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1: Science. 1999 Oct 8;286(5438):309-12.Click here to read Links
Comment in:
Science. 1999 Oct 8;286(5438):223, 225.

The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase.

Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC.

The Salk Institute, Molecular Biology and Virology Laboratory, La Jolla, CA 92037, USA.

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.

PMID: 10514377 [PubMed - indexed for MEDLINE]