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. Identified as the protein product of the c-cbl proto-oncogene, the cellular homolog to the transforming gene of a murine retrovirus, Cbl comprises an N-terminal transforming region (Cbl-N), which contains a phosphotyrosine binding (PTB) domain, and a C-terminal modular region (Cbl-C) containing 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 finger 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, Crk and the p85 subunit of PI-3-kinase. Additionally, both Caenorhabditis elegans and Drosophila Cbl homologs, SLI-1 and D-Cbl, respectively, have been identified as negative regulators of the LET-23/DER receptor tyrosine kinases. Finally, oncogenic mutants of Cbl, when expressed in fibroblasts, upregulate the signaling cascade downstream of the platelet-derived growth factor receptor alpha in a Cbl-PTB domain-dependent 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 elucidation of the mechanisms of Cbl's negative regulatory effect may provide a new avenue to control tyrosine kinases for therapeutic purposes.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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Lupher
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Andoniou
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Bonita
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Miyake
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D000818:Animals; D017173:Caenorhabditis elegans; D004330:Drosophila; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C067419:CBL protein, human