This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Scrimgeour, A. G. Articles by LeRoith, D. Search for Related Content PubMed PubMed Citation Articles by Scrimgeour, A. G. Articles by LeRoith, D.

Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase Pathways Are Not Sufficient for Insulin-Like Growth Factor I-Induced Mitogenesis and Tumorigenesis

From the Section on Molecular and Cellular Physiology, Diabetes Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892-1770

Address all correspondence and requests for reprints to: Derek LeRoith, M.D., Ph.D., Diabetes Branch/NIDDK, Building 10, Room 8S-235A, 10 Center Drive, MSC 1770, Bethesda, Maryland 20892-1770. E-mail: derek{at}helix.nih.gov

Insulin-like growth factor-I (IGF-I) and insulin are known to activate a signaling cascade involving ras raf-1 mitogen-activated protein (MAP) kinase kinase (MEK) p42/p44 MAP kinase (Erk-1 and -2). Recent reports suggest that activation of this ras/MAP kinase pathway is involved in mitogenesis and c-fos transcription but is not required for insulin action on metabolic processes such as glycogen synthesis, lipogenesis, and GLUT-4-mediated glucose transport. Previously we and others have demonstrated that substitution of both tyrosines at positions 1250 and 1251 in the carboxy-terminal region of the human IGF-I receptor has relatively small effects on receptor and endogenous substrate phosphorylation but completely abrogated the ability of these cells to form tumors in nude mice or proliferate in response to IGF-I in culture. Replacement of the tyrosine at position 1316 also did not affect the kinase activity of the receptor with respect to autophosphorylation or phosphorylation of endogenous substrates but did reduce the ability of the receptor to mediate mitogenic or tumorigenic signals. To further characterize the role of these tyrosines in IGF-I receptor function, we have used three distinct approaches to examine the ras/MAP kinase pathway in IGF-I-induced mitogenesis and tumorigenesis in NIH-3T3 cells overexpressing wild-type and mutated IGF-I receptors: 1) tyrosine phosphorylation of the MAP kinases Erk-1 and -2; 2), mobility shifts indicative of MAP kinase phosphorylation; and 3) in vitro MAP kinase activation. We have also examined IGF-I-induced phosphatidylinositol (PI) 3-kinase activation in the same cell lines. By each method we show that the IGF-I-induced MAP kinase phosphorylation/activation and PI 3-kinase activation, are not different between cells overexpressing wild-type IGF-I receptors and cells carrying IGF-I receptors having tyrosine motifs replaced at positions 1250 and 1251. We conclude that mitogenic and tumorigenic signals involving tyrosine residues in the C-terminal domain of the IGF-I-receptor include pathways other than the MAP kinase and PI 3-kinase pathways.

This article has been cited by other articles:

				I. Tack, S. J. Elliot, M. Potier, A. Rivera, G. E. Striker, and L. J. Striker Autocrine Activation of the IGF-I Signaling Pathway in Mesangial Cells Isolated From Diabetic NOD Mice Diabetes, January 1, 2002; 51(1): 182 - 188. [Abstract] [Full Text] [PDF]

				M. Navarro and R. Baserga Limited Redundancy of Survival Signals from the Type 1 Insulin-Like Growth Factor Receptor Endocrinology, March 1, 2001; 142(3): 1073 - 1081. [Abstract] [Full Text] [PDF]

				G. von Wichert, P. M. Jehle, A. Hoeflich, S. Koschnick, H. Dralle, E. Wolf, B. Wiedenmann, B. O. Boehm, G. Adler, and T. Seufferlein Insulin-like Growth Factor-I Is an Autocrine Regulator of Chromogranin A Secretion and Growth in Human Neuroendocrine Tumor Cells Cancer Res., August 1, 2000; 60(16): 4573 - 4581. [Abstract] [Full Text]

				Y. Imai and D. R. Clemmons Roles of Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase Pathways in Stimulation of Vascular Smooth Muscle Cell Migration and Deoxyriboncleic Acid Synthesis by Insulin-Like Growth Factor-I Endocrinology, September 1, 1999; 140(9): 4228 - 4235. [Abstract] [Full Text]

				G. Gabriëls, A. Werners, S. Mauss, and J. Greven Evidence for Differential Regulation of Renal Proximal Tubular p-Aminohippurate and Sodium-Dependent Dicarboxylate Transport J. Pharmacol. Exp. Ther., August 1, 1999; 290(2): 710 - 715. [Abstract] [Full Text]

				J. Zheng, I. M. Bird, A. N. Melsaether, and R. R. Magness Activation of the Mitogen-Activated Protein Kinase Cascade Is Necessary But Not Sufficient for Basic Fibroblast Growth Factor- and Epidermal Growth Factor-Stimulated Expression of Endothelial Nitric Oxide Synthase in Ovine Fetoplacental Artery Endothelial Cells Endocrinology, March 1, 1999; 140(3): 1399 - 1407. [Abstract] [Full Text]

				S. Pugazhenthi, T. Boras, D. O'Connor, M. K. Meintzer, K. A. Heidenreich, and J. E.-B. Reusch Insulin-like Growth Factor I-mediated Activation of the Transcription Factor cAMP Response Element-binding Protein in PC12 Cells. INVOLVEMENT OF p38 MITOGEN-ACTIVATED PROTEIN KINASE-MEDIATED PATHWAY J. Biol. Chem., January 29, 1999; 274(5): 2829 - 2837. [Abstract] [Full Text] [PDF]

				A. Casamassima and E. Rozengurt Insulin-like Growth Factor I Stimulates Tyrosine Phosphorylation of p130Cas, Focal Adhesion Kinase, and Paxillin. ROLE OF PHOSPHATIDYLINOSITOL 3'-KINASE AND FORMATION OF A p130Cas·Crk COMPLEX J. Biol. Chem., October 2, 1998; 273(40): 26149 - 26156. [Abstract] [Full Text] [PDF]

				J. Wang and H. Riedel Insulin-like Growth Factor-I Receptor and Insulin Receptor Association with a Src Homology-2 Domain-containing Putative Adapter J. Biol. Chem., February 6, 1998; 273(6): 3136 - 3139. [Abstract] [Full Text] [PDF]

				J.-L. Liu, V. A. Blakesley, J. S. Gutkind, and D. LeRoith The Constitutively Active Mutant Galpha 13 Transforms Mouse Fibroblast Cells Deficient in Insulin-like Growth Factor-I Receptor J. Biol. Chem., November 21, 1997; 272(47): 29438 - 29441. [Abstract] [Full Text] [PDF]

				P. Sachdev, Y.-X. Jiang, W. Li, T. Miki, H. Maruta, M. S. A. Nur-e-Kamal, and L.-H. Wang Differential Requirement for Rho Family GTPases in an Oncogenic Insulin-like Growth Factor-I Receptor-induced Cell Transformation J. Biol. Chem., July 6, 2001; 276(28): 26461 - 26471. [Abstract] [Full Text] [PDF]

				L. Heron-Milhavet, M. Karas, C. M. Goldsmith, B. J. Baum, and D. LeRoith Insulin-like Growth Factor-I (IGF-I) Receptor Activation Rescues UV-damaged Cells through a p38 Signaling Pathway. POTENTIAL ROLE OF THE IGF-I RECEPTOR IN DNA REPAIR J. Biol. Chem., May 18, 2001; 276(21): 18185 - 18192. [Abstract] [Full Text] [PDF]