Characterization of ADAMTS-9 and ADAMTS-20 as a Distinct ADAMTS Subfamily Related to Caenorhabditis elegans GON-1*

By R. Somerville, Jean-Michel Longpré, Katherine A. Jungers, J. M. Engle, M. Ross, S. Evanko, T. Wight, R. Leduc, S. Apte. 2003

336 citations recorded by the source corpus.

We demonstrate that in humans, two metalloproteases, ADAMTS-9 (1935 amino acids) and ADAMTS-20 (1911 amino acids) are orthologs of GON-1, an ADAMTS protease required for gonadal morphogenesis in Caenorhabditis elegans. ADAMTS-9 and ADAMTS-20 have an identical modular structure, are distinct in possessing 15 TSRs and a unique C-terminal domain, and have a similar gene structure, suggesting that they comprise a new subfamily of human ADAMTS proteases. ADAMTS20 is very sparingly expressed, although it is detectable in epithelial cells of the breast and lung. However, ADAMTS9 is highly expressed in embryonic and adult tissues, and therefore we characterized the ADAMTS-9 protein further. Although the ADAMTS-9 zymogen has many proprotein convertase processing sites, pulse-chase analysis, site-directed mutagenesis, and amino acid sequencing demonstrated that maturation to the active form occurs by selective proprotein convertase (e.g. furin) cleavage of the Arg287–Phe288 bond. Although lacking a transmembrane sequence, ADAMTS-9 is retained near the cell surface as well as in the ECM of transiently transfected COS-1 and 293 cells. COS-1 cells transfected with ADAMTS9 (but not vector-transfected cells) proteolytically cleaved bovine versican and aggrecan core proteins at the Glu441–Ala442bond of versican V1 and the Glu1771–Ala1772bond of aggrecan, respectively. In contrast, the ADAMTS-9 catalytic domain alone was neither localized to the cell surface nor able to confer these proteolytic activities on cells, demonstrating that the ancillary domains of ADAMTS-9, including the TSRs, are required both for specific extracellular localization and for its versicanase and aggrecanase activities.

Subfields: Immunology, Molecular Biology

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Citations in the corpus

ADAMTS proteins in human disorders (2018, background): “ADAMTS9 is associated with diverse traits and phenotypes, perhaps because it is widely expressed, for example, by capillary endothelial cells of nearly all organs [40], or cleaves a widely distributed ECM component, versican [41] or because the associated genome variants may be highly polymorphic.”
A Disintegrin and Metalloproteinase with Thrombospondin Motifs 18 Deficiency Leads to Visceral Adiposity and Associated Metabolic Syndrome in Mice. (2017, background): “…(ADAMTSs 1, 8, and 9) 17,18 ; degradation of cartilage oligomeric matrix protein (ADAMTSs 7 and 12) 19 ; cleavage of the matrix proteoglycan aggrecan, versican, and brevican (ADAMTSs 1, 4, 5, 8, 9, and 15) 20 e 23 ; and cleavage of ultralarge e molecular-weight von Willebrand factor (ADAMTS13).”
Human and mouse proteases: a comparative genomic approach (2003, methodology): “This is the case with ADAMTSs, which contain as many as 15 thrombospondin (TS) repeats in their structur”
Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis (2010, background): “7 ) are known targets of FURIN cleavage 57 - 59 .”
ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells. (2010, methodology): “15–17 Indeed, ADAMTS1 was previously shown to inhibit angiogenesis via both proteolytic and non-proteolytic mechanisms, ie, by cleavage of TSP-1 and TSP-2, releasing anti-angiogenic fragments, as well as by sequestration of the pro-angiogenic growth factor vascular endothelial growth factor (VEGF)16”
ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro (2005, background): “ADAMTS1, 8 and 9 have weak aggrecan-degrading activit”
The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family (2015, background): “elegans Gon-1), which contains 10 conserved cysteine residues [23].”