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Metalloprotease disintegrin-mediated ectodomain shedding of EGFR ligands promotes intestinal epithelial restitution.
- Source :
-
American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2004 Dec; Vol. 287 (6), pp. G1213-9. Date of Electronic Publication: 2004 Jul 29. - Publication Year :
- 2004
-
Abstract
- EGF receptor (EGFR) promotes intestinal epithelial restitution, an important early process in the reepithelialization of ulcers. During epithelial restitution, the mechanism of EGFR activation is not known. We evaluated the role of TNF-converting enzyme (TACE), a metalloprotease disintegrin that proteolytically processes plasma membrane-anchored EGFR ligand precursors into their mature active forms, in wound-induced EGFR activation and epithelial restitution. With the use of scrape-wounded rat intestinal epithelial-1 (RIE-1) cell monolayers to model epithelial ulceration and restitution, we observed the rapid wound-dependent release of EGFR ligands into culture medium. RIE-1 cells express TACE, and treatment with phorbol ester, an established TACE stimulus, triggered the extracellular release of an EGFR ligand, transforming growth factor-alpha. Blockade of TACE using TNF processing inhibitor (TAPI-1), a specific hydroxamate inhibitor of metalloprotease disintegrins, prevented release of EGFR ligands from wounded RIE-1 cell monolayers. The restitution of wounded RIE-1 cell monolayers was also dose-dependently inhibited by TAPI-1, establishing the role of metalloprotease disintegrins in this process. These results have established a mechanism of EGFR activation in wounded intestinal epithelium and show an important functional role for metalloprotease disintegrin-mediated ectodomain shedding during intestinal epithelial restitution. Therefore, activation of the TACE-EGFR system might promote the healing of intestinal tract ulcers in patients.
- Subjects :
- ADAM Proteins
ADAM17 Protein
Animals
Autocrine Communication physiology
Blotting, Western
Cell Line
Culture Media, Conditioned
Epithelium growth & development
Epithelium physiology
Immunoprecipitation
Indicators and Reagents
Intestinal Mucosa growth & development
Ligands
Metalloendopeptidases metabolism
Neutralization Tests
Paracrine Communication physiology
Protease Inhibitors pharmacology
Quinazolines
Rats
Transforming Growth Factor alpha biosynthesis
Tyrphostins pharmacology
ErbB Receptors physiology
Intestinal Mucosa physiology
Metalloproteases physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0193-1857
- Volume :
- 287
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Gastrointestinal and liver physiology
- Publication Type :
- Academic Journal
- Accession number :
- 15284022
- Full Text :
- https://doi.org/10.1152/ajpgi.00149.2004