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  • Title: DOK1 mediates SHP-2 binding to the alphaVbeta3 integrin and thereby regulates insulin-like growth factor I signaling in cultured vascular smooth muscle cells.
    Author: Ling Y, Maile LA, Badley-Clarke J, Clemmons DR.
    Journal: J Biol Chem; 2005 Feb 04; 280(5):3151-8. PubMed ID: 15546884.
    Abstract:
    Recruitment of the Src homology 2 domain tyrosine phosphatase (SHP-2) to the phosphorylated beta3 subunit of the alphaVbeta3 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 beta3, we attempted to identify a linker protein that could mediate SHP-2/beta3 association. DOK1 is a member of insulin receptor substrate protein family that binds beta3 and contains YXXL/I motifs that are potential binding sites for SHP-2. Our results show that IGF-I induces DOK1 binding to beta3 and to SHP-2. Preincubation of cells with synthetic peptides that blocked either DOK1/beta3 or DOK1/SHP-2 association inhibited SHP-2 recruitment to beta3. Expression of a DOK1 mutant that does not bind to beta3 also disrupts SHP-2/beta3 association. As a result of SHP-2/beta3 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/beta3 association in response to IGF-I thereby mediating the effect of integrin ligand occupancy on IGF-IR-linked signaling in smooth muscle cells.
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