The ADAMTS proteases, extracellular matrix, and vascular disease: waking the sleeping giant(s)!

The importance of proteases as mediators of extracellular matrix (ECM) degradation and vascular cell phenotype in the pathogenesis of vascular disease is indisputable. In fact, excellent cases can be made for the matrix metalloproteinases (MMPs) (see review1), the serine proteases (see review2), and the cysteine and aspartic proteases (see review3) being involved in many of the events in vascular disease. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Jonsson-Rylander and her colleagues show us that ADAMTS1, a member of another family of proteases, is also involved.4 Descendants from the ADAM family of proteases, the ADAMTS members (a disintegrinlike and metalloproteinase with thrombospondin type 1 motifs), currently numbering 19, evolved as nonintegral membrane proteins that associate with the cell surface and ECM through specific protein domains (see reviews5,6). Like the ADAM family, the ADAMTS proteases are multidomain proteins with common structural motifs that include an N-terminal signal sequence, a prodomain, a catalytic domain with Zn binding site, an ancillary domain, a disintegrin-like domain, a central thrombospondin repeat domain (TSR), a cysteine rich domain, a cysteine free spacer domain, and usually one or more TSRs. Some of the ADAMTS members also contain unique C-terminal domains that can contain PLAC and/or CUB sequences. These proteases are synthesized as zymogens that undergo processing by convertases such as furin and by metalloproteinases such as MT-4 MMP.7,8 Like the MMPs, the ADAMTS members can be inhibited by tissue inhibitors of matrix metalloproteinases or TIMPs. For example TIMP-3 is a potent inhibitor of ADAMTS4 and 5.9 Other inhibitors exist as well. For example, C-terminal truncation of ADAMTS4 can be blocked by TIMP-1.7 Proteins that share structural homology to the ADAMTS members also may function as ADAMTS inhibitors. One example is papilin, a protein produced by the fruit fly Drosophila melanogaster which shares a set of homologous domains with ADAMTS members including the ancillary domain but excluding the catalytic domain. Papilin is capable of interacting with ADAMTS2 and inhibiting the activity of this protease.10 BLAST searches reveal homologous but not identical proteins in mouse. In fact, other mammalian proteins that appear to be similar to the invertebrate papilin have recently been found and termed punctin 1 or ADAMTSL-1 and punctin 2 or ADAMTSL-3.11,12 The name punctin derives from its punctate distribution associated with the cells and within the ECM.11 Whether these proteins influence ADAMTS activity remains to be shown.