Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling.
Several distinct mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are associated with non-small cell lung cancer, but mechanisms underlying their oncogenic potential are incompletely understood. Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain ... EGFR mutants escape this regulation. Defective endocytosis characterizes a deletion mutant of EGFR, as well as a point mutant (L858R-EGFR), whose association with c-Cbl and ubiquitinylation are impaired. Our data raise the possibility that refractoriness of L858R-EGFR to downregulation is due to enhanced heterodimerization with the oncogene product HER2, which leads to persistent stimulation.
Mesh Terms:
Biotinylation, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Dimerization, Down-Regulation, Humans, Immunoblotting, Immunoprecipitation, Lung Neoplasms, Lysosomes, Mutagenesis, Site-Directed, Mutation, Proto-Oncogene Proteins c-cbl, Receptor, Epidermal Growth Factor, Receptor, erbB-2, STAT3 Transcription Factor, Signal Transduction, Transcription, Genetic, Ubiquitin, Ubiquitination
Biotinylation, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Dimerization, Down-Regulation, Humans, Immunoblotting, Immunoprecipitation, Lung Neoplasms, Lysosomes, Mutagenesis, Site-Directed, Mutation, Proto-Oncogene Proteins c-cbl, Receptor, Epidermal Growth Factor, Receptor, erbB-2, STAT3 Transcription Factor, Signal Transduction, Transcription, Genetic, Ubiquitin, Ubiquitination
Oncogene
Date: Oct. 25, 2007
PubMed ID: 17486068
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