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 also can induce DNA synthesis and cellular proliferation; therefore, tight regulation of their kinase activities is important for the cell to maintain proliferative control. Posttranslational phosphorylation and dephosphorylation 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 ubiquitin protein ligase involved in ubquitin-mediated degradation, led us to the identification of members of the Src family kinases as potential substrates for E6AP. We have found that E6AP can bind to several of the Src family tyrosine kinases. Here we show that activated Blk is preferentially degraded by the ubiquitin-proteasome pathway and that its ubiquitination is mediated by E6AP. Identification of members of the Src tyrosine kinase family as substrates of the E6AP ubiquitin-protein ligase implicates a role for the ubiquitin pathway in regulating the activities of individual members of this important family of signaling molecules.
Oda
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H
Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Kumar
S
S
Howley
P M
PM
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002478:Cells, Cultured; D004789:Enzyme Activation; D004795:Enzyme Stability; D008025:Ligases / Q000378:metabolism*; D051379:Mice; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
D014452:Ubiquitins; D044767:Ubiquitin-Protein Ligases; C082599:protein-tyrosine kinase p55(blk); D019061:src-Family Kinases; D008025:Ligases