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ZINC-INDUCED EGF RECEPTOR SIGNALING REQUIRES SRC-MEDIATED PHOSPHORYLATION OF THE EGF RECEPTOR ON TYROSINE 845 (Y845)
Weidong, W., L. M. Graves, J M. Samet, AND G. N. Gill. ZINC-INDUCED EGF RECEPTOR SIGNALING REQUIRES SRC-MEDIATED PHOSPHORYLATION OF THE EGF RECEPTOR ON TYROSINE 845 (Y845). Presented at American Thoracic Society, Atlanta, GA, May 17-22, 2002.
ZINC-INDUCED EGF RECEPTOR SIGNALING REQUIRES Src-MEDIATED PHOSPHORYLATION OF THE EGF RECEPTOR ON TYROSINE 845 (Y845)
Weidong Wu1, Lee M. Graves2, Gordon N. Gill3 and James M. Samet4 1Center for Environmental Medicine and Lung Biology; 2Department of Pharmacology, University of North Carolina, Chapel Hill, NC; 3Cellular and Molecular Medicine, University of California San Diego, CA; and 4Human Studies Division, National Health Effects and Environmental Research Laboratory, ORD, US EPA, Research Triangle Park, NC
Recent studies have implicated Zinc (Zn) as a bioactive constituent that may contribute to the health effects of PM exposure. Zn ions can induce Ras and MAPK activation through the epidermal growth factor receptor (EGFR). In order to characterize the role of EGFR in Zn-induced signaling, we used murine B82L cells expressing no EGFR (B82L-par), wild-type EGFR (B82L-wt), kinase deficient EGFR (B82L-K721M), truncated EGFR (B82L-c'958), or EGFR containing a mutation at a known Src phosphorylation site (B82L-Y845F). Assay of GTP-bound Ras levels indicated that Zn-induced activation of Ras requires EGFR with an intact tyrosine at 845, but not EGFR tyrosine kinase activity or auto-phosphorylation sites. PP1, a selective Src kinase inhibitor, significantly blocked Zn-induced Ras activation. Additionally, immunoprecipitation and Western blotting showed that Zn induces Src phosphorylation and association with EGFR in B82L-wt cells. Furthermore, Zn treatment causes the phosphorylation of EGFR onY845 of the EGFR molecule but not on Y1068, a major autophosphorylation site. Moreover, Zn-induced Y845 phosphorylation could also be blocked by PP1. In summary, these data demonstrate that EGFR-dependent signaling initiated by Zn ions involves Src activation and specific phosphorylation of EGFR at Y845. These findings may provide a contributing mechanism for the adverse effects of ambient PM. This abstract of a proposed presentation does not necessarily reflect the EPA policy