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Am J Physiol Lung Cell Mol Physiol 282: L1040-L1048, 2002; doi:10.1152/ajplung.00390.2001
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Vol. 282, Issue 5, L1040-L1048, May 2002

Role of Ras in metal-induced EGF receptor signaling and NF-kappa B activation in human airway epithelial cells

Weidong Wu1, Ilona Jaspers1, Wenli Zhang1, Lee M. Graves2, and James M. Samet3

1 Center for Environmental Medicine and Lung Biology and 2 Department of Pharmacology, University of North Carolina, Chapel Hill 27599; and 3 Human Studies Division, National Health Effects and Environmental Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711

We showed previously that epithelial growth factor (EGF) receptor (EGFR) signaling is triggered by metallic compounds associated with ambient air particles. Specifically, we demonstrated that As, Zn, and V activated the EGFR tyrosine kinase and the downstream kinases MEK1/2 and ERK1/2. In this study, we examined the role of Ras in EGFR signaling and the nuclear factor-kappa B (NF-kappa B) activation pathway and the possible interaction between these two signaling pathways in a human airway epithelial cell line (BEAS-2B) exposed to As, V, or Zn ions. Each metal significantly increased Ras activity, and this effect was inhibited by the EGFR tyrosine kinase activity inhibitor PD-153035. Adenoviral-mediated overexpression of a dominant-negative mutant form of Ras(N17) significantly blocked MEK1/2 or ERK1/2 phosphorylation in As-, Zn-, or V-exposed BEAS-2B cells but caused little inhibition of V-, Zn- or EGF-induced EGFR tyrosine phosphorylation. This confirmed Ras as an important intermediate effector in EGFR signaling. Interestingly, V, but not As, Zn, or EGF, induced Ikappa Balpha serine phosphorylation, Ikappa Balpha breakdown, and NF-kappa B DNA binding. Moreover, PD-153035 and overexpression of Ras(N17) each significantly blocked V-induced Ikappa Balpha breakdown and NF-kappa B activation, while inhibition of MEK activity with PD-98059 failed to do so. In summary, exposure to As, Zn, and V initiated EGFR signaling and Ras-dependent activation of MEK1/2 and ERK1/2, but only V induced Ras-dependent NF-kappa B nuclear translocation. EGFR signaling appears to cross talk with NF-kappa B signaling at the level of Ras, but additional signals appear necessary for NF-kappa B activation. Together, these data suggest that, in V-treated BEAS-2B cells, Ras-dependent signaling is essential, but not sufficient, for activation of NF-kappa B.

G proteins; epidermal growth factor receptor; nuclear factor-kappa B; mitogen-activated protein kinases; air pollution


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