Adamalysins in biology and disease.
ADAMs (a disintegrin and metalloprotease) are membrane-bound enzymes, capable of shedding a multitude of proteins from the surface of the cell. They are therefore considered crucial modulators of physiological and pathophysiological processes. The structure and function of ADAMs is related to those of a family of snake venom metalloproteases which also possess a potential adhesion domain as well as a potential protease domain. Mammalian ADAMs are involved in various biological and disease-related processes, such as cell-cell fusion, adhesion and intracellular signalling. Functional involvement has been described in sperm-egg binding and fusion, trophoblast invasion and matrix degradation during pregnancy, angiogenesis and neovascularization. Clinically, ADAMs are implicated in pathological processes, including cancer, inflammation, neurodegeneration and fibrosis, through shedding of the apoptosis-inducing FAS ligand, cytokines and growth factors. A second group of proteins within the ADAM family has recently been discovered. These contain several thrombospondin-like repeats in their C-terminal regions, in the absence of the transmembrane domain known to be present in ADAMs. These proteins were called the ADAMTS (ADAM with thrombospondin domains) family. The relevance of ADAMTS enzymes has become evident in patients with a deficiency in ADAMTS-13, a von Willebrand factor cleaving protease. These patients develop thrombotic thrombocytopenic purpura, a devastating thrombotic disorder caused by widespread microvascular thrombi composed of platelets and von Willebrand factor (VWF). Here we focus on the genetic, developmental, functional and disease-related aspects of ADAMs and ADAMTS. Finally we discuss the perspectives of the therapeutical potential of ADAMs in disease.
van Goor
Harry
H
Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, The Netherlands. h.van.goor@path.umcg.nl
Melenhorst
Wynand B W H
WB
Turner
Anthony J
AJ
Holgate
Stephen T
ST
D000544:Alzheimer Disease / Q000503:physiopathology; D047108:Embryonic Development / Q000502:physiology; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000503:physiopathology; D011697:Purpura, Thrombotic Thrombocytopenic / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship
D066246:ErbB Receptors; D008666:Metalloendopeptidases; C028220:Crotalus adamanteus proteinase II