Activation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway.
Authors
Bergin, David AGreene, Catherine M
Sterchi, Erwin E
Kenna, Cliona
Geraghty, Patrick
Belaaouaj, Abderrazzaq
Taggart, Clifford C
O'Neill, Shane J
McElvaney, Noel G
Affiliation
Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.Issue Date
2008-11-14MeSH
BronchiBronchoalveolar Lavage Fluid
Cell Line
Enzyme Activation
Epithelial Cells
Gene Expression Regulation
Humans
Interleukin-8
Leukocyte Elastase
Metalloproteases
Myeloid Differentiation Factor 88
NF-kappa B
RNA, Messenger
Receptor, Epidermal Growth Factor
Tiopronin
Transforming Growth Factor alpha
Metadata
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Activation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway. 2008, 283 (46):31736-44 J. Biol. Chem.Journal
The Journal of biological chemistryDOI
10.1074/jbc.M803732200PubMed ID
18772136Additional Links
http://www.ncbi.nlm.nih.gov/pubmed/18772136Abstract
Neutrophil Elastase (NE) is a pro-inflammatory protease present at higher than normal levels in the lung during inflammatory disease. NE regulates IL-8 production from airway epithelial cells and can activate both EGFR and TLR4. TACE/ADAM17 has been reported to trans-activate EGFR in response to NE. Here, using 16HBE14o-human bronchial epithelial cells we demonstrate a new mechanism by which NE regulates both of these events. A high molecular weight soluble metalloprotease activity detectable only in supernatants from NE-treated cells by gelatin and casein zymography was confirmed to be meprin alpha by Western immunoblotting. In vitro studies demonstrated the ability of NE to activate meprin alpha, which in turn could release soluble TGFalpha and induce IL-8 production from 16HBE14o- cells. These effects were abrogated by actinonin, a specific meprin inhibitor. NE-induced IL-8 expression was also inhibited by meprin alpha siRNA. Immunoprecipitation studies detected EGFR/TLR4 complexes in NE-stimulated cells overexpressing these receptors. Confocal studies confirmed colocalization of EGFR and TLR4 in 16HBE14o- cells stimulated with meprin alpha. NFkappaB was also activated via MyD88 in these cells by meprin alpha. In bronchoalveolar lavage fluid from NE knock-out mice infected intra-tracheally with Pseudomonas aeruginosa meprin alpha was significantly decreased compared with control mice, and was significantly increased and correlated with NE activity, in bronchoalveolar lavage fluid from individuals with cystic fibrosis but not healthy controls. The data describe a previously unidentified lung metalloprotease meprin alpha, and its role in NE-induced EGFR and TLR4 activation and IL-8 production.Item Type
ArticleLanguage
enISSN
0021-9258ae974a485f413a2113503eed53cd6c53
10.1074/jbc.M803732200
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