Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling

K. Shtiegman, B. S. Kochupurakkal, Y. Zwang, G. Pines, A. Starr, A. Vexler, A. Citri, M. Katz, S. Lavi, Y. Ben-Basat, S. Benjamin, S. Corso, J. Gan, R. B. Yosef, S. Giordano, Y. Yarden

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)6968-6978
Number of pages11
Issue number49
Publication statusPublished - Oct 25 2007


  • Endocytosis
  • Gefitinib
  • Growth factor
  • Tyrosine kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics


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