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J. Biol. Chem. 276 (37): 35185-35193

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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

Masahiro YokouchiDagger §||, Takeshi Kondo**, Archana SanjayDagger §Dagger Dagger , Adam HoughtonDagger §Dagger Dagger , Akihiko Yoshimura§§, Seturo Komiya, Hui Zhang**, and Roland BaronDagger §¶¶

From the Departments of Dagger  Cell Biology, § Orthopaedics, and ** Genetics, Yale University School of Medicine, New Haven, Connecticut 06511, the  Department of Orthopaedic Surgery, Faculty of Medicine, Kagoshima University, Kagoshima 890-8520, Japan, and §§ Institute of Life Science, Kurume University, Kurume 893-0861, Japan

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.

* This work was supported by Grant AR-42927 from the NIAMS and The Office of Research on Women's Health, National Institutes of Health (NIH) (to R.B.) and by NIH Grant CA-72878 (to H.Z.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| Recipient of fellowships from the Japan Society for the Promotion of Science and from the Hip Joint Foundation of Japan, Inc.

Dagger Dagger Recipients of post-doctoral fellowships from the Arthritis Foundation.

¶¶ To whom correspondence should be addressed: Depts. of Cell Biology and Orthopaedics, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510. Tel.: 203-785-4150; Fax: 203-785-2744; E-mail: roland.baron@yale.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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