This Article Full Text Full Text (PDF) All Versions of this Article: 19/1/1    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 Clemmons, D. R. Articles by Maile, L. A. Search for Related Content PubMed PubMed Citation Articles by Clemmons, D. R. Articles by Maile, L. A.

Interaction between Insulin-Like Growth Factor-I Receptor and Vß3 Integrin Linked Signaling Pathways: Cellular Responses to Changes in Multiple Signaling Inputs

Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599

Address all correspondence and requests for reprints to: David R. Clemmons, Division of Endocrinology, University of North Carolina, CB 7170, Chapel Hill, North Carolina 27599. E-mail: endo{at}med.unc.edu.

Integrins are heterodimeric transmembrane proteins that mediate cell attachment to extracellular matrix, migration, division, and inhibition of apoptosis. Because growth factors are also important for these processes, there has been interest in cooperative signaling between growth factor receptors and integrins. IGF-I is an important growth factor for vascular cells. One integrin, Vß3, that is expressed in smooth muscle cells modulates IGF-I actions. Ligand occupancy of Vß3 is required for IGF-I to stimulate cell migration and division. Src homology 2 containing tyrosine phosphatase (SHP-2) is a tyrosine phosphatase whose recruitment to signaling molecules is stimulated by growth factors including IGF-I. If Vß3 ligand occupancy is inhibited, there is no recruitment of SHP-2 to Vß3 and its transfer to downstream signaling molecules is blocked. Ligand occupancy of Vß3 stimulates tyrosine phosphorylation of the ß3-subunit, resulting in recruitment of SHP-2. This transfer is mediated by an insulin receptor substrate-1-related protein termed DOK-1. Subsequently, SHP-2 is transferred to another transmembrane protein, SHPS-1. This transfer requires IGF-I receptor-mediated tyrosine phosphorylation of SHPS-1, which contains two YXXL motifs that mediate SHP-2 binding. The transfer of SHP-2 to SHPS-1 is also required for recruitment of Shc to SHPS-1. Ligand occupancy of Vß3 results in sustained Shc phosphorylation and enhanced Shc recruitment. Shc activation results in induction of MAPK. Inhibition of the Shc/SHPS-1 complex formation results in failure to achieve sustained MAPK activation and an attenuated mitogenic response. Thus, within the vessel wall, a mechanism exists whereby ligand occupancy of the Vß3 integrin is required for assembly of a multicomponent membrane signaling complex that is necessary for cells to respond optimally to IGF-I.

This article has been cited by other articles:

				L. R. Fiedler, E. Schonherr, R. Waddington, S. Niland, D. G. Seidler, D. Aeschlimann, and J. A. Eble Decorin Regulates Endothelial Cell Motility on Collagen I through Activation of Insulin-like Growth Factor I Receptor and Modulation of {alpha}2{beta}1 Integrin Activity J. Biol. Chem., June 20, 2008; 283(25): 17406 - 17415. [Abstract] [Full Text] [PDF]

				R. J. Santulli, W. A. Kinney, S. Ghosh, B. L. DeCorte, L. Liu, R. W. A. Tuman, Z. Zhou, N. Huebert, S. E. Bursell, A. C. Clermont, et al. Studies with an Orally Bioavailable {alpha}V Integrin Antagonist in Animal Models of Ocular Vasculopathy: Retinal Neovascularization in Mice and Retinal Vascular Permeability in Diabetic Rats J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 894 - 901. [Abstract] [Full Text] [PDF]

				B. G. Hollier, J. A. Kricker, D. R. Van Lonkhuyzen, D. I. Leavesley, and Z. Upton Substrate-Bound Insulin-Like Growth Factor (IGF)-I-IGF Binding Protein-Vitronectin-Stimulated Breast Cell Migration Is Enhanced by Coactivation of the Phosphatidylinositide 3-Kinase/AKT Pathway by {alpha}v-Integrins and the IGF-I Receptor Endocrinology, March 1, 2008; 149(3): 1075 - 1090. [Abstract] [Full Text] [PDF]

				S. Perrini, A. Natalicchio, L. Laviola, A. Cignarelli, M. Melchiorre, F. De Stefano, C. Caccioppoli, A. Leonardini, S. Martemucci, G. Belsanti, et al. Abnormalities of Insulin-Like Growth Factor-I Signaling and Impaired Cell Proliferation in Osteoblasts from Subjects with Osteoporosis Endocrinology, March 1, 2008; 149(3): 1302 - 1313. [Abstract] [Full Text] [PDF]

				K.-H. W. Lau, S. Kapur, C. Kesavan, and D. J. Baylink Up-regulation of the Wnt, Estrogen Receptor, Insulin-like Growth Factor-I, and Bone Morphogenetic Protein Pathways in C57BL/6J Osteoblasts as Opposed to C3H/HeJ Osteoblasts in Part Contributes to the Differential Anabolic Response to Fluid Shear J. Biol. Chem., April 7, 2006; 281(14): 9576 - 9588. [Abstract] [Full Text] [PDF]

				L. A. Maile, W. H. Busby, K. Sitko, B. E. Capps, T. Sergent, J. Badley-Clarke, and D. R. Clemmons Insulin-Like Growth Factor-I Signaling in Smooth Muscle Cells Is Regulated by Ligand Binding to the 177CYDMKTTC184 Sequence of the {beta}3-Subunit of {alpha}V{beta}3 Mol. Endocrinol., February 1, 2006; 20(2): 405 - 413. [Abstract] [Full Text] [PDF]

				S. Kapur, S. Mohan, D. J. Baylink, and K.-H. W. Lau Fluid Shear Stress Synergizes with Insulin-like Growth Factor-I (IGF-I) on Osteoblast Proliferation through Integrin-dependent Activation of IGF-I Mitogenic Signaling Pathway J. Biol. Chem., May 20, 2005; 280(20): 20163 - 20170. [Abstract] [Full Text] [PDF]