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 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.
Harris
K F
KF
Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Shoji
I
I
Cooper
E M
EM
Kumar
S
S
Oda
H
H
Howley
P M
PM
D000818:Animals; D019556:COS Cells; D000081247:CSK Tyrosine-Protein Kinase; D002645:Chickens; D004789:Enzyme Activation; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D014452:Ubiquitins; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D015688:Oncogene Protein pp60(v-src); D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases