c-Cbl is a suppressor of the Neu oncogene

被引:63
作者
Levkowitz, G
Oved, S
Klapper, LN
Harari, D
Lavi, S
Sela, M
Yarden, Y [1 ]
机构
[1] Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel
[2] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel
关键词
D O I
10.1074/jbc.M002661200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:35532 / 35539
页数:8
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