Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Biotinylation
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Dimerization
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Down-Regulation
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Humans
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Immunoblotting
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Immunoprecipitation
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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Lysosomes / metabolism*
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Mutagenesis, Site-Directed
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Mutation
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / metabolism
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism
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STAT3 Transcription Factor
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Signal Transduction / physiology*
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Transcription, Genetic
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Ubiquitin / metabolism*
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Ubiquitination
Substances
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STAT3 Transcription Factor
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Ubiquitin
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Proto-Oncogene Proteins c-cbl
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ErbB Receptors
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Receptor, ErbB-2
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CBL protein, human