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Molecular and Cellular Aspects of the Insulin-Like Growth Factor I Receptor

Section on Molecular and Cellular Physiology, Diabetes Branch, National Institute of Diabetes andDigestive and Kidney Diseases, National Institutes of Health Bethesda, Maryland 20892

Correspondence: Address requests for reprints to: Derek LeRoith, M.D., Ph.D., National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 8S239, 9000 Rockville Pike, Bethesda, Maryland 20892.

Abstract

I. Introduction: THE insulin-like growth factors (IGFs) and their receptors and binding proteins constitute a family of cellular modulators that play essential roles in the regulation of growth and development. The IGF ligands include three structurally related peptides: insulin, IGF-I, and IGF-II. Unlike insulin, IGF-I and IGF-II are expressed ubiquitously, albeit in a highly regulated manner (see reviews in Refs. 1-5). The biological functions of the IGFs are mediated by a family of transmembrane receptors, which includes the insulin, IGF-I, and IGF-II/mannose-6-phosphate (M-6-P) receptors. While the IGF-I receptor is the primary mediator of IGF action, the insulin and IGF-II/M-6-P receptors may also mediate some of these functions (Fig. 1) (6, 7). The biological actions of the IGFs are modulated by a family of at least six IGF-binding proteins (IGFBPs) that are found in the circulation and in extracellular compartments and are produced by most tissues. The IGFBPs are capable of inhibiting or enhancing IGF effects and may even have ligand-independent effects (see reviews in Refs. 8–11). This review will focus on the IGF-I receptor and will discuss various aspects of its molecular structure and the cellular effects elicited by its activation.

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				S. Oesterreicher, W. F. Blum, B. Schmidt, T. Braulke, and B. Kubler Interaction of Insulin-like Growth Factor II (IGF-II) with Multiple Plasma Proteins: HIGH AFFINITY BINDING OF PLASMINOGEN TO IGF-II AND IGF-BINDING PROTEIN-3 J. Biol. Chem., March 18, 2005; 280(11): 9994 - 10000. [Abstract] [Full Text] [PDF]

				L. Laviola, S. Perrini, G. Belsanti, A. Natalicchio, C. Montrone, A. Leonardini, A. Vimercati, M. Scioscia, L. Selvaggi, R. Giorgino, et al. Intrauterine Growth Restriction in Humans Is Associated with Abnormalities in Placental Insulin-Like Growth Factor Signaling Endocrinology, March 1, 2005; 146(3): 1498 - 1505. [Abstract] [Full Text] [PDF]

				M. A Martin, P. Serradas, S. Ramos, E. Fernandez, L. Goya, M. N. Gangnerau, M. Lacorne, A. M. Pascual-Leone, F. Escriva, B. Portha, et al. Protein-Caloric Food Restriction Affects Insulin-Like Growth Factor System in Fetal Wistar Rat Endocrinology, March 1, 2005; 146(3): 1364 - 1371. [Abstract] [Full Text] [PDF]

				A. Rose, P. Froment, V. Perrot, M. J. Quon, D. LeRoith, and J. Dupont The Luteinizing Hormone-releasing Hormone Inhibits the Anti-apoptotic Activity of Insulin-like Growth Factor-1 in Pituitary {alpha}T3 Cells by Protein Kinase C{alpha}-mediated Negative Regulation of Akt J. Biol. Chem., December 10, 2004; 279(50): 52500 - 52516. [Abstract] [Full Text] [PDF]

				L. Shahrabani-Gargir, T. K. Pandita, and H. Werner Ataxia-Telangiectasia Mutated Gene Controls Insulin-Like Growth Factor I Receptor Gene Expression in a Deoxyribonucleic Acid Damage Response Pathway via Mechanisms Involving Zinc-Finger Transcription Factors Sp1 and WT1 Endocrinology, December 1, 2004; 145(12): 5679 - 5687. [Abstract] [Full Text] [PDF]

				J. Hsieh, K. Nakashima, T. Kuwabara, E. Mejia, and F. H. Gage Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells PNAS, November 23, 2004; 101(47): 16659 - 16664. [Abstract] [Full Text] [PDF]

				A. M. Valverde, C. Mur, M. Brownlee, and M. Benito Susceptibility to Apoptosis in Insulin-like Growth Factor-I Receptor-deficient Brown Adipocytes Mol. Biol. Cell, November 1, 2004; 15(11): 5101 - 5117. [Abstract] [Full Text] [PDF]

				A. Natalicchio, L. Laviola, C. De Tullio, L. A. Renna, C. Montrone, S. Perrini, G. Valenti, G. Procino, M. Svelto, and F. Giorgino Role of the p66Shc Isoform in Insulin-like Growth Factor I Receptor Signaling through MEK/Erk and Regulation of Actin Cytoskeleton in Rat Myoblasts J. Biol. Chem., October 15, 2004; 279(42): 43900 - 43909. [Abstract] [Full Text] [PDF]

				K. Hayashi, K. Shibata, T. Morita, K. Iwasaki, M. Watanabe, and K. Sobue Insulin Receptor Substrate-1/SHP-2 Interaction, a Phenotype-dependent Switching Machinery of Insulin-like Growth Factor-I Signaling in Vascular Smooth Muscle Cells J. Biol. Chem., September 24, 2004; 279(39): 40807 - 40818. [Abstract] [Full Text] [PDF]

				M. S. Kim, C. Y. Yoon, P. G. Jang, Y. J. Park, C. S. Shin, H. S. Park, J. W. Ryu, Y. K. Pak, J. Y. Park, K. U. Lee, et al. The Mitogenic and Antiapoptotic Actions of Ghrelin in 3T3-L1 Adipocytes Mol. Endocrinol., September 1, 2004; 18(9): 2291 - 2301. [Abstract] [Full Text] [PDF]

				U. Sivaprasad, J. Fleming, P. S. Verma, K. A. Hogan, G. Desury, and W. S. Cohick Stimulation of Insulin-Like Growth Factor (IGF) Binding Protein-3 Synthesis by IGF-I and Transforming Growth Factor-{alpha} Is Mediated by Both Phosphatidylinositol-3 Kinase and Mitogen-Activated Protein Kinase Pathways in Mammary Epithelial Cells Endocrinology, September 1, 2004; 145(9): 4213 - 4221. [Abstract] [Full Text] [PDF]

				M. Rubinstein, G. Idelman, S. R. Plymate, G. Narla, S. L. Friedman, and H. Werner Transcriptional Activation of the Insulin-Like Growth Factor I Receptor Gene by the Kruppel-Like Factor 6 (KLF6) Tumor Suppressor Protein: Potential Interactions between KLF6 and p53 Endocrinology, August 1, 2004; 145(8): 3769 - 3777. [Abstract] [Full Text] [PDF]

				K. A. Green, M. J. Naylor, E. T. Lowe, P. Wang, E. Marshman, and C. H. Streuli Caspase-mediated Cleavage of Insulin Receptor Substrate J. Biol. Chem., June 11, 2004; 279(24): 25149 - 25156. [Abstract] [Full Text] [PDF]

				Y. Toyoshima, M. Karas, S. Yakar, J. Dupont, Lee Helman, and D. LeRoith TDAG51 Mediates the Effects of Insulin-like Growth Factor I (IGF-I) on Cell Survival J. Biol. Chem., June 11, 2004; 279(24): 25898 - 25904. [Abstract] [Full Text] [PDF]

				I. Demeestere, C. Gervy, J. Centner, F. Devreker, Y. Englert, and A. Delbaere Effect of Insulin-Like Growth Factor-I During Preantral Follicular Culture on Steroidogenesis, In Vitro Oocyte Maturation, and Embryo Development in Mice Biol Reprod, June 1, 2004; 70(6): 1664 - 1669. [Abstract] [Full Text] [PDF]

				C. A. Conover, L. K. Bale, M. T. Overgaard, E. W. Johnstone, U. H. Laursen, E.-M. Fuchtbauer, C. Oxvig, and J. van Deursen Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development Development, March 1, 2004; 131(5): 1187 - 1194. [Abstract] [Full Text] [PDF]

				P. Delafontaine, Y.-H. Song, and Y. Li Expression, Regulation, and Function of IGF-1, IGF-1R, and IGF-1 Binding Proteins in Blood Vessels Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 435 - 444. [Abstract] [Full Text]

				C.-L. Hu, R. G. Cowan, R. M. Harman, and S. M. Quirk Cell Cycle Progression and Activation of Akt Kinase Are Required for Insulin-Like Growth Factor I-Mediated Suppression of Apoptosis in Granulosa Cells Mol. Endocrinol., February 1, 2004; 18(2): 326 - 338. [Abstract] [Full Text] [PDF]

				J. L. Fowlkes, D. M. Serra, R. C. Bunn, K. M. Thrailkill, J. J. Enghild, and H. Nagase Regulation of Insulin-Like Growth Factor (IGF)-I Action by Matrix Metalloproteinase-3 Involves Selective Disruption of IGF-I/IGF-Binding Protein-3 Complexes Endocrinology, February 1, 2004; 145(2): 620 - 626. [Abstract] [Full Text] [PDF]

				A. Girnita, L. Girnita, F. d. Prete, A. Bartolazzi, O. Larsson, and M. Axelson Cyclolignans as Inhibitors of the Insulin-Like Growth Factor-1 Receptor and Malignant Cell Growth Cancer Res., January 1, 2004; 64(1): 236 - 242. [Abstract] [Full Text] [PDF]

				M. J. Abuzzahab, A. Schneider, A. Goddard, F. Grigorescu, C. Lautier, E. Keller, W. Kiess, J. Klammt, J. Kratzsch, D. Osgood, et al. IGF-I Receptor Mutations Resulting in Intrauterine and Postnatal Growth Retardation N. Engl. J. Med., December 4, 2003; 349(23): 2211 - 2222. [Abstract] [Full Text] [PDF]

				Y. Okubo, K. Siddle, H. Firth, S. O'Rahilly, L. C. Wilson, L. Willatt, T. Fukushima, S.-I. Takahashi, C. J. Petry, T. Saukkonen, et al. Cell Proliferation Activities on Skin Fibroblasts from a Short Child with Absence of One Copy of the Type 1 Insulin-Like Growth Factor Receptor (IGF1R) Gene and a Tall Child with Three Copies of the IGF1R Gene J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5981 - 5988. [Abstract] [Full Text] [PDF]

				C. Biedi, D. Panetta, D. Segat, R. Cordera, and D. Maggi Specificity of Insulin-Like Growth Factor I and Insulin on Shc Phosphorylation and Grb2 Recruitment in Caveolae Endocrinology, December 1, 2003; 144(12): 5497 - 5503. [Abstract] [Full Text] [PDF]

				Y.-x. Shan, T.-L. Yang, R. Mestril, and P. H. Wang Hsp10 and Hsp60 Suppress Ubiquitination of Insulin-like Growth Factor-1 Receptor and Augment Insulin-like Growth Factor-1 Receptor Signaling in Cardiac Muscle: IMPLICATIONS ON DECREASED MYOCARDIAL PROTECTION IN DIABETIC CARDIOMYOPATHY J. Biol. Chem., November 14, 2003; 278(46): 45492 - 45498. [Abstract] [Full Text] [PDF]

				I. Bentov, D. LeRoith, and H. Werner The WT1 Wilms' Tumor Suppressor Gene: A Novel Target for Insulin-Like Growth Factor-I Action Endocrinology, October 1, 2003; 144(10): 4276 - 4279. [Abstract] [Full Text] [PDF]

				A. M. Y. Nomura, G. N. Stemmermann, J. Lee, and M. N. Pollak Serum Insulin-like Growth Factor I and Subsequent Risk of Colorectal Cancer among Japanese-American Men Am. J. Epidemiol., September 1, 2003; 158(5): 424 - 431. [Abstract] [Full Text] [PDF]

				A. M. Etgen and M. Acosta-Martinez Participation of Growth Factor Signal Transduction Pathways in Estradiol Facilitation of Female Reproductive Behavior Endocrinology, September 1, 2003; 144(9): 3828 - 3835. [Abstract] [Full Text] [PDF]

				E. K. Maloney, J. L. McLaughlin, N. E. Dagdigian, L. M. Garrett, K. M. Connors, X.-M. Zhou, W. A. Blattler, T. Chittenden, and R. Singh An Anti-Insulin-like Growth Factor I Receptor Antibody That Is a Potent Inhibitor of Cancer Cell Proliferation Cancer Res., August 15, 2003; 63(16): 5073 - 5083. [Abstract] [Full Text] [PDF]

				X. Wu, G. Tortolero-Luna, H. Zhao, D. Phatak, M. R. Spitz, and M. Follen Serum Levels of Insulin-like Growth Factor I and Risk of Squamous Intraepithelial Lesions of the Cervix Clin. Cancer Res., August 1, 2003; 9(9): 3356 - 3361. [Abstract] [Full Text] [PDF]

				R. Robitaille, J. Dusseault, N. Henley, L. Rosenberg, and J.-P. Halle Insulin-Like Growth Factor II Allows Prolonged Blood Glucose Normalization with a Reduced Islet Cell Mass Transplantation Endocrinology, July 1, 2003; 144(7): 3037 - 3045. [Abstract] [Full Text] [PDF]

				T. H. Ngo, R. J. Barnard, P.-S. Leung, P. Cohen, and W. J. Aronson Insulin-Like Growth Factor I (IGF-I) and IGF Binding Protein-1 Modulate Prostate Cancer Cell Growth and Apoptosis: Possible Mediators for the Effects of Diet and Exercise on Cancer Cell Survival Endocrinology, June 1, 2003; 144(6): 2319 - 2324. [Abstract] [Full Text] [PDF]