Adamalysins. A family of metzincins including TNF-alpha converting enzyme (TACE).
The adamalysins are a family of proteins in the metzincin superfamily 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-alpha to generate soluble TNF-alpha. 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-alpha than do wild-type cells. Irradiated mice that are reconstituted with TACE knock-out hematopoeitic stem cells have markedly reduced levels of serum TNF-alpha following LPS challenge, compared to irradiated mice reconstituted with wild-type cells, suggesting that TACE is the major TNF-alpha 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.
Killar
L
L
Oncology/Immunoinflammatory Diseases, Wyeth-Ayerst Research, Princeton, New Jersey 08543, USA. killarl@war.wyeth.com
White
J
J
Black
R
R
Peschon
J
J
D051722:ADAM Proteins; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012910:Snake Venoms / Q000378:metabolism; D013084:Sperm-Ovum Interactions; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008565:Membrane Proteins; D012910:Snake Venoms; D014409:Tumor Necrosis Factor-alpha; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse