The ADAM10 prodomain is a specific inhibitor of ADAM10 proteolytic activity and inhibits cellular shedding events

Moss, Marcia L. and Bomar, Martha and Liu, Qian and Sage, Harvey and Dempsey, Peter and Lenhart, Patricia M. and Gillispie, Patricia A. and Stoeck, Alexander and Wildeboer, Dirk and Bartsch, Jorg W. and Palmisano, Ralf and Zhou, Pei (2007) The ADAM10 prodomain is a specific inhibitor of ADAM10 proteolytic activity and inhibits cellular shedding events. Journal of Biological Chemistry, 282 (49). pp. 35712-35721. ISSN 0021-9258

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Official URL: http://dx.doi.org/10.1074/jbc.M703231200

Abstract

ADAM10 is a disintegrin metalloproteinase that processes amyloid precursor protein and ErbB ligands and is involved in the shedding of many type I and type II single membrane-spanning proteins. Like tumor necrosis factor-α-converting enzyme (TACE or ADAM17), ADAM10 is expressed as a zymogen, and removal of the prodomain results in its activation. Here we report that the recombinant mouse ADAM10 prodomain, purified from Escherichia coli, is a potent competitive inhibitor of the human ADAM10 catalytic/disintegrin domain, with a Ki of 48 nm. Moreover, the mouse ADAM10 prodomain is a selective inhibitor as it only weakly inhibits other ADAM family proteinases in the micromolar range and does not inhibit members of the matrix metalloproteinase family under similar conditions. Mouse prodomains of TACE and ADAM8 do not inhibit their respective enzymes, indicating that ADAM10 inhibition by its prodomain is unique. In cell-based assays we show that the ADAM10 prodomain inhibits betacellulin shedding, demonstrating that it could be of potential use as a therapeutic agent to treat cancer.

Item Type:Article
Research Areas:Middlesex University Schools and Centres > School of Science and Technology > Natural Sciences
Citations on ISI Web of Science:40
ID Code:3877
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Deposited On:28 Jan 2010 16:29
Last Modified:22 Oct 2013 08:09

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