Src-catalyzed Phosphorylation of c-Cbl Leads to the Interdependent Ubiquitination of Both Proteins

Masahiro Yokouchi, Takeshi Kondo, Archana Sanjay, Adam Houghton, Akihiko Yoshimura, Seturo Komiya, Hui Zhang, Roland Baron

Research output: Contribution to journalArticle

172 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)35185-35193
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number37
DOIs
Publication statusPublished - 2001 Sep 14

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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