Src-catalyzed phosphorylation of c-Cbl leads to the interdependent ubiquitination of both proteins.
The protooncogene c-Cbl has recently emerged as an E3 ubiquitin ligase for activated receptor tyrosine kinases. We report here that c-Cbl also mediates the ubiquitination of another protooncogene, the non-receptor tyrosine kinase c-Src, as well as of itself. The c-Cbl-dependent ubiquitination of Src and c-Cbl requires c-Cbl's RING finger, Src kinase activity, and c-Cbl's tyrosine phosphorylation, probably on Tyr-371. In vitro, c-Cbl forms a stable complex with the ubiquitin-conjugating enzyme UbcH7, but active Src destabilizes this interaction. In contrast, Src inhibition stabilizes the c-Cbl. UbcH7.Src complex. Finally, c-Cbl reduces v-Src protein levels and suppresses v-Src-induced STAT3 activation. Thus, in addition to mediating the ubiquitination of activated receptor tyrosine kinases, c-Cbl also acts as a ubiquitin ligase for the non-receptor tyrosine kinase Src, thereby down-regulating Src.
Yokouchi
M
M
Departments of Cell Biology, Orthopaedics, and Genetics, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
Kondo
T
T
Sanjay
A
A
Houghton
A
A
Yoshimura
A
A
Komiya
S
S
Zhang
H
H
Baron
R
R
D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation; D015688:Oncogene Protein pp60(v-src) / Q000032:analysis; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism*; D019061:src-Family Kinases / Q000502:physiology*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D014452:Ubiquitins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D015688:Oncogene Protein pp60(v-src); D019061:src-Family Kinases