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Originally published In Press as doi:10.1074/jbc.M000604200 on March 23, 2000

J. Biol. Chem., Vol. 275, Issue 21, 15839-15844, May 26, 2000
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Activation of Tumor Necrosis Factor-alpha -converting Enzyme-mediated Ectodomain Shedding by Nitric Oxide*

Zili ZhangDagger §, Jay K. KollsDagger §||**, Peter OliverDagger §, David GoodDagger , Paul O. SchwarzenbergerDagger , Mahesh S. JoshiDagger Dagger , Julie L. Ponthier§§, and Jack R. Lancaster Jr.||Dagger Dagger

From the Dagger  Louisiana State University Health Sciences Gene Therapy Program and the Departments of  Pediatrics, || Medicine, Dagger Dagger  Surgery, and §§ Physiology, Louisiana State University School of Medicine, New Orleans, Louisiana 70112

Ectodomain shedding of cell surface proteins is an important process in a wide variety of physiological and developmental events. Recently, tumor necrosis factor-alpha -converting enzyme (TACE) has been found to play an essential role in the shedding of several critical surface proteins, which is evidenced by multiple developmental defects exhibited by TACE knockout mice. However, little is known about the physiological activation of TACE. Here, we show that nitric oxide (NO) activates TACE-mediated ectodomain shedding. Using an in vitro model of TACE activation, we show that NO activates TACE by nitrosation of the inhibitory motif of the TACE prodomain. Thus, NO production activates the release of cytokines, cytokine receptors, and adhesion molecules, and NO may be involved in other ectodomain shedding processes.

* This work was supported by United States Public Health Service Grants F32-AA05543-01 (to Z. Z.), R29AA10384, RO1-HL62052-01, RO1-HL61721-01 (to J. K. K.), and RO1 DK46935 (to J. R. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

** To whom correspondence should be addressed. E-mail: jkolls@lsumc.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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