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Science 286 (5438): 309-312

Copyright © 1999 by the American Association for the Advancement of Science

The Tyrosine Kinase Negative Regulator c-Cbl as a RING-Type, E2-Dependent Ubiquitin-Protein Ligase

Claudio A. P. Joazeiro, 1 Simon S. Wing, 2 Han-kuei Huang, 1 Joel D. Leverson, 1 Tony Hunter, 1* Yun-Cai Liu 3

Ubiquitination of receptor protein-tyrosine kinases (RPTKs) terminates signaling by marking active receptors for degradation. c-Cbl, an adapter protein for RPTKs, positively regulates RPTK ubiquitination in a manner dependent on its variant SRC homology 2 (SH2) and RING finger domains. Ubiquitin-protein ligases (or E3s) are the components of ubiquitination pathways that recognize target substrates and promote their ligation to ubiquitin. The c-Cbl protein acted as an E3 that can recognize tyrosine-phosphorylated substrates, such as the activated platelet-derived growth factor receptor, through its SH2 domain and that recruits and allosterically activates an E2 ubiquitin-conjugating enzyme through its RING domain. These results reveal an SH2-containing protein that functions as a ubiquitin-protein ligase and thus provide a distinct mechanism for substrate targeting in the ubiquitin system.

1 The Salk Institute, Molecular Biology and Virology Laboratory, La Jolla, CA 92037, USA.
2 Department of Medicine, McGill University, Montreal, Quebec H3A 2B2, Canada.
3 La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
*   To whom correspondence should be addressed. E-mail: hunter{at}salk.edu

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Regulation of the Src Family Kinase Lck by Hsp90 and Ubiquitination.
A. Giannini and M.-J. Bijlmakers (2004)
Mol. Cell. Biol. 24, 5667-5676
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