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Epidermal growth factor receptor exposed to cigarette smoke is aberrantly activated and undergoes perinuclear trafficking
Author(s) -
Khan Elaine M.,
Lanir Roni,
Danielson Aaron R.,
Goldkorn Tzipora
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7729com
Subject(s) - epidermal growth factor receptor , microbiology and biotechnology , ubiquitin ligase , protein kinase b , chemistry , growth factor receptor , amphiregulin , growth factor , ubiquitin , receptor , phosphorylation , cancer research , signal transduction , biology , biochemistry , gene
Exposure to hydrogen peroxide (H 2 O 2 ), one of the reactive oxidants in the gas phase of cigarette smoke (CS), induces aberrant phosphorylation of the epidermal growth factor receptor (EGFR), resulting in the lack of ubiquitination by c‐Cbl, and impaired degradation. EGFR activation without the feedback regulation of normal degradation leads to uncontrolled cell growth and tumor promotion. Using immunoprecipitation, immuno‐blotting, and confocal microscopy, we now demonstrate that the pattern of EGFR activation by CS is similar to H 2 O 2 . We found that exposure of human airway epithelial cells to CS, as with exposure to H 2 O 2 , not only results in an increase in EGFR activation over time, but the EGFR activated by H 2 O 2 or CS is neither ubiquitinated nor subsequently degraded due to its inability to bind the E3 ubiquitin ligase, c‐Cbl, either directly or indirectly via the Grb2 adapter protein. Moreover, the stabilized H 2 O 2 ‐ and CS‐activated EGFR remains plasma membrane‐bound, while a population of the receptor is trafficked to a perinuclear region. Concomitantly, CS exposure results in the activation of downstream Akt and ERK1/2 survival and proliferation pathways. Therefore, exposure to CS, like exposure to H 2 O 2, results in prolonged signaling by the EGFR and may contribute to uncontrolled lung cell growth.—Khan, E. M., Lanir, R., Danielson, A. R., Goldkorn, T. Epidermal growth factor receptor exposed to cigarette smoke is aberrantly activated and undergoes perinuclear trafficking. FASEB J . 22, 910–917 (2008)