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Am J Physiol Gastrointest Liver Physiol 287: G1213-G1219, 2004. First published July 29, 2004; doi:10.1152/ajpgi.00149.2004
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MUCOSAL BIOLOGY

Metalloprotease disintegrin-mediated ectodomain shedding of EGFR ligands promotes intestinal epithelial restitution

Gennett M. Myhre,1 Murat Toruner,1 Susan Abraham,2 and Laurence J. Egan1

1Gastroenterology Research Unit and 2Department of Pathology, Mayo Clinic, Rochester, Minnesota 55905

Submitted 5 April 2004 ; accepted in final form 15 July 2004

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.

RIE-1 cells


Address for reprint requests and other correspondence: L. J. Egan, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (E-mail: egan.laurence{at}mayo.edu)




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[Abstract] [Full Text] [PDF]


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