The c-Cbl oncoprotein

Int J Biochem Cell Biol. 1998 Apr;30(4):439-44. doi: 10.1016/s1357-2725(97)00075-7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Caenorhabditis elegans
  • Drosophila
  • Humans
  • Protein-Tyrosine Kinases / physiology
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-cbl
  • Signal Transduction*
  • Ubiquitin-Protein Ligases*

Substances

  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Protein-Tyrosine Kinases
  • CBL protein, human