c-Cbl is a suppressor of the Neu oncogene

A rodent oncogenic mutant of the Neu receptor tyrosine kinase is a useful e xperimental 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 as sociated with the product of the c-cbl proto-oncogene and is part of a larg e complex that includes the phosphoinositide 3-kinase and Shc. Ectopic expr ession of c-Cbl, a ubiquitin-protein isopeptide ligase specific to activate d tyrosine kinases, causes rapid removal of Neu from the cell surface-and s everely reduces signaling downstream of oncogenic Neu. c-Cbl-induced down-r egulation of Neu involves covalent attachment of ubiquitin molecules and re quires 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. I n an in vivo model, infection of a Neu-transformed neuroblastoma with: a c- Cbl-encoding retrovirus caused enhanced down-regulation of Neu and correlat ed with tumor retardation. Our results implicate c-Cbl in negative regulati on of Neu and offer a potential target for treatment of HER2/ErbB-2-positiv e human malignancies.