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The Tyrosine Kinase Negative Regulator c-Cbl as a RING-Type, E2-Dependent Ubiquitin-Protein Ligase
Claudio A. P. Joazeiro, Simon S. Wing, Han-kuei Huang, Joel D. Leverson, Tony Hunter and Yun-Cai Liu
New Series, Vol. 286, No. 5438 (Oct. 8, 1999), pp. 309-312
Published by: American Association for the Advancement of Science
Stable URL: http://www.jstor.org/stable/2899695
Page Count: 4
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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.
Science © 1999 American Association for the Advancement of Science