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ROLE OF THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) IN THE ACTIVATION OF MEK INDUCED BY ZN EXPOSURE
Citation:
Samet, J M., L. M. Graves, AND W. Wu. ROLE OF THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) IN THE ACTIVATION OF MEK INDUCED BY ZN EXPOSURE. Presented at American Thoracic Society Annual Meeting, San Francisco, CA, May 18-23, 2001.
Description:
Zn is a ubiquitous ambient air pollutant typically found associated with particulate matter. Divalent Zn inhibits tyrosine phosphatases and induces EGFR- and MAPK- dependent signaling in human airway epithelial cells. To further characterize Zn-induced intracellular signaling, we used a lung fibroblast line to examine the role of EGFR in the activation of MEK following Zn exposure. The EGFR deficient B82L line untransfected or stably transfected to express wild-type EGFR (B82 WT), a truncated EGFR missing all autophosphorylation sites (B82 C'958), or a kinase activity deficient EGFR (B82 K721), was exposed to 500 uM ZnSO4 or to 100 ng/ml EGF for 20 min. MEK phosphorylation was determined using anti-phospho-MEK (P-MEK) antibodies, while EGFR phosphorylation was measured in immunoprecipitates using anti-phosphotyrosine antibodies. Treatment of B82 WT cells with either Zn or EGF resulted in a pronounced increase in levels of P-EGFR and P-MEK. In contrast, neither Zn nor EGF could induce MEK phosphorylation in cells devoid of EGFR (B82L cells). In B82 C958 cells, Zn or EGF did not cause phosphorylation of EGFR but did increase levels of P-MEK. Exposure of B82 K721 cells to either Zn or EGF induced EGFR phosphorylation, but only Zn increased P-MEK levels in these cells. These data indicate that phosphorylation of MEK by Zn requires EGFR but not EGFR autophosphorylation or EGFR kinase activity. These findings imply that Zn-induced MEK phosphorylation is the result of EGFR transactivation by another Zn regulated kinase. Elucidation of the mechanism of toxicity of Zn may contribute to our understanding of the effects of particulate matter inhalation. This abstract of a proposed presentation does not necessarily reflect EPA policy.