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Epidermal growth factor receptor exposed to cigarette smoke is aberrantly activated and undergoes perinuclear trafficking

Signal Transduction Laboratory, Department of Internal Medicine, University of California, School of Medicine, Davis, California, USA

¹Correspondence: Signal Transduction Laboratory, Department of Internal Medicine, University of California, Genome and Biomedical Sciences Facility, Rm. 6321, 451 E. Health Sciences Dr., Davis, California, 95616. E-mail: ttgoldkorn{at}ucdavis.edu

Exposure to hydrogen peroxide (H₂O₂), 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, immunoblotting, and confocal microscopy, we now demonstrate that the pattern of EGFR activation by CS is similar to H₂O₂. We found that exposure of human airway epithelial cells to CS, as with exposure to H₂O₂, not only results in an increase in EGFR activation over time, but the EGFR activated by H₂O₂ 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 H₂O₂- 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 H₂O_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.

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Regarding detection of hydrogen peroxide in cigarette smoke

I. B. Chatterjee and Neekam Dey
FASEB J 2008 22: 3755. [Full Text] [PDF]

This article has been cited by other articles:

				I. B. Chatterjee and N. Dey Regarding detection of hydrogen peroxide in cigarette smoke FASEB J, November 1, 2008; 22(11): 3755 - 3755. [Full Text] [PDF]

				E. M. Khan and T. Goldkorn Response to: "Regarding detection of hydrogen peroxide in cigarette smoke" FASEB J, November 1, 2008; 22(11): 3755 - 3756. [Full Text] [PDF]