Src-catalyzed phosphorylation of c-Cbl leads to the interdependent ubiquitination of both proteins

The protooncogene c-Cbl has recently emerged as an E3 ubiquitin ligase for activated receptor tyrosine kinases. We report here that c-Cbl also mediate s the ubiquitination of another protooncogene, the non-receptor tyrosine ki nase c-Src, as well as of itself. The c-Cbl-dependent ubiquitination of Src and c-Cbl requires c-Cbl's RING finger, Src kinase activity, and c-Cbl's t yrosine phosphorylation, probably on Tyr-371.. In vitro, c-Cbl forms a stab le complex with the ubiquitin-conjugating enzyme UbcH7, but active Src dest abilizes this interaction. In contrast, Src inhibition stabilizes the c-Cbl .UbcH7.Src complex. Finally, c-Cbl reduces v-Src protein levels and suppres ses v-Src-induced STAT3 activation. Thus, in addition to mediating the ubiq uitination of activated receptor tyrosine kinases, c-Cbl also acts as a ubi quitin ligase for the non-receptor tyrosine kinase Src, thereby down-regula ting Src.