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

168 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
Externally publishedYes

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Phosphorylation
src-Family Kinases
Ubiquitination
Receptor Protein-Tyrosine Kinases
Oncogene Protein pp60(v-src)
Ubiquitin-Conjugating Enzymes
Ubiquitin-Protein Ligases
Ligases
Ubiquitin
Tyrosine
Proteins
Chemical activation
CSK tyrosine-protein kinase

ASJC Scopus subject areas

  • Biochemistry

Cite this

Src-catalyzed Phosphorylation of c-Cbl Leads to the Interdependent Ubiquitination of Both Proteins. / Yokouchi, Masahiro; Kondo, Takeshi; Sanjay, Archana; Houghton, Adam; Yoshimura, Akihiko; Komiya, Seturo; Zhang, Hui; Baron, Roland.

In: Journal of Biological Chemistry, Vol. 276, No. 37, 14.09.2001, p. 35185-35193.

Research output: Contribution to journalArticle

Yokouchi, M, Kondo, T, Sanjay, A, Houghton, A, Yoshimura, A, Komiya, S, Zhang, H & Baron, R 2001, 'Src-catalyzed Phosphorylation of c-Cbl Leads to the Interdependent Ubiquitination of Both Proteins', Journal of Biological Chemistry, vol. 276, no. 37, pp. 35185-35193. https://doi.org/10.1074/jbc.M102219200
Yokouchi, Masahiro ; Kondo, Takeshi ; Sanjay, Archana ; Houghton, Adam ; Yoshimura, Akihiko ; Komiya, Seturo ; Zhang, Hui ; Baron, Roland. / Src-catalyzed Phosphorylation of c-Cbl Leads to the Interdependent Ubiquitination of Both Proteins. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 37. pp. 35185-35193.
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