Inhibition of protein tyrosine phosphatase activity mediates epidermal growth factor receptor signaling in human airway epithelial cells exposed to Zn{sup 2+}
- Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599 (United States)
- Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599 (United States)
- Human Studies Division MD-58D, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, 104 Mason Farm, Chapel Hill, NC 27599-7315 (United States)
- Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina, Chapel Hill, NC 27599 (United States)
Epidemiological studies have implicated zinc (Zn{sup 2+}) in the toxicity of ambient particulate matter (PM) inhalation. We previously showed that exposure to metal-laden PM inhibits protein tyrosine phosphatase (PTP) activity in human primary bronchial epithelial cells (HAEC) and leads to Src-dependent activation of EGFR signaling in B82 and A431 cells. In order to elucidate the mechanism of Zn{sup 2+}-induced EGFR activation in HAEC, we treated HAEC with 500 {mu}M ZnSO{sub 4} for 5-20 min and measured the state of activation of EGFR, c-Src and PTPs. Western blots revealed that exposure to Zn{sup 2+} results in increased phosphorylation at both trans- and autophosphorylation sites in the EGFR. Zn{sup 2+}-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 Zn{sup 2+} treatment of HAEC, consistent with Src-independent EGFR transactivation in HAEC exposed to Zn{sup 2+}. The rate of exogenous EGFR dephosphorylation in lysates of HAEC exposed to Zn{sup 2+} or V{sup 4+} was significantly diminished. Moreover, exposure of HAEC to Zn{sup 2+} also resulted in a significant impairment of dephosphorylation of endogenous EGFR. These data show that Zn{sup 2+}-induced activation of EGFR in HAEC involves a loss of PTP activities whose function is to dephosphorylate EGFR in opposition to baseline EGFR kinase activity. These findings also suggest that there are marked cell-type-specific differences in the mechanism of EGFR activation induced by Zn{sup 2+} exposure.
- OSTI ID:
- 20850353
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 214, Issue 1; Other Information: DOI: 10.1016/j.taap.2005.11.011; PII: S0041-008X(05)00662-9; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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