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Src kinase activation by direct interaction with the integrin β cytoplasmic domain

2003; National Academy of Sciences; Volume: 100; Issue: 23 Linguagem: Inglês

10.1073/pnas.2336149100

1091-6490

Elena G. Arias‐Salgado, Sérgio Lizano, Sugata Sarkar, Joan S. Brugge, Mark H. Ginsberg, Sanford J. Shattil,

Monoclonal and Polyclonal Antibodies Research

Src tyrosine kinases transmit integrin-dependent signals pivotal for cell movement and proliferation. Here, we establish a mechanism for Src activation by integrins. c-Src is shown to bind constitutively and selectively to β3 integrins through an interaction involving the c-Src SH3 domain and the carboxyl-terminal region of the β3 cytoplasmic tail. Clustering of β3 integrins in vivo activates c-Src and induces phosphorylation of Tyr-418 in the c-Src activation loop, a reaction essential for adhesion-dependent phosphorylation of Syk, a c-Src substrate. Unlike c-Src, Hck, Lyn, and c-Yes bind more generally to β1A, β2, and β3 cytoplasmic tails. These results invoke a model whereby Src is primed for activation by direct interaction with an integrin β tail, and integrin clustering stabilizes activated Src by inducing intermolecular autophosphorylation. The data provide a paradigm for integrin regulation of Src and a molecular basis for the similar functional defects of osteoclasts or platelets from mice lacking β3 integrins or c-Src.