c-Cbl is a suppressor of the neu oncogene.
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.
Mesh Terms:
3T3 Cells, Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, Antibodies, Monoclonal, Biotinylation, CHO Cells, Cell Line, Cricetinae, DNA, Complementary, DNA-Binding Proteins, Down-Regulation, Electrophoresis, Polyacrylamide Gel, Fibroblasts, Humans, Immunoblotting, Ligases, Male, Mice, Mice, Nude, Neoplasm Transplantation, Neuroblastoma, Nuclear Proteins, Phosphatidylinositol 3-Kinases, Phosphorylation, Precipitin Tests, Protein Structure, Tertiary, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Rats, Receptor, erbB-2, Retroviridae, Serum Response Factor, Shc Signaling Adaptor Proteins, Signal Transduction, Time Factors, Transfection, Ubiquitin-Protein Ligases
3T3 Cells, Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, Antibodies, Monoclonal, Biotinylation, CHO Cells, Cell Line, Cricetinae, DNA, Complementary, DNA-Binding Proteins, Down-Regulation, Electrophoresis, Polyacrylamide Gel, Fibroblasts, Humans, Immunoblotting, Ligases, Male, Mice, Mice, Nude, Neoplasm Transplantation, Neuroblastoma, Nuclear Proteins, Phosphatidylinositol 3-Kinases, Phosphorylation, Precipitin Tests, Protein Structure, Tertiary, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Rats, Receptor, erbB-2, Retroviridae, Serum Response Factor, Shc Signaling Adaptor Proteins, Signal Transduction, Time Factors, Transfection, Ubiquitin-Protein Ligases
J. Biol. Chem.
Date: Nov. 10, 2000
PubMed ID: 10940298
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