Adamalysins: A Family of Metzincins Including TNF‐α Converting Enzyme (TACE)

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Abstract
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‐α to generate soluble TNF‐α. 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‐α than do wild‐type cells. Irradiated mice that are reconstituted with TACE knock‐out hematopoeitic stem cells have markedly reduced levels of serum TNF‐α following LPS challenge, compared to irradiated mice reconstituted with wild‐type cells, suggesting that TACE is the major TNF‐α 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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