Journal
ONCOGENE
Volume 26, Issue 49, Pages 6968-6978Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210503
Keywords
endocytosis; Gefitinib; growth factor; NSCLC; tyrosine kinase
Funding
- NCI NIH HHS [CA72981] Funding Source: Medline
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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.
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