Cbl: Complex formation and functional implications

Cbl, a 120-kDa proto-oncogene product, whose gene was first identified as part of a transforming gene of a murine retrovirus and whose expression is predominant in haematopoietic cells, consists of an aminoterminal transforming region, a zinc Ring finger, multiple proline-rich stretches, and several potential phosphotyrosine containing motifs. Cbl is rapidly tyrosine-phosphorylated in response to stimulation of a variety of cell-surface receptors and becomes associated with a number of intracellular signalling molecules such as protein tyrosine kinases, phosphatidylinositol 3-kinase, Crk, and 14-3-3 proteins through different protein-interacting modules, leading to the formation of multimolecular signalling complexes. Cbl and its transforming mutants have been shown to display both negative and positive regulatory activities in protein tyrosine kinase- and Ras-mediated signalling pathways. Nevertheless, the exact biological function of this adaptor protein remains largely unknown. The present review summarizes recent progress in our understanding of the structure, regulation and biological function of Cbl and defines open questions for future research. (C) 1998 Elsevier Science Inc.