 | INHIBITION OF MATRIX METALLOPROTEINASES THERAPEUTIC APPLICATIONS
Copyright © 1999 by the New York Academy of Sciences
description
Annals of the New York Academy of Sciences 878:442-452 (1999)
© 1999 New York Academy of Sciences
Adamalysins: A Family of Metzincins Including TNF- Converting Enzyme (TACE)
LORAN KILLARa,d,
JUDITH WHITEb,
ROY BLACKc AND
JACQUES PESCHONc
aOncology/Immunoinflammatory Diseases, Wyeth-Ayerst Research, Princeton, New Jersey 08543, USA
bDepartment of Cell Biology, University of Virginia, Charlottesville, Virginia 22908, USA
cImmunex Corporation, Seattle, Washington 98101, USA
dAddress for telecommunication: Phone, 432/274-4046; fax, 732/274-4129; e-mail killarl{at}war.wyeth.com
The adamalysins are a family of proteins in the metzincin super-family of metalloproteases, which also includes the matrix metalloproteinases. There are two subfamilies of adamalysins: the snake venom metalloproteases (SVMPs) and the ADAMs (proteins containing a disintegrin and metalloprotease domain). At least 23 ADAMs have been identified to date. The ADAMs are expressed by a wide variety of cell types, and are involved in functions as diverse as sperm-egg binding, myotube formation, neurogenesis, and proteolytic processing of cell surface proteins. An overview of the ADAM family and their functions will be presented. TACE is a unique member of the ADAM family that cleaves membrane-bound TNF-  to generate soluble TNF- . Mice lacking proteolytically active TACE have been generated and characterized. The TACE knock-out results in perinatal lethality. Cells from the TACE-deficient mice release 80-90% less soluble TNF- than do wild-type cells. Irradiated mice that are reconstituted with TACE knock-out hematopoeitic stem cells have markedly reduced levels of serum TNF- following LPS challenge, compared to irradiated mice reconstituted with wild-type cells, suggesting that TACE is the major TNF- converting enzyme in vivo. TACE-deficient cells are compromised in the generation of other soluble proteins that are produced as the result of cleavage of a membrane precursor form, suggesting that TACE is involved in multiple shedding events.
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