Related Experiment Videos
The c-Cbl oncoprotein
M L Lupher1, C E Andoniou, D Bonita
1Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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.
Insights
Cbl protein regulates tyrosine kinase signaling pathways. Oncogenic Cbl mutants activate signaling, suggesting therapeutic potential for controlling tyrosine kinases.
Area of Science:
- Molecular Biology
- Cell Signaling
- Oncogenesis
Background:
- Cbl is a signal transducing protein downstream of tyrosine kinase receptors.
- It is the product of the c-cbl proto-oncogene and has distinct functional domains (Cbl-N and Cbl-C).
- Wild-type Cbl is non-transforming, while certain deletions render it oncogenic.
Purpose of the Study:
- To elucidate the role of Cbl in tyrosine kinase signaling pathways.
- To investigate the function of Cbl domains and its interaction with other signaling molecules.
- To explore the therapeutic potential of targeting Cbl in cancer.
Main Methods:
- Analysis of Cbl protein structure and function, including domain deletions.
- Investigating Cbl's interaction with tyrosine kinases and adaptor proteins (Grb2, Crk, PI-3-kinase).
- Studying Cbl homologs in model organisms (C. elegans, Drosophila) and oncogenic Cbl mutant effects in fibroblasts.
Main Results:
- Cbl acts as a substrate for tyrosine kinases and binds to key signaling adaptors.
- Oncogenic Cbl mutants, particularly those with deletions, activate signaling cascades.
- Cbl homologs function as negative regulators of receptor tyrosine kinases in model organisms.
Conclusions:
- Cbl is a central regulator of tyrosine kinase signaling.
- Understanding Cbl's regulatory mechanisms and binding motifs offers therapeutic avenues.
- Targeting Cbl may provide novel strategies for controlling aberrant tyrosine kinase activity in diseases like cancer.