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J. Biol. Chem., Vol. 280, Issue 5, 3151-3158, February 4, 2005

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DOK1 Mediates SHP-2 Binding to the V3 Integrin and Thereby Regulates Insulin-like Growth Factor I Signaling in Cultured Vascular Smooth Muscle Cells^*

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

From the University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27599

Recruitment of the Src homology 2 domain tyrosine phosphatase (SHP-2) to the phosphorylated 3 subunit of the V3 integrin is required for insulin-like growth factor I (IGF-I)-stimulated cell migration and proliferation in vascular smooth muscle cells. Because SHP-2 does not bind directly to 3, we attempted to identify a linker protein that could mediate SHP-2/3 association. DOK1 is a member of insulin receptor substrate protein family that binds 3 and contains YXXL/I motifs that are potential binding sites for SHP-2. Our results show that IGF-I induces DOK1 binding to 3 and to SHP-2. Preincubation of cells with synthetic peptides that blocked either DOK1/3 or DOK1/SHP-2 association inhibited SHP-2 recruitment to 3. Expression of a DOK1 mutant that does not bind to 3 also disrupts SHP-2/3 association. As a result of SHP-2/3 disruption, IGF-I dependent phosphorylation of Akt and p44/p42 mitogen-activated protein kinase and its ability to stimulate cell migration and proliferation were significantly impaired. These results demonstrate that DOK1 mediates SHP-2/3 association in response to IGF-I thereby mediating the effect of integrin ligand occupancy on IGF-IR-linked signaling in smooth muscle cells.

Received for publication, September 24, 2004 , and in revised form, November 3, 2004.

^* This work was supported by Grants HL56850 and AG02331 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: CB# 7170, 6111 Thurston-Bowles, Division of Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7170. Tel.: 919-966-4735; Fax: 919-966-6025; E-mail: endo{at}med.unc.edu.

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