Abstract
The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future.
Highlights
The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology
The remaining three subgroups, which are defined on the basis of their domain organizations, each contain a pair of enzymes (ADAMTS6 and 10; ADAMTS16 and 18; ADAMTS17 and 19) whose physiological substrates have yet to be identified, and are currently called the ‘orphan’ sub-groups
Inhibition of ADAMTS4 aggrecanase activity by Tissue inhibitors of metalloproteinases (TIMP)-3 is enhanced by aggrecan, through a mechanism that involves the interaction of aggrecan GAG chains with the type sequence repeat (TSR) and spacer regions of ADAMTS4 [38]
Summary
The 19 human ADAMTS proteins can be assembled into eight ‘clades’ on the basis of their domain organization and their known functions. The aggrecanase and proteoglycanase clades (ADAMTS1, 4, 5, 8, 15, and ADAMTS9 and 20) can cleave hyaluronan-binding chondroitin sulfate proteoglycan (CSPG) extracellular proteins, including aggrecan, versican, brevican and neurocan [5] This subgroup has been labeled ‘angioinhibitory’ on the basis of the original identification of ADAMTS1 and 8 as antiangiogenic factors [6]; ADAMTSs in other clades have effects on angiogenesis. The likely sequence of events is that an ancestral ADAMTS gene duplicated approximately 650 million years ago, prior to the divergence of the protostomes (that is, the insects, crustaceans and nematodes) from the deuterostomes (chordates and vertebrates) One of these early duplicated genes gave rise to the aggrecanase/proteoglycanase sub-group (the right-hand branch in Fig. 2), while the other duplicate was the founder of the remaining family members. The expansion of the ADAMTS family during vertebrate evolution goes hand-in-hand with the increased complexity of the ECM, which has arisen through the duplication, retention and modification of ancestral genes [17]
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