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Published ahead of print on September 11, 2003, doi:10.1165/rcmb.2003-0233OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 4, April 2004, 540-547

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Submitted on June 18, 2003
Revised on September 11, 2003

Heparin-binding EGF Cleavage Mediates Zinc-induced EGF Receptor Phosphorylation

Weidong Wu1*, James M Samet2, Robert Silbajoris2, Lisa A Dailey2, Dean Sheppard3, Philip A Bromberg1, and Lee M Graves4

1 Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina, Chapel Hill, NC, USA, 2 Human Studies Division, US Environmental Protection Agency, RTP, NC, USA, 3 Department of Medicine, University of California San Francisco, San Francisco, CA, USA, 4 Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA

* To whom correspondence should be addressed. E-mail: weidong_wu{at}med.unc.edu.

We have previously shown that exposure to zinc ions can activate EGF receptor (EGFR) signaling in murine fibroblasts and A431 cells through a mechanism involving Src kinase. While studying the effects of zinc ions in normal human bronchial epithelial cell, we uncovered evidence for an additional mechanism of Zn2+-induced EGFR activation. Exposure to Zn2+ induced phosphorylation of EGFR at tyrosine 1068, a major autophosphorylation site in a dose- and time-dependent fashion. This effect of Zn2+ on EGFR was significantly blocked with an antibody against the ligand-binding domain of the receptor. Neutralizing antibodies against EGFR ligands revealed the involvement of heparin-binding EGF (HB-EGF) in Zn2+-induced EGFR phosphorylation. This observation was further supported by immunoblots showing elevated levels of HB-EGF released by Zn2+-exposed cells. Zymography showed the existence of matrix metalloproteinase-3 (MMP-3) in Zn-challenged cells. Incubation with a specific MMP-3 inhibitor suppressed Zn-induced EGFR phosphorylation as well as HB-EGF release. Therefore, these data support an autocrine or paracrine mechanism whereby Zn induces EGFR phosphorylation through the extracellular release of EGFR ligands, which may be mediated by metalloproteinases.




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