MMPs and ADAMTSs: functional studies.
Members of the MMP (matrix metalloproteinase) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin type I motifs) families of enzymes are capable of cleaving a diverse array of cellular, extracellular and extracellular matrix substrates, including collagens and procollagens, proteoglycans, cytokines and cytokine ligands, chemokines, elastin and von Willebrand factor, thereby modulating tissue structure and function during both health and disease. Physiologically relevant roles attributable to various members of these metalloproteinase families have been discerned from functional studies correlating in vitro substrate processing events with catabolic cleavages occurring in vivo/in situ, and the consequences thereof. Mechanisms regulating the post-translational activities of MMPs and ADAMTSs can clearly also have an influential impact on cell metabolism and tissue structure/function, and a number of functional studies have addressed the contributions of ancillary (non-catalytic) domains and endogenous inhibitors in this regard. Further revelations and affirmations of proteinase function, in an in vivo context, have emanated with the characterization of genetically manipulated animals misexpressing specific MMPs or ADAMTSs (or their substrates). An increased understanding thereby attained for the physiological functions of MMPs and ADAMTSs, and the means by which their activities are controlled, may lead to the realization of rational therapeutic strategies to counteract pathologies associated with aberrant proteolysis of homeostatic tissue macromolecules.
Flannery
Carl R
CR
Wyeth Research, Cambridge, Massachusetts 02140, USA. cflannery@wyeth.com
D051722:ADAM Proteins / Q000378:metabolism / Q000502:physiology*; D020816:Amino Acid Motifs; D000818:Animals; D002384:Catalysis; D020134:Catalytic Domain; D016326:Extracellular Matrix Proteins; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000473:pathology; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
D016326:Extracellular Matrix Proteins; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases