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J. Biol. Chem., Vol. 278, Issue 25, 22331-22340, June 20, 2003

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Catalytic Properties of ADAM19^*

Valérie Chesneau , J. David Becherer , Yufang Zheng  ¶, Hediye Erdjument-Bromage ||, Paul Tempst || and Carl P. Blobel  **

From the Cellular Biochemistry and Biophysics Program, ^||Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, the Department of Biochemical and Analytical Pharmacology, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, and ^¶Graduate Program in Physiology, Biophysics, and Molecular Medicine, Weill Graduate School of Medical Science of Cornell University, New York, New York 10021

ADAMs are membrane-anchored glycoproteins with functions in fertilization, heart development, neurogenesis, and protein ectodomain shedding. Here we report an evaluation of the catalytic activity of recombinantly expressed soluble forms of ADAM19, a protein that is essential for cardiovascular morphogenesis. Proteolytic activity of soluble forms of ADAM19 was first demonstrated by their autocatalytic removal of a purification tag (Myc-His) and their ability to cleave myelin basic protein and the insulin B chain. The metalloprotease activity of ADAM19 is sensitive to the hydroxamic acid-type metalloprotease inhibitor BB94 (batimastat) but not to tissue inhibitors of metalloproteases (TIMPs) 1–3. Moreover, ADAM19 cleaves peptides corresponding to the known cleavage sites of tumor necrosis factor- (TNF–), TNF-related activation-induced cytokine (TRANCE, also referred to as osteoprotegerin ligand), and kit ligand-1 (KL-1) in vitro. Although ADAM19 is not required for shedding of TNF and TRANCE in mouse embryonic fibroblasts, its overexpression in COS-7 cells results in strongly increased TRANCE shedding. This suggests a potential role for ADAM19 in shedding TRANCE in cells where both molecules are highly expressed, such as in osteoblasts. Interestingly, our results also indicate that ADAM19 can function as a negative regulator of KL-1 shedding in both COS-7 cells and mouse embryonic fibroblasts, instead of acting directly on KL-1. The identification of potential in vitro substrates offers the basis for further functional studies of ADAM19 in cells and in mice.

Received for publication, March 18, 2003

^* This work was supported by a grant from GlaxoSmithKline (to C. P. B.), by the Memorial Sloan-Kettering Cancer Center Support Grant NCI-P30-CA-08748, by the Samuel and May Rudin Foundation, and by the DeWitt Wallace Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Cellular Biochemistry and Biophysics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, Box 368, 1275 York Ave., New York, NY 10021. Tel.: 212-639-2915; Fax: 212-717-3047; E-mail: c-blobel{at}ski.mskcc.org.

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