Metalloprotease disintegrin-mediated ectodomain shedding of EGFR ligands promotes intestinal epithelial restitution
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, vol.287, no.6, 2004 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 287 Issue: 6
- Publication Date: 2004
- Doi Number: 10.1152/ajpgi.00149.2004
- Journal Name: AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Keywords: RIE-1 cells, NECROSIS-FACTOR-ALPHA, GROWTH-FACTOR RECEPTOR, ENZYME TACE ACTIVITY, CONVERTING-ENZYME, TRANSFORMING-GROWTH, FACTOR-BETA, CELL MIGRATION, COLONIC MUCOSA, CROHNS-DISEASE, IN-VITRO
- Ankara University Affiliated: Yes
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 ofTNF-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.