Open AccessSrc kinase activation by direct interaction with the integrin β cytoplasmic domain
Author(s) -
Elena G Arias-Salgado,
Sérgio Lizano,
Sugata Sarkar,
Joan S. Brugge,
Mark H. Ginsberg,
Sanford J. Shattil
Publication year - 2003
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2336149100
Subject(s) - proto oncogene tyrosine protein kinase src , integrin , autophosphorylation , lyn , microbiology and biotechnology , tyrosine protein kinase csk , sh3 domain , phosphorylation , src family kinase , tyrosine phosphorylation , tyrosine kinase , sh2 domain , chemistry , biology , signal transduction , biochemistry , receptor , protein kinase a
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 beta3 integrins through an interaction involving the c-Src SH3 domain and the carboxyl-terminal region of the beta3 cytoplasmic tail. Clustering of beta3 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 beta1A, beta2, and beta3 cytoplasmic tails. These results invoke a model whereby Src is primed for activation by direct interaction with an integrin beta 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 beta3 integrins or c-Src.