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

Elaine M. Khan, Roni Lanir, Aaron Danielson, Tzipora Goldkorn

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

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 H 2O2-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 H2O2, results in prolonged signaling by the EGFR and may contribute to uncontrolled lung cell growth.

Original languageEnglish (US)
Pages (from-to)910-917
Number of pages8
JournalFASEB Journal
Volume22
Issue number3
DOIs
StatePublished - Mar 2008

Fingerprint

cigarettes
smoke
Epidermal Growth Factor Receptor
Smoke
Tobacco Products
Chemical activation
Cell growth
cell growth
Degradation
ubiquitin-protein ligase
Phosphorylation
Ubiquitin-Protein Ligases
degradation
Confocal microscopy
Ubiquitination
Cell membranes
Growth
epidermal growth factor receptors
immunoblotting
Immunoprecipitation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Epidermal growth factor receptor exposed to cigarette smoke is aberrantly activated and undergoes perinuclear trafficking. / Khan, Elaine M.; Lanir, Roni; Danielson, Aaron; Goldkorn, Tzipora.

In: FASEB Journal, Vol. 22, No. 3, 03.2008, p. 910-917.

Research output: Contribution to journalArticle

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