Ubiquitin-Mediated Degradation of Active Src Tyrosine Kinase

Src family tyrosine kinases are involved in modulating various signal transduction pathways leading to the induction of DNA synthesis and cytoskeletal reorganization in response to cell-cell or cell-matrix adhesion. The critical role of these kinases in regulating cellular signaling pathways require...

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Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS 1999-11, Vol.96 (24), p.13738-13743
Main Authors:	Harris, Kimya F., Shoji, Ikuo, Cooper, Eric M., Kumar, Sushant, Oda, Hideaki, Howley, Peter M.
Format:	Article
Language:	eng
Subjects:	Animals Antibodies Biochemistry Biological Sciences Chickens COS Cells Enzyme Activation Enzymes Family members Gene expression regulation Half lives Oncogene Protein pp60(v-src) - genetics Oncogene Protein pp60(v-src) - metabolism Phosphorylation Physiological regulation Protein-Tyrosine Kinases Proteins Proto-Oncogene Proteins pp60(c-src) - genetics Proto-Oncogene Proteins pp60(c-src) - metabolism src-Family Kinases - genetics src-Family Kinases - metabolism Transfection Ubiquitins Ubiquitins - metabolism
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Summary:	Src family tyrosine kinases are involved in modulating various signal transduction pathways leading to the induction of DNA synthesis and cytoskeletal reorganization in response to cell-cell or cell-matrix adhesion. The critical role of these kinases in regulating cellular signaling pathways requires that their activity be tightly controlled. Src family proteins are regulated through reversible phosphorylation and dephosphorylation events that alter the conformation of the kinase. We have found evidence that Src also is regulated by ubiquitination. Activated forms of Src are less stable than either wild-type or kinase-inactive Src mutants and can be stabilized by proteasome inhibitors. In addition, poly-ubiquitinated forms of active Src have been detected in vivo. Taken together, our results establish ubiquitin-mediated proteolysis as a previously unidentified mechanism for irreversibly attenuating the effects of active Src kinase.
ISSN:	0027-8424 1091-6490