Molecules in focus: The c-Cbl oncoprotein

Mark L. Lupher, Christopher E. Andoniou, David Bonita, Sachiko Miyake, Hamid Band

Research output: Contribution to journalArticle

56 Citations (Scopus)

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 Caenorhahditis 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 α 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.

Original languageEnglish (US)
Pages (from-to)439-444
Number of pages6
JournalInternational Journal of Biochemistry and Cell Biology
Volume30
Issue number4
DOIs
StatePublished - Apr 30 1998

Fingerprint

Oncogene Proteins
Protein-Tyrosine Kinases
Phosphotyrosine
Molecules
Proto-Oncogene Proteins c-cbl
RING Finger Domains
Linear Energy Transfer
Platelet-Derived Growth Factor Receptors
Leucine Zippers
Proteins
Receptor Protein-Tyrosine Kinases
Cell Surface Receptors
Retroviridae
Fibroblasts
Phosphatidylinositol 3-Kinases
Oncogenes
Proline
Drosophila
Up-Regulation
Genes

Keywords

  • Signal transduction

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Molecules in focus : The c-Cbl oncoprotein. / Lupher, Mark L.; Andoniou, Christopher E.; Bonita, David; Miyake, Sachiko; Band, Hamid.

In: International Journal of Biochemistry and Cell Biology, Vol. 30, No. 4, 30.04.1998, p. 439-444.

Research output: Contribution to journalArticle

Lupher, Mark L. ; Andoniou, Christopher E. ; Bonita, David ; Miyake, Sachiko ; Band, Hamid. / Molecules in focus : The c-Cbl oncoprotein. In: International Journal of Biochemistry and Cell Biology. 1998 ; Vol. 30, No. 4. pp. 439-444.
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