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INHIBITION OF PHOSPHATASE ACTIVITY MEDIATES EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) SIGNALING IN HUMAN AIRWAY EPITHELIAL CELLS (HAEC) EXPOSED TO ZN2+
Citation:
Silbajoris, R, T. Tal, L. M. Graves, P A. Bromberg, W. Wu, AND J M. Samet. INHIBITION OF PHOSPHATASE ACTIVITY MEDIATES EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) SIGNALING IN HUMAN AIRWAY EPITHELIAL CELLS (HAEC) EXPOSED TO ZN2+. Presented at American Thoracic Society Annual Meeting, San Diego, CA, March 20 - 25, 2005.
Description:
A number of studies have implicated zinc in the toxicity of ambient particulate matter (PM) inhalation. We previously showed that exposure to metal-laden particulate matter inhibits protein tyrosine phosphatase activity in HAEC and leads to Src-dependent activation of EGFR signaling in B82 and A431 cells. In order to elucidate the mechanism of Zn2+-induced EGFR activation in human bronchial epithelium, we treated HAEC with non-cytotoxic levels of ZnSO4 (0-500 uM for 5-20min) and measured the state of activation of EGFR, c-Src and tyrosine phosphatases. Western blots revealed that exposure to Zn2+ results in increased phosphorylation at both kinase and autophosphorylation domains of EGFR in HAEC. Zn2+ mediated EGFR phosphorylation did not require ligand binding and was ablated by the EGFR kinase inhibitor PD153035, but not by the Src kinase inhibitor PP2. Src activity was inhibited by Zn2+ treatment of HAEC, further arguing against Zn2+-induced Src-dependent EGFR transactivation in HAEC. We next measured the rate of EGFR dephosphorylation in HAEC exposed to Zn2+ or vehicle following EGF-stimulated EGFR phosphorylation and treatment with a fast-acting inhibitor of EGFR kinase activity. Exposure to Zn2+ resulted in a significant impairment of EGFR dephosphorylation in HAEC. These data show that Zn2+ -induced activation of the EGFR in HAEC is the result of a loss of tyrosine phosphatase activities which function to dephosphorylate EGFR in opposition to baseline EGFR kinase activity. In addition, these findings show striking cell-type specific differences in the mechanism of EGFR activation by Zn2+. THIS ABSTRACT OF A PROPOSED PRESENTATION DOES NOT NECESSARILY REFLECT EPA POLICY.