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

FASEB J. 2008 Mar;22(3):910-7. doi: 10.1096/fj.06-7729com. Epub 2007 Oct 30.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Nucleus / metabolism*
  • Cell Transformation, Neoplastic
  • Dose-Response Relationship, Drug
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • ErbB Receptors / drug effects
  • ErbB Receptors / metabolism*
  • Humans
  • Hydrogen Peroxide / adverse effects
  • Hydrogen Peroxide / pharmacology*
  • Lung / cytology
  • Nicotiana*
  • Phosphorylation / drug effects
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Signal Transduction / drug effects
  • Smoke*
  • Time Factors

Substances

  • Smoke
  • Hydrogen Peroxide
  • Proto-Oncogene Proteins c-cbl
  • ErbB Receptors
  • CBL protein, human