c‐Abl kinase is activated in response to a variety of biological stimuli. Crk family adaptor proteins can interact physically with c‐Abl and be involved in the activation of c‐Abl kinase.

We report that the Crk family of adaptor proteins act as trans‐acting activators of c‐Abl kinase. The interaction of the amino‐terminal Src‐homology (SH) 3 domain of c‐Crk and the proline‐rich motifs of c‐Abl is an essential step for the phosphorylation of c‐Crk by c‐Abl, as well as the activation of c‐Abl by c‐Crk. The activation of c‐Abl by c‐Crk is negatively regulated by phosphorylation of the tyrosine 221 of c‐Crk. Our data suggest that, in the absence of phosphorylation of the tyrosine Y221, the SH2 domain of c‐Crk becomes free to bind to target molecules while the carboxyl‐terminal SH3 domain of c‐Crk binds to the proline‐rich region of c‐Abl, inducing the activation of c‐Abl by c‐Crk.

This study suggests that the Crk family functions as trans‐acting activators of c‐Abl kinase. The phosphorylation of c‐Crk may regulate c‐Abl kinase.