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

Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13298-302. doi: 10.1073/pnas.2336149100. Epub 2003 Oct 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blood Platelets / metabolism
  • Blotting, Western
  • CHO Cells
  • Cell Adhesion
  • Chromatography
  • Cricetinae
  • Cytoplasm / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme-Linked Immunosorbent Assay
  • Glutathione Transferase / metabolism
  • Integrin beta Chains / metabolism*
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Osteoclasts / metabolism
  • Peptides / chemistry
  • Phosphorylation
  • Plasmids / metabolism
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Sequence Homology, Amino Acid
  • Tyrosine / chemistry
  • src Homology Domains
  • src-Family Kinases / metabolism*


  • Integrin beta Chains
  • Peptides
  • Tyrosine
  • Glutathione Transferase
  • Proto-Oncogene Proteins pp60(c-src)
  • src-Family Kinases