This Article Full Text Full Text (PDF) All Versions of this Article: 144/12/5497    most recent Author Manuscript (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 Biedi, C. Articles by Maggi, D. Search for Related Content PubMed PubMed Citation Articles by Biedi, C. Articles by Maggi, D.

Specificity of Insulin-Like Growth Factor I and Insulin on Shc Phosphorylation and Grb2 Recruitment in Caveolae

Department of Endocrinology and Metabolism, University of Genova, 16132 Genova, Italy; and Department of Biology, University of Padova (D.S.), 35121 Padova, Italy

Address all correspondence and requests for reprints to: Dr. Renzo Cordera, Di.S.E.M., Viale Benedetto XV 6, 16132 Genova, Italy. E-mail: record{at}unige.it.

Caveolae are lipid raft microdomains that regulate endocytosis and signal transduction. IGF-I receptor (IGF-IR) localizes in caveolae and tyrosine phosphorylates caveolin 1, supporting a role for these subcellular regions in the compartmentalization of IGF-I signaling. Src homology 2/-collagen related protein (Shc) is the main mediator of IGF-I mitogenic action, coupling IGF-IR phosphorylation to Ras-MAPK activation. Here we show that IGF-I induces Shc tyrosine phosphorylation in the caveolae with a time course significantly different from that observed in the nonraft cellular fractions. In the same time, IGF-I recruits growth factor receptor bound protein 2 (Grb2) to caveolae and activates p42/p44 MAPKs in these microdomains. Src family kinases regulate IGF-I action through an Shc-dependent mechanism. In R-IGF-IR^WT cells, IGF-I causes Fyn enrichment in the caveolae with a time course consistent with Shc phosphorylation and Grb2 recruitment in these regions. Finally, we have observed that after IGF-I stimulation, IGF-IR and Fyn colocalize in lipid raft caveolin 1-enriched microdomains. As insulin and IGF-I share common substrates, the effect of insulin on these cellular processes was measured. Here we show that insulin also induces Shc phosphorylation and Grb2 recruitment to caveolae, but with a significantly different time course compared with IGF-I. Our results suggest that 1) IGF-I causes the colocalization of signaling proteins in caveolae through a phosphorylation-regulated mechanism; and 2) the time course of phosphorylation and recruitment of substrates in caveolae by insulin receptor and IGF-IR could determine the specific actions of these receptors.

This article has been cited by other articles:

				B. Salani, L. Briatore, S. Garibaldi, R. Cordera, and D. Maggi Caveolin-1 Down-Regulation Inhibits Insulin-Like Growth Factor-I Receptor Signal Transduction in H9C2 Rat Cardiomyoblasts Endocrinology, February 1, 2008; 149(2): 461 - 465. [Abstract] [Full Text] [PDF]

				A. A. Samani, S. Yakar, D. LeRoith, and P. Brodt The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights Endocr. Rev., February 1, 2007; 28(1): 20 - 47. [Abstract] [Full Text] [PDF]

				J. Lieskovska, Y. Ling, J. Badley-Clarke, and D. R. Clemmons The Role of Src Kinase in Insulin-like Growth Factor-dependent Mitogenic Signaling in Vascular Smooth Muscle Cells J. Biol. Chem., September 1, 2006; 281(35): 25041 - 25053. [Abstract] [Full Text] [PDF]

				J. J. Kulstad, P. S. Green, D. G. Cook, G. S. Watson, M. A. Reger, L. D. Baker, S. R. Plymate, S. Asthana, K. Rhoads, P. D. Mehta, et al. Differential modulation of plasma {beta}-amyloid by insulin in patients with Alzheimer disease Neurology, May 23, 2006; 66(10): 1506 - 1510. [Abstract] [Full Text] [PDF]

				T. O. Keku, P. K. Lund, J. Galanko, J. G. Simmons, J. T. Woosley, and R. S. Sandler Insulin Resistance, Apoptosis, and Colorectal Adenoma Risk Cancer Epidemiol. Biomarkers Prev., September 1, 2005; 14(9): 2076 - 2081. [Abstract] [Full Text] [PDF]

				Y. Ling, L. A. Maile, J. Lieskovska, J. Badley-Clarke, and D. R. Clemmons Role of SHPS-1 in the Regulation of Insulin-like Growth Factor I-stimulated Shc and Mitogen-activated Protein Kinase Activation in Vascular Smooth Muscle Cells Mol. Biol. Cell, July 1, 2005; 16(7): 3353 - 3364. [Abstract] [Full Text] [PDF]

				C. Puri, D. Tosoni, R. Comai, A. Rabellino, D. Segat, F. Caneva, P. Luzzi, P. P. Di Fiore, and C. Tacchetti Relationships between EGFR Signaling-competent and Endocytosis-competent Membrane Microdomains Mol. Biol. Cell, June 1, 2005; 16(6): 2704 - 2718. [Abstract] [Full Text] [PDF]

				J. Kaput, K. G. Klein, E. J. Reyes, W. A. Kibbe, C. A. Cooney, B. Jovanovic, W. J. Visek, and G. L. Wolff Identification of genes contributing to the obese yellow Avy phenotype: caloric restriction, genotype, diet x genotype interactions Physiol Genomics, August 11, 2004; 18(3): 316 - 324. [Abstract] [Full Text] [PDF]

				N. Yang, Y. Huang, J. Jiang, and S. J. Frank Caveolar and Lipid Raft Localization of the Growth Hormone Receptor and Its Signaling Elements: IMPACT ON GROWTH HORMONE SIGNALING J. Biol. Chem., May 14, 2004; 279(20): 20898 - 20905. [Abstract] [Full Text] [PDF]