c-Cbl is a suppressor of the Neu oncogene

Gil Levkowitz, Shlomo Oved, Leah N. Klapper, Daniel Harari, Sara Lavi, Michael Sela, Yosef Yarden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

A rodent oncogenic mutant of the Neu receptor tyrosine kinase is a useful experimental model because over-expression 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.

Original languageEnglish
Pages (from-to)35532-35539
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number45
DOIs
StatePublished - 10 Nov 2000
Externally publishedYes

Funding

FundersFunder number
National Cancer InstituteR01CA072981

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