Wu, Weidong, Ilona Jaspers, Wenli Zhang, Lee M. Graves, and James M. Samet. Role of Ras in metal-induced EGF receptor signaling and NF-B activation in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 282: L1040-L1048, 2002 10.1152/ajplung.00390.2001.-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

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... e 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-B (NF-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 IB␣ serine phosphorylation, IB␣ breakdown, and NF-B DNA binding. Moreover, PD-153035 and overexpression of Ras(N17) each significantly blocked V-induced IB␣ breakdown and NF-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-B nuclear translocation. EGFR signaling appears to cross talk with NF-B signaling at the level of Ras, but additional signals appear necessary for NF-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-B. G proteins; epidermal growth factor receptor; nuclear factor-B; mitogen-activated protein kinases; air pollution Address for reprint requests and other correspondence: J. M. Samet, Human Studies Div.,