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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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   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 »
The U-Box Protein CMPG1 Is Required for Efficient Activation of Defense Mechanisms Triggered by Multiple Resistance Genes in Tobacco and Tomato.
R. Gonzalez-Lamothe, D. I. Tsitsigiannis, A. A. Ludwig, M. Panicot, K. Shirasu, and J. D.G. Jones (2006)
PLANT CELL 18, 1067-1083
   Abstract »    Full Text »    PDF »
Elmo1 inhibits ubiquitylation of Dock180.
Y. Makino, M. Tsuda, S. Ichihara, T. Watanabe, M. Sakai, H. Sawa, K. Nagashima, S. Hatakeyama, and S. Tanaka (2006)
J. Cell Sci. 119, 923-932
   Abstract »    Full Text »    PDF »
Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change.
E. Gallagher, M. Gao, Y.-C. Liu, and M. Karin (2006)
PNAS 103, 1717-1722
   Abstract »    Full Text »    PDF »
Src-Like Adaptor Protein Regulates B Cell Development and Function.
L. L. Dragone, M. D. Myers, C. White, T. Sosinowski, and A. Weiss (2006)
J. Immunol. 176, 335-345
   Abstract »    Full Text »    PDF »
Mechanistic insight into the allosteric activation of a ubiquitin-conjugating enzyme by RING-type ubiquitin ligases.
E. Ozkan, H. Yu, and J. Deisenhofer (2005)
PNAS 102, 18890-18895
   Abstract »    Full Text »    PDF »
Active Site Residues and Amino Acid Specificity of the Ubiquitin Carrier Protein-binding RING-H2 Finger Domain.
S. Katoh, Y. Tsunoda, K. Murata, E. Minami, and E. Katoh (2005)
J. Biol. Chem. 280, 41015-41024
   Abstract »    Full Text »    PDF »
A novel dileucine lysosomal-sorting-signal mediates intracellular EGF-receptor retention independently of protein ubiquitylation.
A. Tsacoumango, S. J. Kil, L. Ma, F. D. Sonnichsen, and C. Carlin (2005)
J. Cell Sci. 118, 3959-3971
   Abstract »    Full Text »    PDF »
The Ubiquitin-Proteasome Pathway and Its Role in Cancer.
A. Mani and E. P. Gelmann (2005)
J. Clin. Oncol. 23, 4776-4789
   Abstract »    Full Text »    PDF »
Ubiquitin-dependent Degradation of Interferon Regulatory Factor-8 Mediated by Cbl Down-regulates Interleukin-12 Expression.
H. Xiong, H. Li, H. J. Kong, Y. Chen, J. Zhao, S. Xiong, B. Huang, H. Gu, L. Mayer, K. Ozato, et al. (2005)
J. Biol. Chem. 280, 23531-23539
   Abstract »    Full Text »    PDF »

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