; 65: 663-675.

59. Lazar DF et al. Mitogen-activated protein kinase inhibition does not block the stimulation of glucose utilization by insulin. J Biol Chem 1995; 270: 20801-20807.

60. Moller DE. New drug targets for type 2 diabetes and the metabolic syndrome. Nature 2001; 414(6865): 821-827.

61. Goldstein BJ, Li PM, Ding WD, Ahmad F, Zhang WR. In: Vitamins and Hormones—Advances in Research and Applications. (ed. Litwack, J.) Academic, San Diego 1998; 54: 67-96.

62. Cohen N et al. Oral vanadyl sulphate improves hepatic and peripheral insulin sensitivity in patients with non-insulin dependent diabetes mellitus. J Clin Invest 1995; 95: 2501-2509.

63. Elchebly M et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 1999; 283: 1544-1548.

64. Bush EN et al. Treatment of Zucker diabetic fatty rats with antisense oligonucleotide to phosphotyrosine phosphatase-1B for 5 weeks halts development of diabetes. Diabetes 2001; 50(Suppl 2): A81.

65. Weston CR, Davis RJ. Signaling specificity—a complex affair. Science 2001; 292: 2439-2440.

66. Henriksen EJ et al. Glycogen synthase kinase-3 inhibitors potentiate glucose tolerance and muscle glycogen synthase activity in the Zucker Diabetic Fatty Rat. Diabetes 2001; 50(Suppl 2): A279.

67. Clement S et al. The lipid phosphatase SHIP2 controls insulin sensitivity. Nature 2001; 409: 92-97.

68. Yuan M et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkb. Science 2001; 293: 1673-1677.

69. Kim JK et al. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 2001; 108: 437-446.

70. Moller DE. Potential role of TNF in the pathogenesis of insulin resistance and type II diabetes. Trends Endocrinol Metab 2000; 11: 212-217.

71. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest 2000; 106: 171-176.