THE C-CBL ONCOPROTEIN

Cbl has emerged as a novel signal transducing protein downstream of a number of cell surface receptors coupled to tyrosine kinases. Identifi ed as the protein product of the c-cbl proto-oncogene, the cellular ho molog to the transforming gene of a murine retrovirus, Cbl comprises a n N-terminal transforming region (Cbl-N), which contains a phosphotyro sine binding (PTB) domain, and a C-terminal modular region (Cbl-C) con taining a RING finger motif, a large proline-rich region and a leucine zipper. Deletion of Cbl-C or small deletions N-terminal to the RING f inger render Cbl oncogenic, whereas wild type Cbl is non-transforming, even if overexpressed. Cbl serves as a substrate of both receptor and non-receptor tyrosine kinases, and binds to adaptor proteins Grb2, Cr k and the p85 subunit of PI-3-kinase. Additionally, both Caenorhabditi s elegans and Drosophila Cbl homologs, SLI-1 and D-Cbl, respectively, have been identified as negative regulators of the LET-73/DER receptor tyrosine kinases. Finally, oncogenic mutants of Cbl, when expressed i n fibroblasts, upregulate the signaling cascade downstream of the plat elet-derived growth factor receptor alpha in a Cbl-PTB domain-dependen t manner. Together, these findings position Cbl as a central player in the regulation of tyrosine kinase signaling pathways. Identification of the Cbl-PTB domain binding motifs on tyrosine kinases and elucidati on of the mechanisms of Cbl's negative regulatory effect may provide a new avenue to control tyrosine kinases for therapeutic purposes. (C) 1998 Elsevier Science Ltd. All rights reserved.