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MATRIX METALLOPROTEINS (MMP)-MEDIATED PHOSPHORYLATION OF THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) IN HUMAN AIRWAY EPITHELIAL CELLS (HAEC) EXPOSED TO ZINC (ZN)
Citation:
Wu, W., J M. Samet, R Silbajoris, L. A. Dailey, L. M. Graves, AND P A. Bromberg. MATRIX METALLOPROTEINS (MMP)-MEDIATED PHOSPHORYLATION OF THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) IN HUMAN AIRWAY EPITHELIAL CELLS (HAEC) EXPOSED TO ZINC (ZN). Presented at American Thoracic Society Meeting, Seattle, WA, May 16-21, 2003.
Description:
Matrix Metalloproteinase (MMP)-Mediated Phosphorylation of The Epidermal Growth Factor Receptor (EGFR) in Human Airway Epithelial Cells (HAEC) Exposed to Zinc (Zn)
Weidong Wu, James M. Samet, Robert Silbajoris, Lisa A. Dailey, Lee M. Graves, and Philip A. Bromberg
Center for Environmental Medicine, Asthma, and Lung Biology; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599; Human Studies Division, United States Environmental Protection Agency, Research Triangle Park, NC 27711
EGFR signaling was previously shown to mediate Zn-induced gene expression of pro-inflammatory mediators. Immunoblot and quantitative PCR using specific antibodies and oligonucleotides were used to investigate the mechanism of Zn-induced EGFR phosphorylation in HAEC. Treatment with 100 mM Zn for 2 hrs induced EGFR phosphorylation at tyrosine 1068, a major autophosphorylation site. Zn-induced EGFR phosphorylation was markedly reduced by an EGFR kinase inhibitor and also by a neutralizing antibody specific for the EGFR ligand-binding domain. To understand whether EGFR ligands were involved, gene expression of EGFR and its ligands was examined. Elevated HB-EGF mRNA levels were observed in Zn-exposed cells while there were no significant changes in expression of other EGFR ligands including EGF, transferring growth factor a, and amphiregulin or EGFR itself. A neutralizing antibody against HB-EGF significantly suppressed Zn-induced EGFR phosphorylation. Furthermore, a specific inhibitor of MMP 3 inhibited Zn-induced EGFR phosphorylation. MMP-3 gene expression was also elevated in Zn-treated cells. In addition, Zn induced phosphorylation of Src, and inhibition of Src family kinases activity blocked Zn- but not EGF-induced EGFR phosphorylation. In summary, Zn induces MMP-3 activation and subsequent ligand-mediated activation of the EGFR by HB-EGF in HAEC. These events appear to be accompanied by Zn-induced activation of Src in HAEC. These data suggest that the adverse effects of Zn inhalation can be mediated through an activation of a physiological signaling pathway. This study was supported by grants US EPA CR#824915 and US EPA R829214).