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.
Shtiegman
K
K
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Kochupurakkal
B S
BS
Zwang
Y
Y
Pines
G
G
Starr
A
A
Vexler
A
A
Citri
A
A
Katz
M
M
Lavi
S
S
Ben-Basat
Y
Y
Benjamin
S
S
Corso
S
S
Gan
J
J
Yosef
R B
RB
Giordano
S
S
Yarden
Y
Y
D019921:Biotinylation; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019281:Dimerization; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
D066246:ErbB Receptors; D050721:Proto-Oncogene Proteins c-cbl; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; D025801:Ubiquitin; C067419:CBL protein, human