Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination

The Src family of nonreceptor tyrosine kinases are important regulators of a variety of cellular processes, including cytoskeletal organization, cell- cell contact, and cell-matrix adhesion. Activation of Src family kinases al so can induce DNA synthesis and cellular proliferation; therefore, tight re gulation of their kinase activities is important for the cell to maintain p roliferative control. Posttranslational phosphorylation and dephosphorylati on are recognized as the principle modifications by which the activities of the Src family of tyrosine kinases are regulated. We have discovered that this family of kinases also is regulated by ubiquitin-mediated proteolysis, Studies aimed at the identification of cellular targets for E6AP, an E3 ub iquitin protein ligase involved in ubquitin-mediated degradation, led us to the identification of members of the Src family kinases as potential subst rates for E6AP, We have found that E6AP can bind to several of the Src fami ly tyrosine kinases, Here we show that activated B1k is preferentially degr aded by the ubiquitin-proteasome pathway and that its ubiquitination is med iated by E6AP, Identification of members of the Src tyrosine kinase family as substrates of the E6AP ubiquitin-protein ligase implicates a role for th e ubiquitin pathway in regulating the activities of individual members of t his important family of signaling molecules.