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c-Cbl is a suppressor of the neu oncogene
G Levkowitz1, S Oved, L N Klapper
1Departments of Biological Regulation and Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Abstract:
A rodent oncogenic mutant of the Neu receptor tyrosine kinase is a useful experimental model because overexpression of the respective receptor, namely HER2/ErbB-2, in human malignancies is associated with relatively aggressive diseases. Here we show that the oncogenic form of Neu is constitutively associated with the product of the c-cbl proto-oncogene and is part of a large complex that includes the phosphoinositide 3-kinase and Shc. Ectopic expression of c-Cbl, a ubiquitin-protein isopeptide ligase specific to activated tyrosine kinases, causes rapid removal of Neu from the cell surface and severely reduces signaling downstream of oncogenic Neu. c-Cbl-induced down-regulation of Neu involves covalent attachment of ubiquitin molecules and requires the carboxyl-terminal domain of Neu. The negative effect of c-Cbl is antagonized by v-Cbl, a virus-encoded oncogenic truncated form of c-Cbl. In an in vivo model, infection of a Neu-transformed neuroblastoma with a c-Cbl-encoding retrovirus caused enhanced down-regulation of Neu and correlated with tumor retardation. Our results implicate c-Cbl in negative regulation of Neu and offer a potential target for treatment of HER2/ErbB-2-positive human malignancies.
Insights
The c-Cbl protein targets the oncogenic Neu receptor tyrosine kinase for degradation, reducing tumor growth. This discovery offers a potential therapeutic strategy for HER2/ErbB-2-positive cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- The Neu receptor tyrosine kinase (also known as HER2/ErbB-2) is implicated in aggressive human malignancies when overexpressed.
- Understanding the regulatory mechanisms of oncogenic receptor tyrosine kinases is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of the c-Cbl proto-oncogene in the regulation of the oncogenic Neu receptor tyrosine kinase.
- To explore the potential of c-Cbl as a therapeutic target for HER2/ErbB-2-positive cancers.
Main Methods:
- Investigated the association of oncogenic Neu with c-Cbl using biochemical assays.
- Examined the effect of ectopic c-Cbl expression on Neu localization, signaling, and ubiquitination.
- Assessed tumor retardation in an in vivo model following c-Cbl retroviral infection.
Main Results:
- Oncogenic Neu constitutively associates with c-Cbl and is part of a larger signaling complex.
- Ectopic c-Cbl expression leads to Neu ubiquitination, removal from the cell surface, and reduced downstream signaling.
- c-Cbl expression in a Neu-transformed neuroblastoma model resulted in tumor retardation in vivo.
Conclusions:
- c-Cbl negatively regulates oncogenic Neu receptor tyrosine kinase activity and promotes its degradation.
- c-Cbl represents a promising therapeutic target for HER2/ErbB-2-positive human malignancies.