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Science 8 October 1999:
Vol. 286. no. 5438, pp. 309 - 312
DOI: 10.1126/science.286.5438.309
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Reports

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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A Novel E3 Ubiquitin Ligase TRAC-1 Positively Regulates T Cell Activation.
H. Zhao, C. C. Li, J. Pardo, P. C. Chu, C. X. Liao, J. Huang, J. G. Dong, X. Zhou, Q. Huang, B. Huang, et al. (2005)
J. Immunol. 174, 5288-5297
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Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT.
J. H. Kim, S.-M. Park, M. R. Kang, S.-Y. Oh, T. H. Lee, M. T. Muller, and I. K. Chung (2005)
Genes & Dev. 19, 776-781
   Abstract »    Full Text »    PDF »
Cbl-mediated ubiquitination of {alpha}5 integrin subunit mediates fibronectin-dependent osteoblast detachment and apoptosis induced by FGFR2 activation.
K. Kaabeche, H. Guenou, D. Bouvard, N. Didelot, A. Listrat, and P. J. Marie (2005)
J. Cell Sci. 118, 1223-1232
   Abstract »    Full Text »    PDF »
Phosphorylation of Carboxyl-terminal Tyrosines Modulates the Specificity of Sprouty-2 Inhibition of Different Signaling Pathways.
C. Rubin, Y. Zwang, N. Vaisman, D. Ron, and Y. Yarden (2005)
J. Biol. Chem. 280, 9735-9744
   Abstract »    Full Text »    PDF »
The Saccharomyces cerevisiae Peroxisomal Import Receptor Pex5p Is Monoubiquitinated in Wild Type Cells.
A. Kragt, T. Voorn-Brouwer, M. van den Berg, and B. Distel (2005)
J. Biol. Chem. 280, 7867-7874
   Abstract »    Full Text »    PDF »
The Ubiquitin-Proteasome Pathway is Involved in Rapid Degradation of Phosphoenolpyruvate Carboxylase Kinase for C4 Photosynthesis.
M. Agetsuma, T. Furumoto, S. Yanagisawa, and K. Izui (2005)
Plant Cell Physiol. 46, 389-398
   Abstract »    Full Text »    PDF »
E3 ubiquitin ligase activity of the trifunctional ARD1 (ADP-ribosylation factor domain protein 1).
A. Vichi, D. M. Payne, G. Pacheco-Rodriguez, J. Moss, and M. Vaughan (2005)
PNAS 102, 1945-1950
   Abstract »    Full Text »    PDF »
X-Linked Inhibitor of Apoptosis Functions as Ubiquitin Ligase toward Mature Caspase-9 and Cytosolic Smac/DIABLO.
Y. Morizane, R. Honda, K. Fukami, and H. Yasuda (2005)
J. Biochem. 137, 125-132
   Abstract »    Full Text »    PDF »
The Poxviral RING Protein p28 Is a Ubiquitin Ligase That Targets Ubiquitin to Viral Replication Factories.
B. T. H. Nerenberg, J. Taylor, E. Bartee, K. Gouveia, M. Barry, and K. Fruh (2005)
J. Virol. 79, 597-601
   Abstract »    Full Text »    PDF »
Functional Analysis of the RING-Type Ubiquitin Ligase Family of Arabidopsis.
S. L. Stone, H. Hauksdottir, A. Troy, J. Herschleb, E. Kraft, and J. Callis (2005)
Plant Physiology 137, 13-30
   Abstract »    Full Text »    PDF »
Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl).
S. Zeng, Z. Xu, S. Lipkowitz, and J. B. Longley (2005)
Blood 105, 226-232
   Abstract »    Full Text »    PDF »
Ubiquitin Ligase Activity of c-Cbl Guides the Epidermal Growth Factor Receptor into Clathrin-coated Pits by Two Distinct Modes of Eps15 Recruitment.
A. A. de Melker, G. van der Horst, and J. Borst (2004)
J. Biol. Chem. 279, 55465-55473
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EphrinB1 Is Essential in T-cell-T-cell Co-operation during T-cell Activation.
G. Yu, H. Luo, Y. Wu, and J. Wu (2004)
J. Biol. Chem. 279, 55531-55539
   Abstract »    Full Text »    PDF »
Muscle-specific RING finger 1 is a bona fide ubiquitin ligase that degrades cardiac troponin I.
V. Kedar, H. McDonough, R. Arya, H.-H. Li, H. A. Rockman, and C. Patterson (2004)
PNAS 101, 18135-18140
   Abstract »    Full Text »    PDF »
Solution Structure of the Kaposi's Sarcoma-associated Herpesvirus K3 N-terminal Domain Reveals a Novel E2-binding C4HC3-type RING Domain.
R. B. Dodd, M. D. Allen, S. E. Brown, C. M. Sanderson, L. M. Duncan, P. J. Lehner, M. Bycroft, and R. J. Read (2004)
J. Biol. Chem. 279, 53840-53847
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Cdc123 and Checkpoint Forkhead Associated with RING Proteins Control the Cell Cycle by Controlling eIF2{gamma} Abundance.
P. Bieganowski, K. Shilinski, P. N. Tsichlis, and C. Brenner (2004)
J. Biol. Chem. 279, 44656-44666
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A Juxtamembrane Tyrosine in the Colony Stimulating Factor-1 Receptor Regulates Ligand-induced Src Association, Receptor Kinase Function, and Down-regulation.
C. M. Rohde, J. Schrum, and A. W.-M. Lee (2004)
J. Biol. Chem. 279, 43448-43461
   Abstract »    Full Text »    PDF »
c-Cbl directs EGF receptors into an endocytic pathway that involves the ubiquitin-interacting motif of Eps15.
A. A. de Melker, G. van der Horst, and J. Borst (2004)
J. Cell Sci. 117, 5001-5012
   Abstract »    Full Text »    PDF »
Structure and Biochemical Function of a Prototypical Arabidopsis U-box Domain.
P. Andersen, B. B. Kragelund, A. N. Olsen, F. H. Larsen, N.-H. Chua, F. M. Poulsen, and K. Skriver (2004)
J. Biol. Chem. 279, 40053-40061
   Abstract »    Full Text »    PDF »


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