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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

122 Scopus citations


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 languageAmerican English
Pages (from-to)6968-6978
Number of pages11
Issue number49
StatePublished - 25 Oct 2007
Externally publishedYes

Bibliographical note

Funding Information:
We thank Drs Wallace Langdon and Dirk Bohmann for plasmids. Our laboratory is supported by research grants from the National Cancer Institute (grant CA72981, to YY), the Israel Cancer Research Fund and the German-Israel Foundation. YY is the incumbent of the Harold and Zelda Gold-enberg Professorial Chair.


  • Endocytosis
  • Gefitinib
  • Growth factor
  • Tyrosine kinase


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