Biological Role of ADAMTS Proteases

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DESCRIPTION (provided by applicant): ADAMTS proteases have important functions such as processing of procollagen (ADAMTS-2, -3 and -14), large aggregating proteoglycans (ADAMTS-4, -5, -1), and von Willebrand factor (ADAMTS-13), with corresponding roles in disorders such as dermatosparaxis, arthritis, brain tumor invasion and idiopathic thrombocytopenic purpura. However, the biological function of most ADAMTS proteases is not known. ADAMTS-9 and ADAMTS-20, two enzymes we have discovered, are the largest of all ADAMTS enzymes. They have a unique domain structure similar to that of the C.elegans GON-1 enzyme that is essential for cell migration during gonadal morphogenesis. ADAMTS-20 is now known to have a role in neural crest cell migration, but the function of ADAMTS-9 is not known. Preliminary studies show that ADAMTS-9 has a unique temporal and spatial expression pattern in mesoderm and its derivatives during mouse development. We have found that this is the first family member to be localized to the cell surface, although it does not have a transmembrane domain. Furthermore, ADAMTS-9 transfected cells can cut a similar site in cartilage aggrecan as ADAMTS-4, suggesting that ADAMTS-9 is a cell surface aggrecanase. We report that ADAMTS-9 is present in rheumatoid synovium. These findings lead to the hypothesis that proteolysis of aggrecan, and related proteoglycans such as versican and brevican, by ADAMTS-9 is crucial to completion of normal development, as well as to diseases such as arthritis. The ancillary domains of ADAMTS-9 may play a substantial role in substrate recognition and targeting to the cell surface. The Specific Aims are to determine the physiological function of ADAMTS-9, characterize its activity against aggrecan and other substrates, and to determine the basis for such activity and for cell surface localization. In doing so, we anticipate comparing ADAMTS-9 to ADAMTS-20, as well as other relevant ADAMTS enzymes. These aims will be addressed by generation of ADAMTS-9 null mice, structure-function analysis, and analysis of potential substrates biochemically and in situ. The significance of these studies lies in improved fundamental understanding of proteolysis during development and human disease, especially arthritis.