Src kinase activation by direct interaction with the integrin beta cytoplasmic domain.
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.
Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Elena G
EG
Arias-Salgado
Sergio
S
Lizano
Sugata
S
Sarkar
Joan S
JS
Brugge
Mark H
MH
Ginsberg
Sanford J
SJ
Shattil
D000595:Amino Acid Sequence; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D015153:Blotting, Western; D016466:CHO Cells; D002448:Cell Adhesion; D002845:Chromatography; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005982:Glutathione Transferase / Q000378:metabolism; D039641:Integrin beta Chains / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014443:Tyrosine / Q000737:chemistry; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism*
D039641:Integrin beta Chains; D010455:Peptides; D014443:Tyrosine; D005982:Glutathione Transferase; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases