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  • Title: Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling.
    Author: Shtiegman K, Kochupurakkal BS, Zwang Y, Pines G, Starr A, Vexler A, Citri A, Katz M, Lavi S, Ben-Basat Y, Benjamin S, Corso S, Gan J, Yosef RB, Giordano S, Yarden Y.
    Journal: Oncogene; 2007 Oct 25; 26(49):6968-78. PubMed ID: 17486068.
    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.
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