METH-1, a Human Ortholog of ADAMTS-1, and METH-2 Are Members of a New Family of Proteins with Angio-inhibitory Activity*

By F. Vázquez, G. Hastings, M. Ortega, T. Lane, S. Oikemus, M. Lombardo, M. Luisa Iruela-Arispe. 1999

We have studied two related proteins that contain a repeated amino acid motif homologous to the anti-angiogenic type 1 repeats of thrombospondin-1 (TSP1). Complete sequence analysis revealed no other similarities with TSP1, but identified unique signal sequences, as well as metalloprotease and disintegrin-like domains in the NH2 termini. We named these proteins METH-1 and METH-2 due to the novel combination of metalloprotease andthrombospondin domains. Overall amino acid sequence identity between METH-1 and METH-2 is 51.7%, yet transcript distribution revealed non-overlapping patterns of expression in tissues and cultured cell lines. To characterize these proteins functionally, we isolated full-length cDNAs, produced recombinant protein, and generated antisera to the recombinant proteins. Both METH-1 and METH-2 represent single copy genes, which encode secreted and proteolytically processed proteins. METH proteins suppressed fibroblast growth factor-2-induced vascularization in the cornea pocket assay and inhibited vascular endothelial growth factor-induced angiogenesis in the chorioallantoic membrane assay. Suppression of vessel growth in both assays was considerably greater than that mediated by either thrombospondin-1 or endostatin on a molar basis. Consistent with an endothelial specific response, METH-1 and METH-2 were shown to inhibit endothelial cell proliferation, but not fibroblast or smooth 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 evolved distinct regulatory mechanisms that potentially allow for fine control of activity during distinct physiological and pathological states.

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Citations in the corpus

• Differentially regulated ADAMTS1, 8, and 18 in gastric adenocarcinoma (2017, background): “While aggrecanase activity specifi c to some ECM substrats including aggrecan and versican is the leading property of ADAMTS1, it has also a potent anti-angiogenic property which was fi rst identifi ed by Vazquez et al (12).”
• The ADAMTS metalloproteinases. (2005, background): “and Iruela-Arispe, M. L. (2000) Characterization of METH-1/ADAMTS1 processing reveals two distinct active forms.”
• Strategies for MMP inhibition in cancer: innovations for the post-trial era (2002, background): “MMPIs also target proteases such as the ADAMTSs, which slow tumour growth through their antiangiogenic activitie”
• The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family (2015, background): “This subgroup has also been labeled ‘angioinhibitory’ on the basis of the original identification of ADAMTS1 and 8 as antiangiogenic factors [6]; nevertheless, ADAMTSs in other clades also have effects on angiogenesis.”
• Expression of ADAMTS1 and Its Correlation with Angiogenesis in Primary Gastric Cancer and Lymph Node Metastasis (2013, background): “It has been demonstrated that ADAMTS1 is a potent inhibitor of angiogenesis and can inhibit VEGF-induced angiogenesis [8, 43].”
• Papilin in development; a pericellular protein with a homology to the ADAMTS metalloproteinases. (2000, background): “Metalloproteinases that contain the papilin cassette can profoundly affect organogenesis positively, as shown by gon1, or negatively, as inhibitors of angiogenesis (Vazquez et al., 1999).”
• Gene expression patterns in human liver cancers. (2002, methodology): “One of the few genes in this group that did not belong to the liver-specific cluster encodes the metalloprotease ADAMTS1, which was recently shown to inhibit endothelial cell proliferation and to have antiangiogenic activity (Vazquez et al., 1999).”
• ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity (2010, background): “As another example, two metalloproteinases of the ADAMTS family, ADAMTS-1 and -8, were also reported to strongly inhibit angiogenesis [13, 14].”
• Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis (2010, unknown): “The finding of antiangiogenic effects for a member of the ADAMTS family is not unprecedented as it has also been described for ADAMTS-1 and ADAMTS-8 (Vazquez et al., 1999; Dunn et al., 2006).”