A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells

Roy A. Black, Charles T. Rauch, Carl J. Kozlosky, Jacques J. Peschon, Jennifer L. Slack, Martin F. Wolfson, Beverly J. Castner, Kim L. Stocking, Pranitha Reddy, Subhashini Srinivasan, Nicole Nelson, Norman Boiani, Kenneth A. Schooley, Mary Gerhart, Raymond Davis, Jeffrey N. Fitzner, Richard S. Johnson, Raymond J. Paxton, Carl J. March and Douglas Pat Cerretti
Additional contact information
Roy A. Black: Immunex Corporation
Charles T. Rauch: Immunex Corporation
Carl J. Kozlosky: Immunex Corporation
Jacques J. Peschon: Immunex Corporation
Jennifer L. Slack: Immunex Corporation
Martin F. Wolfson: Immunex Corporation
Beverly J. Castner: Immunex Corporation
Kim L. Stocking: Immunex Corporation
Pranitha Reddy: Immunex Corporation
Subhashini Srinivasan: Immunex Corporation
Nicole Nelson: Immunex Corporation
Norman Boiani: Immunex Corporation
Kenneth A. Schooley: Immunex Corporation
Mary Gerhart: Immunex Corporation
Raymond Davis: Immunex Corporation
Jeffrey N. Fitzner: Immunex Corporation
Richard S. Johnson: Immunex Corporation
Raymond J. Paxton: Immunex Corporation
Carl J. March: Immunex Corporation
Douglas Pat Cerretti: Immunex Corporation

Nature, 1997, vol. 385, issue 6618, 729-733

Abstract: Abstract Mammalian cells proteolytically release (shed) the extracellular domains of many cell-surface proteins1. Modification of the cell surface in this way can alter the cell's responsiveness to its environment2 and release potent soluble regulatory factors3. The release of soluble tumour-necrosis factor-α (TNF-α) from its membrane-bound precursor4,5 is one of the most intensively studied shedding events because this inflammatory cytokine is so physiologically important6,7. The inhibition of TNF-α release (and many other shedding phenomena) by hydroxamic acid-based inhibitors indicates that one or more metalloproteinases is involved3,8,9. We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-α. Inactivation of the gene in mouse cells caused a marked decrease in soluble TNF-α production. This enzyme (called the TNF-α-converting enzyme, or TACE) is a new member of the family of mammalian adama-lysins (or ADAMs)10, for which no physiological catalytic function has previously been identified. Our results should facilitate the development of therapeutically useful inhibitors of TNF-α release, and they indicate that an important function of adamalysins may be to shed cell-surface proteins.

Date: 1997
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DOI: 10.1038/385729a0

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