Abstract : ADAMTSl/METHl is a secreted protease that belongs to the metallospondin/ADAMTS sub-family of the zinc-metalloprotease superfamily. This family is characterized by proteins that contain a modular structure that includes A, Disintegrin-like, Metalloprotease, and type-1 ThromboSpondin domains. ADAMTSl has been shown to inhibit both endothelial cell proliferation in vitro, as well as angiogenesis in vivo. We have investigated the role of ADAMTSl and its proteolytic activity, through the creation of a catalytically inactive mutant (ADAMTSl(sub E385A), in tumor growth by overexpressing the coding region in a human breast carcinoma cell line (T47D) and generating xenograft tumors in nude mice. T47D ADAMTSl(sub E385A) tumors displayed no significant difference in growth kinetics when compared to CON tumors; whereas wild-type ADAMTSl tumors exhibited two-fold growth inhibition at 40 days post- implantation. We have also studied the activity of ADAMTSl on endothelial cells in vitro and have determined that ADAMTSl releases proteins from the cell surface. We also provide evidence to support that the catalytic activity of ADAMTSl either directly or indirectly affects growth factor signaling impairing VEGF:VEGFR2 interactions both in vitro and in vivo. Thus ADAMTSl can be distinguished as a secreted metalloprotease that inhibits tumor growth and angiogenesis through its activity as a protease.