Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Mol. Biol. Cell 14 (9): 3519-3528

Copyright © 2003 by The American Society for Cell Biology.

The Association between Integrin-associated Protein and SHPS-1 Regulates Insulin-like Growth Factor-I Receptor Signaling in Vascular Smooth Muscle Cells

Laura A. Maile, Jane Badley-Clarke, and David R. Clemmons *

Division of Endocrinology, University of North Carolina, Chapel Hill, North Carolina 27599-7170

Received for publication April 17, 2003. Revision received May 14, 2003. Accepted for publication May 15, 2003.

Monitoring Editor: Carl-Henrik Heldin

Abstract: Growth factor signaling is usually analyzed in isolation without considering the effect of ligand occupancy of transmembrane proteins other than the growth factor receptors themselves. In smooth muscle cells, the transmembrane protein Src homology 2 domain containing protein tyrosine phosphatase substrate-1 (SHPS-1) has been shown to be an important regulator of insulin-like growth factor-I (IGF-I) signaling. SHPS-1 is phosphorylated in response to IGF-I, leading to recruitment of Src homology 2 domain tyrosine phosphatase (SHP-2). Subsequently, SHP-2 is transferred to IGF-I receptor and regulates the duration of IGF-I receptor phosphorylation. Whether ligand occupancy of SHPS-1 influences SHPS-1 phosphorylation or SHP-2 recruitment, thereby altering growth factor signaling, is unknown. Previous studies have shown that integrin associated protein (IAP) associates with SHPS-1. We undertook these studies to determine whether this interaction controlled SHPS-1 phosphorylation and/or SHP-2 recruitment and thereby regulated IGF-I signaling. Disruption of IAP-SHPS-1 binding, by using an IAP monoclonal antibody or cells expressing mutant forms of IAP that did not bind to SHPS-1, inhibited IGF-I–stimulated SHPS-1 phosphorylation and SHP-2 recruitment. This was associated with a lack of SHP-2 transfer to IGF-I receptor and sustained receptor phosphorylation. This resulted in an inability of IGF-I to stimulate sustained mitogen-activated protein kinase activation, cell proliferation, and cell migration. The effect was specific for IGF-I because disruption of the IAP–SHPS-1 interaction had no effect on platelet-derived growth factor-stimulated SHPS-1 phosphorylation or cell migration. In summary, our results show that 1) ligand occupancy of SHPS-1 is a key determinant of its ability to be phosphorylated after IGF-I stimulation, and 2) the interaction between IAP and SHPS-1 is an important regulator of IGF-I signaling because disruption of the results in impaired SHP-2 recruitment and subsequent inhibition of IGF-I–stimulated cell proliferation and migration.


Article published online ahead of print. Mol. Biol. Cell 10.1091/mbc.E03–04–0239. Article and publication date are at www.molbiolcell.org/cgi/doi/10.1091/mbc.E03-04-0239.

* Corresponding author. E-mail address: endo{at}med.unc.edu.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Thrombospondin-1 Activation of Signal-Regulatory Protein-{alpha} Stimulates Reactive Oxygen Species Production and Promotes Renal Ischemia Reperfusion Injury.
M. Yao, N. M. Rogers, G. Csanyi, A. I. Rodriguez, M. A. Ross, C. St. Croix, H. Knupp, E. M. Novelli, A. W. Thomson, P. J. Pagano, et al. (2014)
J. Am. Soc. Nephrol.
   Abstract »
Spatial association of the Cav1.2 calcium channel with α5{beta}1-integrin.
J.-T. Chao, P. Gui, G. W. Zamponi, G. E. Davis, and M. J. Davis (2011)
Am J Physiol Cell Physiol 300, C477-C489
   Abstract »    Full Text »    PDF »
Insulin-like Growth Factor-I-stimulated Insulin Receptor Substrate-1 Negatively Regulates Src Homology 2 Domain-containing Protein-tyrosine Phosphatase Substrate-1 Function in Vascular Smooth Muscle Cells.
Y. Radhakrishnan, W. H. Busby Jr., X. Shen, L. A. Maile, and D. R. Clemmons (2010)
J. Biol. Chem. 285, 15682-15695
   Abstract »    Full Text »    PDF »
Identification of Novel SHPS-1-associated Proteins and Their Roles in Regulation of Insulin-like Growth Factor-dependent Responses in Vascular Smooth Muscle Cells.
X. Shen, G. Xi, Y. Radhakrishnan, and D. R. Clemmons (2009)
Mol. Cell. Proteomics 8, 1539-1551
   Abstract »    Full Text »    PDF »
Genetic and cell biological analysis of integrin outside-in signaling.
K. R. Legate, S. A. Wickstrom, and R. Fassler (2009)
Genes & Dev. 23, 397-418
   Abstract »    Full Text »    PDF »
Integrin-Associated Protein Association With Src Homology 2 Domain Containing Tyrosine Phosphatase Substrate 1 Regulates IGF-I Signaling In Vivo.
L. A. Maile, B. E. Capps, E. C. Miller, A. W. Aday, and D. R. Clemmons (2008)
Diabetes 57, 2637-2643
   Abstract »    Full Text »    PDF »
Novel Structural Determinants on SIRP{alpha} that Mediate Binding to CD47.
W. Y. Lee, D. A. Weber, O. Laur, E. A. Severson, I. McCall, R. P. Jen, A. C. Chin, T. Wu, K. M. Gernet, and C. A. Parkos (2007)
J. Immunol. 179, 7741-7750
   Abstract »    Full Text »    PDF »
Insulin-like Growth Factor-I Receptor Mediates the Prosurvival Effect of Fibronectin.
M. Edderkaoui, P. Hong, J. K. Lee, S. J. Pandol, and A. S. Gukovskaya (2007)
J. Biol. Chem. 282, 26646-26655
   Abstract »    Full Text »    PDF »
Dual Regulation of SIRP{alpha} Phosphorylation by Integrins and CD47.
M. L. Johansen and E. J. Brown (2007)
J. Biol. Chem. 282, 24219-24230
   Abstract »    Full Text »    PDF »
Regulation of IGF-I Signaling in Retinal Endothelial Cells by Hyperglycemia.
E. C. Miller, B. E. Capps, R. R. Sanghani, D. R. Clemmons, and L. A. Maile (2007)
Invest. Ophthalmol. Vis. Sci. 48, 3878-3887
   Abstract »    Full Text »    PDF »
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.
Y. Ling, L. A. Maile, J. Lieskovska, J. Badley-Clarke, and D. R. Clemmons (2005)
Mol. Biol. Cell 16, 3353-3364
   Abstract »    Full Text »    PDF »
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.
S. Kapur, S. Mohan, D. J. Baylink, and K.-H. W. Lau (2005)
J. Biol. Chem. 280, 20163-20170
   Abstract »    Full Text »    PDF »
DOK1 Mediates SHP-2 Binding to the {alpha}V{beta}3 Integrin and Thereby Regulates Insulin-like Growth Factor I Signaling in Cultured Vascular Smooth Muscle Cells.
Y. Ling, L. A. Maile, J. Badley-Clarke, and D. R. Clemmons (2005)
J. Biol. Chem. 280, 3151-3158
   Abstract »    Full Text »    PDF »
Integrin-Associated Protein Binding Domain of Thrombospondin-1 Enhances Insulin-Like Growth Factor-I Receptor Signaling in Vascular Smooth Muscle Cells.
L. A. Maile and D. R. Clemmons (2003)
Circ. Res. 93, 925-931
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882