: The c-CbI protooncogene was isolated as a cellular homologue of v-Cbl oncogene. The 120-kDa product of c-CbI, CbI, is composed of an amino-terminal variant SH2 domain, a RING finger, and a carboxy terminal proline-rich domain with potential tyrosine phosphorylation sites. CbI is rapidly tyrosine phosphorylated upon engagement of a wide range of cell surface receptors including T cell antigen receptor (TCR), suggesting its role in signal transduction. Numerous biochemical studies have showed that Cbl acts as an adaptor protein by interacting with protein tyrosine kinases and other critical signal molecules to form Cbl complexes. Genetic studies showed that Cbl is a negative regulator in TCR-mediated signaling and is involved in fine-tuning of the signals required for thymocyte development. One of the most recent significant developments is the discovery that Cbl functions as an E3 ubiquitin (Ub) ligase, whose RING finger recruit Ub conjugation enzyme and whose variant SH2 domain binds to activated receptor tyrosine kinases, and that Cbl then facilitates Ub conjugation to the protein tyrosine kinases it associates with. However, the molecular mechanisms that link Cbl E3 Ub ligase activity and its negative regulation of T cell development and activation remain unclear. The working hypotheses which serve as a basis for this application of competitive renewal are that: First, Cbl, both as an adaptor protein and an E3 ligase, targets protein substrates for Ub conjugation through the interaction of Cbl protein binding domains and through the RING finger-dependent recruitment of Ubc E2s; Second, Cbl negatively regulates intracellular signal transduction in thymocytes and peripheral T cells via ubiquitination of its binding proteins; and Third, Cbl, as an E3 Ub ligase, is involved in the thymocyte development and the generation of hyporesponsive peripheral T cells. Deficiency of Cbl may change the threshold of T cell activation and induce breakdown of self-tolerance and the onset of autoimmune responses. The long-term goal is to understand how Cbl is involved in T cell tolerance induction under physiological conditions and the development of abnormal immune responses under pathological conditions, which may lead to new therapeutic approaches for the treatment of immunological diseases.
