c-Cbl: A regulator of T cell receptor-mediated signalling

The 120-kDa protein product of the c-Cbl proto-oncogene is a ubiquitously expressed cytoplasmic protein that is especially abundant in the thymus, indicating an important role for Cbl in thymic signalling. c-Cbl possesses a highly conserved N-terminal phosphotyrosine binding domain, a C3HC4 RING finger motif, multiple proline-rich motifs, and a number of potential tyrosine phosphorylation sites. Cbl is an early and prominent substrate of protein tyrosine kinases following stimulation of a variety of cell surface receptors, and forms constitutive and inducible associations with a wide range of signalling intermediates. Genetic studies of the Cbl homologue Sli-1 in Caenorhabditis elegans predicted a role for Cbl as a negative regulator of protein tyrosine kinase-mediated signalling pathways. Numerous studies have now shown that expression of Cbl and its oncogenic variants can indeed modulate signalling from activated protein tyrosine kinases. The present review highlights some of the recent developments in our understanding of Cbl function, with particular reference to its participation and possible roles in TCR-mediated signalling.