Insulin and Insulin-Like Growth Factor-1 Receptors and Signaling Pathways: Similarities and Differences

  • Derek LeRoith
  • Michael J. Quon
  • Yehiel Zick
Part of the Endocrine Updates book series (ENDO, volume 17)

Abstract

Insulin and the insulin-like growth factors (IGFs) play critical roles in normal physiology. Pathological perturbations in these hormone systems result in serious medical consequences. Insulin is considered to be primarily a “metabolic” hormone with important effects on the normal homeostasis of glucose, fat and protein. If insulin production or insulin action at target tissues are impaired, diabetes and numerous concomitant conditions of insulin resistance including hypertension and hypertriglyceridemia will ensue. The IGFs, on the other hand, primarily control growth and development of the organism. IGFs control growth by facilitating cellular proliferation in terminally differentiated cells and by inhibiting apoptosis. In adult tissues, these growth factors also have various tissue-specific functions. While there are clear differences in the physiological roles of insulin and the IGFs, these hormones/growth factors also share many similarities. The hormones have similar tertiary structures, and they share ~50% amino acid identity. Both insulin and IGFs interact with specific cell surface receptors that represent one sub-class of the tyrosine kinase receptor family. The signaling cascades induced by activation of the insulin receptor (IR) and IGF-I receptor (IGF-IR) are highly overlapping, with some subtle differences, as will be discussed in more detail below.

Keywords

Insulin Receptor Human Insulin Receptor Juxtamembrane Region Vascular Endothelial Growth Factor Gene Expression Alanine Scanning Mutagenesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Ullrich, A., Gray, A., Tam, A.W., Yang-Feng, T., Tsubokawa, M., Collins, C., Henzel, W., Le Bon, T., Kathuria, S., and Chen, E. (1986) Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. Embo J 5, 2503–2512.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Ullrich, A., Bell, J.R., Chen, E.Y., Herrera, R., Petruzzelli, L.M., Dull, T.J., Gray, A., Coussens, L., Liao, Y.C., and Tsubokawa, M. (1985) Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313, 756–761.PubMedCrossRefGoogle Scholar
  3. 3.
    Garrett, T.P., McKern, N.M., Lou, M., Frenkel, M.J., Bentley, J.D., Lovrecz, G.O., Elleman, T.C., Cosgrove, L.J. and Ward, C.W. (1998) Crystal structure of the first three domains of the type-1 insulin-like growth factor receptor. Nature 394, 395–399.CrossRefGoogle Scholar
  4. 4.
    Hubbard, S.R. (1997) Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. Embo J 16, 5572–5581.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Hubbard, S.R., Wei, L., Ellis, L. and Hendrickson, W.A. (1994) Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature 372, 746–754.PubMedCrossRefGoogle Scholar
  6. 6.
    Kahn, C.R., Baird, K.L., Flier, J.S., Grunfeld, C., Harmon, J.T., Harrison, L.C., Karlsson, F.A., Kasuga, M., King, G.L., Lang, U.C., Podskalny, J.M. and Van Obberghen, E. (1981) Insulin receptors, receptor antibodies, and the mechanism of insulin action. Recent Prog Horm Res 37, 477–538.Google Scholar
  7. 7.
    Kristensen, C., Wiberg, F.C., Schaffer, L. and Andersen, A.S. (1998) Expression and characterization of a 70-kDa fragment of the insulin receptor that binds insulin. Minimizing ligand binding domain of the insulin receptor. J Biol Chem 273, 1778017786.Google Scholar
  8. 8.
    Kristensen, C., Wiberg, F.C. and Andersen, A.S. (1999) Specificity of insulin and insulin-like growth factor I receptors investigated using chimeric mini-receptors. Role of C-terminal of receptor alpha subunit. J Biol Chem 274, 37351–37356.PubMedCrossRefGoogle Scholar
  9. 9.
    Leconte, I., Carpentier, J.L. and Clauser, E. (1994) The functions of the human insulin receptor are affected in different ways by mutation of each of the four Nglycosylation sites in the beta subunit. J Biol Chem 269, 18062–18071.PubMedGoogle Scholar
  10. 10.
    Elleman, T.C., Frenkel, M.J., Hoyne, P.A., McKern, N.M., Cosgrove, L., Hewish, D.R., Jachno, K.M., Bentley, J.D., Sankovich, S.E. and Ward, C.W. (2000) Mutational analysis of the N-linked glycosylation sites of the human insulin receptor. Biochem J 347 Pt 3, 771–779.CrossRefGoogle Scholar
  11. 11.
    Schumacher, R., Mosthaf, L., Schlessinger, J., Brandenburg, D. and Ullrich, A. (1991) Insulin and insulin-like growth factor-1 binding specificity is determined by distinct regions of their cognate receptors. J Biol Chem 266, 19288–19295.PubMedGoogle Scholar
  12. 12.
    Kurose, T., Pashmforoush, M., Yoshimasa, Y., Caroll, R., Schwartz, G.P., Burke, G.T., Katsoyannis, P.G., Steiner, D.F. Cross-linking of a B25 azidophenylananine insulin derivative to the carboxyl-terminal region of the alpha-subunit of the insulin receptor. (1994) Identification of a new insulin-binding domain in the insulin receptor. J Biol Chem 269, 29190–29197Google Scholar
  13. 13.
    Williams, P.F., Mynarcik, D.C., Yu, G.Q., Whittaker, J. (1995) Mapping of an NH2- terminal ligand binding site of the insulin receptor by alanine scanning mutagenesis. J Biol Chem 270, 3012–3016PubMedCrossRefGoogle Scholar
  14. 14.
    Kaburagi, Y., Momomura, K., Yamamoto-Honda, R., Tobe, K., Tamori, Y., Sakura, H., Akanuma, Y., Yazaki, Y. and Kadowaki, T. (1993) Site-directed mutagenesis of the juxtamembrane domain of the human insulin receptor. J Biol Chem 268, 1661016622.Google Scholar
  15. 15.
    White, M.F., Livingston, J.N., Backer, J.M., Lauris, V., Dull, T.J., Ullrich, A. and Kahn, C.R. (1988) Mutation of the insulin receptor at tyrosine 960 inhibits signal transmission but does not affect its tyrosine kinase activity. Cell 54, 641–649.CrossRefGoogle Scholar
  16. 16.
    Keegan, A.D., Nelms, K., White, M., Wang, L.M., Pierce, J.H. and Paul, W.E. (1994) An IL-4 receptor region containing an insulin receptor motif is important for IL-4mediated IRS-1 phosphorylation and cell growth. Cell 76, 811–820.PubMedCrossRefGoogle Scholar
  17. 17.
    Koval, A.P., Blakesley, V.A., Roberts Jr, C.T., Zick, Y. and Leroith, D. (1998) Interaction in vitro of the product of the c-Crk-II proto-oncogene with the insulin-like growth factor I receptor. Biochem J 330, 923–932.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Eck, M.J., Dhe-Paganon, S., Trub, T., Nolte, R.T. and Shoelson, S.E. (1996) Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor. Cell 85, 695–705.CrossRefGoogle Scholar
  19. 19.
    Paz, K., Voliovitch, H., Hadari, Y.R., Roberts, C.T., Jr., LeRoith, D. and Zick, Y. (1996) Interaction between the insulin receptor and its downstream effectors. Use of individually expressed receptor domains for structure/function analysis. J Biol Chem 271, 6998–7003.Google Scholar
  20. 20.
    Haft, C.R., Klausner, R.D. and Taylor, S.I. (1994) Involvement of dileucine motifs in the internalization and degradation of the insulin receptor. J Biol Chem 269, 2628626294.Google Scholar
  21. 21.
    Tavare, J.M. and Siddle, K. (1993) Mutational analysis of insulin receptor function: consensus and controversy. Biochim Biophys Acta 1178, 21–39.PubMedCrossRefGoogle Scholar
  22. 22.
    LeRoith, D., Werner, H., Beitner-Johnson, D. and Roberts, C.T., Jr. (1995) Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 16, 143–163.PubMedGoogle Scholar
  23. 23.
    Cheatham, B. and Kahn, C.R. (1995) Insulin action and the insulin signaling network. Endocr Rev 16, 117–142.PubMedGoogle Scholar
  24. 24.
    Pang, L., Milarski, K.L., Ohmichi, M., Takata, Y., Olefsky, J.M. and Saltiel, A.R. (1994) Mutation of the two carboxyl-terminal tyrosines in the insulin receptor results in enhanced activation of mitogen-activated protein kinase. J Biol Chem 269, 10604–10608.PubMedGoogle Scholar
  25. 25.
    Maegawa, H., McClain, D.A., Freidenberg, G., Olefsky, J.M., Napier, M., Lipari, T., Dull, T.J., Lee, J. and Ullrich, A. (1988) Properties of a human insulin receptor with a COOH-terminal truncation. II. Truncated receptors have normal kinase activity but are defective in signaling metabolic effects. J Biol Chem 263, 8912–8917.Google Scholar
  26. 26.
    Thies, R.S., Ullrich, A. and McClain, D.A. (1989) Augmented mitogenesis and impaired metabolic signaling mediated by a truncated insulin receptor. J Biol Chem 264, 12820–12825.PubMedGoogle Scholar
  27. 27.
    Surmacz, E., Sell, C., Swantek, J., Kato, H., Roberts, C.T., Jr., LeRoith, D. and Baserga, R. (1995) Dissociation of mitogenesis and transforming activity by C-terminal truncation of the insulin-like growth factor-I receptor. Exp Cell Res 218, 370–380.CrossRefGoogle Scholar
  28. 28.
    Faria, T.N., Blakesley, V.A., Kato, H., Stannard, B., LeRoith, D. and Roberts, C.T., Jr. (1994) Role of the carboxyl-terminal domains of the insulin and insulin-like growth factor I receptors in receptor function. J Biol Chem 269, 13922–13928.PubMedGoogle Scholar
  29. 29.
    Kalloo-Hosein, H.E., Whitehead, J.P., Soos, M., Tavare, J.M., Siddle, K. and O’Rahilly, S. (1997) Differential signaling to glycogen synthesis by the intracellular domain of the insulin versus the insulin-like growth factor-1 receptor. Evidence from studies of TrkC-chimeras. J Biol Chem 272, 24325–24332.Google Scholar
  30. 30.
    Heldin, C.H. (1995) Dimerization of cell surface receptors in signal transduction. Cell 80, 213–223.PubMedCrossRefGoogle Scholar
  31. 31.
    van der Geer, P., Hunter, T. and Lindberg, R.A. (1994) Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol 10, 251–337.CrossRefGoogle Scholar
  32. 32.
    Lee, J., Pilch, P.F., Shoelson, S.E. and Scarlata, S.F. (1997) Conformational changes of the insulin receptor upon insulin binding and activation as monitored by fluorescence spectroscopy. Biochemistry 36, 2701–2708.PubMedCrossRefGoogle Scholar
  33. 33.
    Songyang, Z., Shoelson, S.E., Chaudhuri, M., Gish, G., Pawson, T., Haser, W.G., King, F., Roberts, T., Ratnofsky, S., and Lechleider, R.J.. (1993) SH2 domains recognize specific phosphopeptide sequences. Cell 72, 767–778.CrossRefGoogle Scholar
  34. 34.
    Staubs, P.A., Reichart, D.R., Saltiel, A.R., Milarski, K.L., Maegawa, H., Berhanu, P., Olefsky, J.M. and Seely, B.L. (1994) Localization of the insulin receptor binding sites for the SH2 domain proteins p85, Syp, and GAP. J Biol Chem 269, 27186–27192.Google Scholar
  35. 35.
    Lavan, B.E., Lane, W.S. and Lienhard, G.E. (1997) The 60-kDa phosphotyrosine protein in insulin-treated adipocytes is a new member of the insulin receptor substrate family J Biol Chem 272, 11439–11443.Google Scholar
  36. 36.
    Myers, M.G., Jr. and White, M.F. (1996) Insulin signal transduction and the IRS proteins. Annu Rev Pharmacol Toxicol 36, 615–658.CrossRefGoogle Scholar
  37. 37.
    Araki, E., Lipes, M.A., Patti, M.E., Bruning, J.C., Haag, B., 3rd, Johnson, R.S. and Kahn, C.R. (1994) Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372, 186–190.CrossRefGoogle Scholar
  38. 38.
    Withers, D.J., Gutierrez, J.S., Towery, H., Burks, D.J., Ren, J.M., Previs, S., Zhang, Y., Bernal, D., Pons, S., Shulman, G.I., Bonner-Weir, S. and White, M.F. (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391, 900–904.CrossRefGoogle Scholar
  39. 39.
    Nystrom, F.H. and Quon, M.J. (1999) Insulin signalling: metabolic pathways and mechanisms for specificity. Cell Signal 11, 563–574.CrossRefGoogle Scholar
  40. 40.
    Alessi, D.R., James, S.R., Downes, C.P., Holmes, A.B., Gaffney, P.R., Reese, C.B. and Cohen, P. (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Cuff Biol 7, 261–269.Google Scholar
  41. 41.
    Paz, K., Liu, Y.F., Shorer, H., Hemi, R., LeRoith, D., Quon, M., Kanety, H., Seger, R. and Zick, Y. (1999) Phosphorylation of insulin receptor substrate-1 (IRS-1) by protein kinase B positively regulates IRS-1 function. J Biol Chem 274, 28816–28822.CrossRefGoogle Scholar
  42. 42.
    Hotamisligil, G.S., Peraldi, P., Budavari, A., Ellis, R., White, M.F. and Spiegelman, B.M. (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha-and obesity-induced insulin resistance. Science 271, 665–668.CrossRefGoogle Scholar
  43. 43.
    Walton, K.M. and Dixon, J.E. (1993) Protein tyrosine phosphatases. Annu Rev Biochem 62, 101–120.CrossRefGoogle Scholar
  44. 44.
    Lammers, R., Bossenmaier, B., Cool, D.E., Tonics, N.K., Schlessinger, J., Fischer, E.H. and Ullrich, A. (1993) Differential activities of protein tyrosine phosphatases in intact cells. J Biol Chem 268, 22456–22462.Google Scholar
  45. 45.
    Chen, H., Wertheimer, S.J., Lin, C.H., Katz, S.L., Amrein, K.E., Burn, P. and Quon, M.J. (1997) Protein-tyrosine phosphatases PTP1B and syp are modulators of insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. J Biol Chem 272, 8026–8031.CrossRefGoogle Scholar
  46. 46.
    Tonics, N.K., Cicirelli, M.F., Diltz, C.D., Krebs, E.G. and Fischer, E.H. (1990) 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.Google Scholar
  47. 47.
    Elchebly, M., Payette, P., Michaliszyn, E., Cromlish, W., Collins, S., Loy, A.L., Normandin, D., Cheng, A., Himms-Hagen, J., Chan, C.C., Ramachandran, C., Gresser, M.J., Tremblay, M.L. and Kennedy, B.P. (1999) Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548.CrossRefGoogle Scholar
  48. 48.
    Milarski, K.L. and Sallie!, A.R. (1994) Expression of catalytically inactive Syp phosphatase in 3T3 cells blocks stimulation of mitogen-activated protein kinase by insulin. J Biol Chem 269, 21239–21243.Google Scholar
  49. 49.
    Maegawa, H., Hasegawa, M., Sugai, S., Obata, T., Ugi, S., Morino, K., Egawa, K., Fujita, T., Sakamoto, T., Nishio, Y., Kojima, H., Haneda, M., Yasuda, H., Kikkawa, R. and Kashiwagi, A. (1999) Expression of a dominant negative SHP-2 in transgenic mice induces insulin resistance. J Biol Chem 274, 30236–30243.CrossRefGoogle Scholar
  50. 50.
    Soni, P., Lakkis, M., Poy, M.N., Fernstrom, M.A. and Najjar, S.M. (2000) The differential effects of pp120 (Ceacam 1) on the mitogenic action of insulin and insulin-like growth factor 1 are regulated by the nonconserved tyrosine 1316 in the insulin receptor. Mol Cell Biol 20, 3896–3905.CrossRefGoogle Scholar
  51. 51.
    Najjar, S.M., Blakesley, V.A., Li Calzi, S., Kato, H., LeRoith, D. and Choice, C.V. (1997) Differential phosphorylation of pp120 by insulin and insulin-like growth factor-1 receptors: role for the C-terminal domain of the beta-subunit. Biochemistry 36, 68276834.Google Scholar
  52. 52.
    Formisano, P., Najjar, S.M., Gross, C.N., Philippe, N., Oriente, F., Kern-Buell, C.L., Accili, D. and Gorden, P. (1995) Receptor-mediated internalization of insulin. Potential role of pp120/HA4, a substrate of the insulin receptor kinase. J Biol Chem 270, 2407324077.Google Scholar
  53. 53.
    Blakesley, V.A., Kalebic, T., Heiman, L.J., Stannard, B., Faria, T.N., Roberts, C.T., Jr. and LeRoith, D. (1996) Tumorigenic and mitogenic capacities are reduced in transfected fibroblasts expressing mutant insulin-like growth factor (IGF)-I receptors. The role of tyrosine residues 1250, 1251, and 1316 in the carboxy-terminus of the IGF-I receptor. Endocrinology 137, 410–417.Google Scholar
  54. 54.
    Porcu, P., Ferber, A., Pietrzkowski, Z., Roberts, C.T., Adamo, M., LeRoith, D. and Baserga, R. (1992) The growth-stimulatory effect of simian virus 40 T antigen requires the interaction of insulinlike growth factor 1 with its receptor. Mol Cell Biol 12, 50695077.Google Scholar
  55. 55.
    Urso, B., Cope, D.L., Kalloo-Hosein, H.E., Hayward, A.C., Whitehead, J.P., O’Rahilly, S. and Siddle, K. (1999) Differences in signaling properties of the cytoplasmic domains of the insulin receptor and insulin-like growth factor receptor in 3T3–L1 adipocytes. J Biol Chem 274, 30864–30873.CrossRefGoogle Scholar
  56. 56.
    Park, B.C., Kido, Y. and Accili, D. (1999) Differential signaling of insulin and IGF-1 receptors to glycogen synthesis in murine hepatocytes. Biochemistry 38, 7517–7523.CrossRefGoogle Scholar
  57. 57.
    Tartare, S., Mothe, I., Kowalski-Chauvel, A., Breittmayer, J.P., Ballotti, R. and Van Obberghen, E. (1994) Signal transduction by a chimeric insulin-like growth factor-1 (IGF-1) receptor having the carboxyl-terminal domain of the insulin receptor. J Biol Chem 269, 11449–11455.Google Scholar
  58. 58.
    Esposito, D.L., Blakesley, V.A., Koval, A.P., Scrimgeour, A.G. and LeRoith, D. (1997) Tyrosine residues in the C-terminal domain of the insulin-like growth factor-I receptor mediate mitogenic and tumorigenic signals. Epdocrinology 138, 2979–2988.CrossRefGoogle Scholar
  59. 59.
    Chow, J.C., Condorelli, G. and Smith, R.J. (1998) Insulin-like growth factor-I receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway. J Biol Chem 273, 4672–4680.CrossRefGoogle Scholar
  60. 60.
    Ceresa, B.P., Kao, A.W., Santeler, S.R. and Pessin, J.E. (1998) Inhibition of clathrin- mediated endocytosis selectively attenuates specific insulin receptor signal transduction pathways. Mol Cell Biol 18, 3862–3870.Google Scholar
  61. 61.
    Emanuelli, B., Peraldi, P., Filloux, C., Sawka-Verhelle, D., Hilton, D. and Van Obberghen, E. (2000) SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem 275, 15985–15991.CrossRefGoogle Scholar
  62. 62.
    Zong, C.S., Chan, J., Levy, D.E., Horvath, C., Sadowski, H.B. and Wang, L.H. (2000) Mechanism of STAT3 activation by insulin-like growth factor I receptor. J Biol Chem 275, 15099–15105.CrossRefGoogle Scholar
  63. 63.
    Dey, B.R., Spence, S.L., Nissley, P. and Furlanetto, R.W. (1998) Interaction of human suppressor of cytokine signaling (SOCS)-2 with the insulin-like growth factor-I receptor. J Biol Chem 273, 24095–24101.CrossRefGoogle Scholar
  64. 64.
    Warren, R.S., Yuan, H., Matli, M.R., Ferrara, N. and Donner, D.B. (1996) Induction of vascular endothelial growth factor by insulin-like growth factor 1 in colorectal carcinoma. J Biol Chem 271, 29483–29488.CrossRefGoogle Scholar
  65. 65.
    Zelzer, E., Levy, Y., Kahana, C., Shilo, B.Z., Rubinstein, M. and Cohen, B. (1998) Insulin induces transcription of target genes through the hypoxia-inducible factor HIFlalpha/ARNT. Embo J 17, 5085–5094.CrossRefGoogle Scholar
  66. 66.
    Miele, C., Rochford, J.J., Filippa, N., Giorgetti-Peraldi, S. and Van Obberghen, E. (2000) Insulin and insulin-like growth factor-I induce vascular endothelial growth factor mRNA expression via different signaling pathways [In Process Citation]. J Biol Chem 275, 21695–21702.CrossRefGoogle Scholar
  67. 67.
    Wertheimer, E., Trebicz, M., Eldar, T., Gartsbein, M., Nofeh-Moses, S. and Tennenbaum, T. (2000) Differential roles of insulin receptor and insulin-like growth factor-1 receptor in differentiation of murine skin keratinocytes [In Process Citation]. J Invest Dermatol 115, 24–29.CrossRefGoogle Scholar
  68. 68.
    Okubo, Y., Blakesley, V.A., Stannard, B., Gutkind, S. and Le Roith, D. (1998) Insulin-like growth factor-I inhibits the stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem 273, 25961–25966.CrossRefGoogle Scholar
  69. 69.
    Fukunaga, K., Noguchi, T., Takeda, H., Matozaki, T., Hayashi, Y., Itoh, H. and Kasuga, M. (2000) Requirement for protein-tyrosine phosphatase SHP-2 in insulin-induced activation of c-Jun NH(2)-terminal kinase. J Biol Chem 275, 5208–5213.PubMedCrossRefGoogle Scholar
  70. 70.
    Nakae, J., Barr, V. and Accili, D. (2000) Differential regulation of gene expression by insulin and IGF-1 receptors correlates with phosphorylation of a single amino acid residue in the forkhead transcription factor FKHR. Embo J 19, 989–996.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Derek LeRoith
    • 1
  • Michael J. Quon
    • 2
  • Yehiel Zick
    • 3
  1. 1.Clinical Endocrinology BranchNIDDKBethesdaUSA
  2. 2.Cardiology BranchNHLBI, NIHBethesdaUSA
  3. 3.The Weizmann Institute of ScienceRehovotIsrael

Personalised recommendations