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

Ubiquitination of receptor protein-tyrosine kinases (RPTKs) terminates sign aling by marking active receptors for degradation. c-Cbl, an adapter protei n for RPTKs, positively regulates RPTK ubiquitination in a manner dependent on its variant SRC homology 2 (SH2) and RING finger domains. Ubiquitin-pro tein Ligases (or E3s) are the components of ubiquitination pathways that re cognize target substrates and promote their Ligation to ubiquitin. The c-Cb l protein acted as an E3 that can recognize tyrosine-phosphorylated substra tes, such as the activated platelet-derived growth factor receptor, through its SH2 domain and that recruits and allosterically activates an E2 ubiqui tin-conjugating enzyme through its RING domain. These results reveal an SH2 -containing protein that functions as a ubiquitin-protein Ligase and thus p rovide a distinct mechanism for substrate targeting in the ubiquitin system .