Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosinekinase converts it into a transforming protein

The c-CbI protooncogene is a negative regulator for several receptor tyrosi ne kinases (RTKs) through its ability to promote their polyubiquitination. Hence, uncoupling c-CbI from RTKs may lead to their deregulation. In testin g this, we show that c-CbI promotes ubiquitination of the Met RTK. This req uires the c-Cbl tyrosine kinase binding (TKB) domain and a juxtamembrane ty rosine residue on Met. This tyrosine provides a direct binding site for the c-CbI TKB domain, and is absent in the rearranged oncogenic Tpr-Met varian t. A Met receptor, where the juxtamembrane tyrosine is replaced by phenylal anine, is not ubiquitinated and has transforming activity in fibroblast and epithelial cells. We propose the uncoupling of c-CbI from RTKs as a mechan ism contributing to their oncogenic activation.