The new kids on the block: ADAMTSs, potentially multifunctional metalloproteinases of the ADAM family Gur P. Kaushal, Sudhir V. Shah J Clin Invest. 2000;105(10):1335-1337. https://doi.org/10.1172/JCI10078. Commentary Cell-cell and cell-matrix interactions are of vital importance not only for proper cellular homeostasis during embryogenesis and development of an organism, but also in pathological states in diseases ranging from tumor metastasis to AIDS. Tissues owe their dynamic structure both to changes in expression of adhesive proteins and their receptors and to the regulated action of secreted proteinases, particularly members of the metalloproteinase family. Many of these secreted and cell surface proteins and metalloproteinases are found at critical locations that facilitate their involvement in cell-cell and cell-matrix interactions. Metalloproteinases belong to a superfamily of zinc-dependent proteases known as metzincins. Based on sequence and structural similarities, metzincins are grouped in four distinct subfamilies: the astacins, the matrixins (matrix metalloproteinases), the adamalysins (reprolysins, or snake venom metalloproteinases [SVMPs], and ADAMs), and the serralysins (large bacterial proteinases) (1). ADAMs are a family of membrane-associated multidomain zinc-dependent metalloproteinases with high sequence homology and domain organization, similar to the SVMPs of the adamalysin subfamily (2–4). The term “ADAM” stands for a disintegrin and metalloproteinase, which represent the two key structural domains in these molecules. Thus, ADAMs are distinct among cell surface proteins in containing features of both adhesive proteins and proteinases, and their roles in cell-cell interactions have attracted particular interest. In addition, ADAM proteins contain a prodomain, as well as cysteine-rich, EGF-like, transmembrane, and […] Find the latest version: https://jci.me/10078/pdf The new kids on the block: ADAMTSs, Commentary potentially multifunctional metalloproteinases See related article, pages 1345–1352. of the ADAM family Gur P. Kaushal and Sudhir V. Shah Department of Medicine, Division of Nephrology, University of Arkansas for Medical Sciences, and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA Address correspondence to: Gur P. Kaushal, University of Arkansas for Medical Sciences, 4301 West Markham Street (Slot 501), Little Rock, Arkansas 72205, USA. Phone: (501) 257-5832; Fax: (501) 257-5827; E-mail: [email protected]. Cell-cell and cell-matrix interactions At present, more than 25 ADAM thrombospondin type I motifs in are of vital importance not only for family members have been identified addition to some of the structurally proper cellular homeostasis during from mammalian and nonmam- conserved domains of other ADAM embryogenesis and development of an malian sources, including Xenopus, family members (Figure 1). The organism, but also in pathological Drosophila, and Caenorhabditis elegans ADAMTSs are also distinguished states in diseases ranging from tumor (1, 4). Biological roles are now emerg- from the ADAMs by their lack of cys- metastasis to AIDS. Tissues owe their ing for some of these proteins. Some teine-rich, EGF-like, transmembrane, dynamic structure both to changes in ADAM family members perform spe- and cytoplasmic domains (10). Kuno expression of adhesive proteins and cialized functions in cell adhesion, et al. first cloned and identified their receptors and to the regulated fusion processes, and shedding of cell ADAMTS-1, a tumor-selective gene action of secreted proteinases, particu- surface proteins (1, 2, 4). For example, expressed in colon tumor cells (13). larly members of the metalloproteinase ADAM1 (fertilin α) and ADAM2 (fer- ADAMTSs 2–11 have now also been family. Many of these secreted and cell tilin β) participate in sperm-egg cloned, and the proteolytic activity surface proteins and metalloproteinas- fusion (5); ADAM17 (TACE) (6), and biological functions of some of es are found at critical locations that ADAM9 (MDC9) (7, 8), and ADAM10 them have been demonstrated. For facilitate their involvement in cell-cell (Kuzbanian) (8) mediate the shedding example, ADAMTS-2 has been impli- and cell-matrix interactions. of cell surface proteins and are called cated in the normal development of Metalloproteinases belong to a super- sheddases; and ADAM12 (meltrin α) the skin. This enzyme was long family of zinc-dependent proteases promotes myoblast fusion (9). known as procollagen N-proteinase known as metzincins. Based on sequence Recently, new members of the (14), a proteinase that proteolytically and structural similarities, metzincins ADAM family, known as ADAMTSs (a removes amino peptides in the pro- are grouped in four distinct subfamilies: disintegrin and metalloproteinase cessing of type I and type II procolla- the astacins, the matrixins (matrix met- with thrombospondin motifs), have gens to collagens, and it was shown to alloproteinases), the adamalysins (repro- been cloned and studied (10–12). be deficient in the skin of individuals lysins, or snake venom metallopro- These proteins, which are not count- with the inherited connective tissue teinases [SVMPs], and ADAMs), and the ed among the 25 known ADAMs, are disorder type VIIC Ehlers-Danros syn- serralysins (large bacterial proteinases) novel in that they contain unique drome and in cows and sheep with a (1). ADAMs are a family of membrane- associated multidomain zinc-dependent metalloproteinases with high sequence homology and domain organization, similar to the SVMPs of the adamalysin subfamily (2–4). The term “ADAM” stands for adisintegrin and metallopro- teinase, which represent the two key structural domains in these molecules. Thus, ADAMs are distinct among cell surface proteins in containing features of both adhesive proteins and proteinas- es, and their roles in cell-cell interactions have attracted particular interest. In addition, ADAM proteins contain a prodomain, as well as cysteine-rich, Figure 1 Comparison of domain structures of ADAMTSs, ADAMs and SVMPs. The first three boxes of each EGF-like, transmembrane, and cytoplas- bar represent, respectively, the common prodomain and the metalloprotease and disintegrin mic tail domains (2–4). These specialized domains present in all of the members of adamalysin family. ADAMTSs also possess a throm- structural domains suggest a possible bospondin domain but lack the cysteine-rich, EGF-like, transmembrane, and cytoplasmic domains role for ADAMs in cell-cell and cell- found in ADAMs. SVMPs and ADAMTSs do not contain transmembrane domains and are there- matrix interactions. fore secreted, whereas ADAMs are transmembrane proteins that localize to the cell surface. The Journal of Clinical Investigation | May 2000 | Volume 105 | Number 10 1335 similar condition, dermatosparaxis. act as a proteinase or may mediate ECM-bound ADAMTS-1. Finally, one With the recent cloning of procolla- changes in cell adhesion through its of the prominent phenotypic abnor- gen N-proteinase (15) came its recog- disintegrin or thrombospondin do- malities observed in the kidney, the nition as a member of the ADAMTS mains. Future studies will no doubt substantial reduction in corti- family, ADAMTS-2. ADAMTS-4 and clarify the molecular interactions that comedullary tissue, may be attributed ADAMTS-11 are known as aggre- account for the organogenesis defects to interstitial fibrosis in the kidney canase-1 and -2 because of their abili- in ADAMTS-1–/– mice. consequent to the obstruction of the ty to cleave specific sites in aggrecan, Given the intriguing domain struc- ureter. However, this interstitial fibro- a proteoglycan that maintains the ture of ADAMTS-1, the pleiotropic sis in the kidney, which is an integral mechanical properties of cartilage developmental defects in these mice part of all progressive kidney diseases, (12, 16, 17). Progressive degradation suggest several fruitful lines of investi- clearly requires a mechanistic explana- and depletion of aggrecan has been gation. First, since ADAMTS-1 is tion. It is conceivable that proteolyti- implicated in degenerative joint dis- secreted (22), contains metalloprotease cally active ADAMTS-1 participates in eases such as osteoarthritis and catalytic site consensus sequence normal ECM turnover and that its inflammatory joint diseases such as HEXXH, and has been shown to have absence contributes to the fibrosis seen rheumatoid arthritis. A human ortho- protease activity (23), the identities of in the mutant mice. logue of ADAMTS-1, known as its physiological substrates at the cell While the knockout mice provide METH-1, and the related protein surface are of great interest. To date, important information on develop- METH-2 have been recently shown to ADAMTS-1 has not been shown to act ment of organs, they do not suggest have antiangiogenic activity (18), and on proteins of the ECM. Second, potential roles for ADAMTS in patho- these or other ADAMTS family mem- because ADAMTS-1 is synthesized as logical states. In vitro studies demon- bers may play important roles in reg- an inactive proform, a conserved cys- strated that ADAMTS-1, like other ulating vascular development. teine residue in its prodomain is pre- matrix-degrading metalloproteinases, dicted to be proteolytically processed is induced by IL-1, indicating that Impaired organogenesis in during its maturation to an active inflammation can induce its expres- ADAMTS-1–/– mice enzyme; other metalloproteinases, sion (13). Indeed, ADAMTS-1 is weak- The report