Receptor-type tyrosine kinases are not the only kinase targets for Cbl-mediated ubiquitination and degradation. Yokouchi et al. report that this E3 ligase also ubiquitinates the cytoplasmic tyrosine kinase Src, thus explaining its negative regulatory effect on Src. The ubiquitination process required Src kinase activity, and because Cbl is a known Src substrate, the authors propose that its phosphorylation on tyrosine by Src somehow activates ubiquitin ligase action. But Cbl also appears to be self destructive, ubiquitinating itself in the process of acting on Src. Cbl is constitutively associated with other components of the ubiqutin system as well as with inactive Src. Upon Src activation, the trimolecular complex dissociated, a release event that may facilitate the transfer of ubiquitin to two different substrates.
M. Yokouchi, T. Kondo, A. Sanjay, A. Houghton, A. Yoshimura, S. Komiya, H. Zhang, R. Baron, Src-catalyzed phosphorylation of c-Cbl leads to the interdependent ubiquitination of both proteins. J. Biol. Chem. 276, 35185-35193 (2001). [Abstract] [Full Text]