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This version published online on June 5, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0143
Molecular Endocrinology Vol. 0, No. 2003 200301431-
doi:10.1210/me.2003-0143
Copyright © 2003 by the Endocrine Society.
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*Substance via MeSH

Submitted on April 16, 2003
Accepted on May 27, 2003

Tyrosine phosphorylation of the {beta}3 subunit of the {alpha}V{beta}3 Integrin is required for membrane association of the tyrosine phosphatase SHP-2 and its further recruitment to the insulin-like growth factor I receptor

Yan Ling1, Laura A. Maile1, and David R. Clemmons1*

1 University of North Carolina, School of Medicine, Chapel Hill, NC 27599

* To whom correspondence should be addressed. E-mail: endo{at}med.unc.edu.

Ligand occupancy of the {alpha}V{beta}3 integrin is required for IGF-I receptor (IGF-IR) phosphorylation of an appropriate duration and for stimulation of IGF-I actions. In vascular smooth muscle cells (SMC), the tyrosine phosphatase SHP-2 regulates the duration of IGF-IR phosphorylation and biological actions. We determined the role of ligand occupancy of the {alpha}V{beta}3 integrin on {beta}3 phosphorylation and studied the role of {beta}3 phosphorylation in regulating both SHP-2 recruitment to the cell membrane and IGF-I dependent biological responses. Vitronectin binding to {alpha}V{beta}3 induced tyrosine phosphorylation of the {beta}3 subunit in subconfluent SMC and was accompanied by increased association of SHP-2 with {beta}3. In confluent SMCs, the {beta}3 subunit was constitutively phosphorylated leading to basal binding of SHP-2. The Src kinase inhibitor PP2 caused a concentration dependent decrease in {beta}3 phosphorylation, and resulted in decreased SHP-2 association with {beta}3 and with the cell membrane. In contrast to control cells, SMCs expressing a mutant {beta}3 that had two tyrosines changed to phenylalanine ({beta}3-FF) showed a 89.9 ± 1.2% decrease in {beta}3 phosphorylation. This decrease was associated with reduced SHP-2 binding to nonphosphorylated {beta}3 and corresponding decrease in the membrane association of SHP-2. When IGF-I was added to cells expressing {beta}3-FF. SHP-2 was not recruited to the Src homology 2 (SH2) domain-containing tyrosine phosphatase substrate-1 (SHPS-1) or to IGF-IR. This was associated with prolonged IGF-IR phosphorylation and an impaired cellular DNA synthesis response to IGF-I. These results define a mechanism by which ligand occupancy of {alpha}V{beta}3 regulates the smooth muscle cell response to IGF-I.
Key words: Tyrosine kinase • Insulin-like growth factor-I • SHPS-1 • SHP-2 • Vitronectin receptor • Integrins




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