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ROLE OF RAS IN METAL-INDUCED EGF RECEPTOR AND NFKB SIGNALING IN HUMAN AIRWAY EPITHELIAL CELLS
Citation:
Wu, W., I. Jaspers, L. M. Graves, R. B. Devlin, AND J M. Samet. ROLE OF RAS IN METAL-INDUCED EGF RECEPTOR AND NFKB SIGNALING IN HUMAN AIRWAY EPITHELIAL CELLS. Presented at American Thoracic Society Annual Meeting, San Francisco, CA, May 18-23, 2001.
Description:
We have shown previously that EGF receptor signaling is triggered by some metals associated with ambient air particles. Western blot using phospho-specific antibodies showed that As, Zn and V activated EGF receptor tyrosine kinase and the downstream kinases, MEK1/2 and ERK1/2. Using BEAS-2B cells infected with dominant negative Ras(N17) we examined the role of Ras in EGF receptor and NF B signaling , and the possible interaction between these two signaling pathways during exposure to As, V and Zn in this study. All three metals significantly increased Ras activity. The EGF receptor tyrosine kinase inhibitor, PD153035, significantly blocked the activation of Ras. Expression 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 EGF receptor tyrosine phosphorylation. This implicated Ras as an important effector in EGF receptor signaling. Mobility shift assay indicated that of the three metals only V caused NF B nuclear translocation. This was suppressed by the Ras(N17), as was V-induced I B breakdown. However, inhibition of MEK activity with PD98059 failed to inhibit V-induced NF B activation. Thus, all three metals initiated EGF receptor signaling, but only V induced Ras-dependent NF B nuclear translocation. EGF receptor signaling appears to cross-talk with NF B signaling through activated Ras, but additional signals appear necessary for NF B activation. These signals are provided V, but not by As or Zn, and may involve oxidants. This abstract does not necessarily reflect EPA policy. Environmental Protection Agency Grant CR 817643