METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity

We have studied two related proteins that contain a repeated amino acid mot if homologous to the anti-angiogenic type 1 repeats of thrombospondin-1 (TS P1), Complete sequence analysis revealed no other similarities with TSP1, b ut identified unique signal sequences, as well as metalloprotease and disin tegrin-like domains in the NH2 termini. We named these proteins METH-1 and METH-S due to the novel combination of metalloprotease and thrombospondin d omains, Overall amino acid sequence identity between METH-1 and METH-2 is 5 1.7%, yet transcript distribution revealed non-overlapping patterns of expr ession in tissues and cultured cell lines. To characterize these proteins f unctionally, we isolated full-length cDNAs, produced recombinant protein, a nd generated antisera to the recombinant proteins. Both METH-1 and METH-2 r epresent single copy genes, which encode secreted and proteolytically proce ssed proteins. METH proteins suppressed fibroblast growth factor-alpha-indu ced vascularization in the cornea pocket assay and inhibited vascular endot helial growth factor-induced angiogenesis in the chorioallantoic membrane a ssay. Suppression of vessel growth in both assays was considerably greater than that mediated by either thrombospondin-1 or endostatin on a molar basi s. Consistent with an endothelial specific response, METH-1 and METH-2 were shown to inhibit endothelial cell proliferation, but not fibroblast or smo oth muscle growth. We propose that METH-1 and METH-2 represent a new family of proteins with metalloprotease, disintegrin, and thrombospondin domains. The distinct distribution of each gene product suggests that each has evol ved distinct regulatory mechanisms that potentially allow for fine control of activity during distinct physiological and pathological states,