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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}

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O. A. Bazirgan, R. M. Garza, and R. Y. Hampton (2006)
J. Biol. Chem. 281, 38989-39001
   Abstract »    Full Text »    PDF »
PDZRN3 (LNX3, SEMCAP3) is required for the differentiation of C2C12 myoblasts into myotubes.
J.-A. Ko, Y. Kimura, K. Matsuura, H. Yamamoto, T. Gondo, and M. Inui (2006)
J. Cell Sci. 119, 5106-5113
   Abstract »    Full Text »    PDF »
Genetic Ablation of the c-Cbl Ubiquitin Ligase Domain Results in Increased Energy Expenditure and Improved Insulin Action.
J. C. Molero, N. Turner, C. B.F. Thien, W. Y. Langdon, D. E. James, and G. J. Cooney (2006)
Diabetes 55, 3411-3417
   Abstract »    Full Text »    PDF »
Human SHPRH is a ubiquitin ligase for Mms2-Ubc13-dependent polyubiquitylation of proliferating cell nuclear antigen.
I. Unk, I. Hajdu, K. Fatyol, B. Szakal, A. Blastyak, V. Bermudez, J. Hurwitz, L. Prakash, S. Prakash, and L. Haracska (2006)
PNAS 103, 18107-18112
   Abstract »    Full Text »    PDF »
Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner.
L. L. Dragone, M. D. Myers, C. White, S. Gadwal, T. Sosinowski, H. Gu, and A. Weiss (2006)
PNAS 103, 18202-18207
   Abstract »    Full Text »    PDF »
Cbl-b Is a Negative Regulator of Inflammatory Cytokines Produced by IgE-Activated Mast Cells.
S. E. Gustin, C. B. F. Thien, and W. Y. Langdon (2006)
J. Immunol. 177, 5980-5989
   Abstract »    Full Text »    PDF »
Mms2-Ubc13-Dependent and -Independent Roles of Rad5 Ubiquitin Ligase in Postreplication Repair and Translesion DNA Synthesis in Saccharomyces cerevisiae.
V. Gangavarapu, L. Haracska, I. Unk, R. E. Johnson, S. Prakash, and L. Prakash (2006)
Mol. Cell. Biol. 26, 7783-7790
   Abstract »    Full Text »    PDF »
Genetic and Expression Aberrations of E3 Ubiquitin Ligases in Human Breast Cancer.
C. Chen, A. K. Seth, and A. E. Aplin (2006)
Mol. Cancer Res. 4, 695-707
   Abstract »    Full Text »    PDF »
Conjugation to Nedd8 Instigates Ubiquitylation and Down-regulation of Activated Receptor Tyrosine Kinases.
S. Oved, Y. Mosesson, Y. Zwang, E. Santonico, K. Shtiegman, M. D. Marmor, B. S. Kochupurakkal, M. Katz, S. Lavi, G. Cesareni, et al. (2006)
J. Biol. Chem. 281, 21640-21651
   Abstract »    Full Text »    PDF »
NARF, an Nemo-like Kinase (NLK)-associated Ring Finger Protein Regulates the Ubiquitylation and Degradation of T Cell Factor/Lymphoid Enhancer Factor (TCF/LEF).
M. Yamada, J. Ohnishi, B. Ohkawara, S. Iemura, K. Satoh, J. Hyodo-Miura, K. Kawachi, T. Natsume, and H. Shibuya (2006)
J. Biol. Chem. 281, 20749-20760
   Abstract »    Full Text »    PDF »
The Sjogren's Syndrome-Associated Autoantigen Ro52 Is an E3 Ligase That Regulates Proliferation and Cell Death.
A. Espinosa, W. Zhou, M. Ek, M. Hedlund, S. Brauner, K. Popovic, L. Horvath, T. Wallerskog, M. Oukka, F. Nyberg, et al. (2006)
J. Immunol. 176, 6277-6285
   Abstract »    Full Text »    PDF »
Evidence for a role of the ubiquitin-proteasome pathway in pancreatic islets..
M. D. Lopez-Avalos, V. F. Duvivier-Kali, G. Xu, S. Bonner-Weir, A. Sharma, and G. C. Weir (2006)
Diabetes 55, 1223-1231
   Abstract »    Full Text »    PDF »
The WD40 Repeats of FANCL Are Required for Fanconi Anemia Core Complex Assembly.
A. M. Gurtan, P. Stuckert, and A. D. D'Andrea (2006)
J. Biol. Chem. 281, 10896-10905
   Abstract »    Full Text »    PDF »
White Spot Syndrome Virus Open Reading Frame 222 Encodes a Viral E3 Ligase and Mediates Degradation of a Host Tumor Suppressor via Ubiquitination.
F. He, B. J. Fenner, A. K. Godwin, and J. Kwang (2006)
J. Virol. 80, 3884-3892
   Abstract »    Full Text »    PDF »
Trim-Cyclophilin A Fusion Proteins Can Restrict Human Immunodeficiency Virus Type 1 Infection at Two Distinct Phases in the Viral Life Cycle.
M. W. Yap, M. P. Dodding, and J. P. Stoye (2006)
J. Virol. 80, 4061-4067
   Abstract »    Full Text »    PDF »
Growth and Motility Inhibition of Breast Cancer Cells by Epidermal Growth Factor Receptor Degradation Is Correlated with Inactivation of Cdc42.
D. S. Hirsch, Y. Shen, and W. J. Wu (2006)
Cancer Res. 66, 3523-3530
   Abstract »    Full Text »    PDF »
Role of Ubiquitylation in Cellular Membrane Transport.
O. Staub and D. Rotin (2006)
Physiol Rev 86, 669-707
   Abstract »    Full Text »    PDF »

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