Tyrosine phosphorylation of Crk-associated substrates by focal adhesion kinase. A putative mechanism for the integrin-mediated tyrosine phosphorylation of Crk-associated substrates

J Biol Chem. 1997 Nov 14;272(46):29083-90. doi: 10.1074/jbc.272.46.29083.


Integrin-ligand binding induces the tyrosine phosphorylation of various proteins including focal adhesion kinase (pp125(FAK)) and Crk-associated substrate (Cas). FAK is activated and autophosphorylated by the ligation of integrins, although the substrate of FAK has not been revealed. We show here that p130(Cas) and Cas-L are FAK substrates. FAK directly phosphorylates Cas proteins primarily at the YDYVHL sequence that is conserved among all Cas proteins. Furthermore, the phosphorylated YDYVHL sequence is a binding site for Src family protein-tyrosine kinases, and the recruited Src family kinase phosphorylates the other tyrosine residues within Cas. The Cas-L YDYVHL sequence is phosphorylated upon integrin-ligand binding, and this integrin-mediated tyrosine phosphorylation is inhibited by the cotransfection of the FAK COOH-terminal domain that does not contain a kinase domain. These findings strongly suggest that FAK initiates integrin-mediated tyrosine phosphorylation of Cas proteins; then, Src family tyrosine kinases, which are recruited to phosphorylated Cas and FAK, further phosphorylate Cas proteins.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cell Adhesion Molecules / metabolism*
  • Focal Adhesion Protein-Tyrosine Kinases
  • Integrins / metabolism
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-cbl
  • Substrate Specificity
  • Tyrosine / metabolism*
  • Ubiquitin-Protein Ligases*


  • Adaptor Proteins, Signal Transducing
  • CRKL protein
  • Cell Adhesion Molecules
  • Integrins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Tyrosine
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Protein-Tyrosine Kinases
  • Focal Adhesion Protein-Tyrosine Kinases