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

Department of Molecular, Cell and Developmental Biology, UCLA, Los Angeles, California 90095, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 09/1999; 274(33):23349-57. DOI: 10.1074/jbc.274.33.23349
Source: PubMed

ABSTRACT 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 NH(2) termini. We named these proteins METH-1 and METH-2 due to the novel combination of metalloprotease and thrombospondin 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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    • "All ADAMTS members contain similar sequences to the second and third repeats of type-1 thrombospondin repeats as shown by protein sequence alignment. It is possible that one or more of the three TSRs of ADAMTS-1 and the two TSRs in ADAMTS-8 contribute to their reported anti-angiogenic activity (Vazquez et al. 1999). ADAMTS-4, although phylogenetically closely related to ADAMTS-1, contains only one TSR, whereas other members of this group of metalloproteinases, such as ADAM- TS-9, contain up to 15 TSRs (Jones & Riley 2005). "
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    ABSTRACT: Angiogenesis is an indispensable mechanism in development and in many pathologies, including cancer, synovitis and aberrant wound healing. Many angiogenic stimulators and inhibitors have been investigated, and some have progressed to the clinic. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a group of multifunctional proteinases. ADAMTS-1 and ADAMTS-8 have been reported to be anti-angiogenic. Here, we provide evidence that ADAMTS-4, like ADAMTS-1, is expressed by endothelial cells and binds to vascular endothelial groth factor (VEGF). Moreover, ADAMTS-4 inhibited human dermal microvascular endothelial cells (HuDMEC) VEGF-stimulated VEGF receptor (R) R2 phosphorylation, differentiation and migration, suggesting that ADAMTS-4 may be a novel anti-angiogenic molecule.
    International Journal of Experimental Pathology 02/2012; 93(1):70-7. DOI:10.1111/j.1365-2613.2011.00802.x · 2.05 Impact Factor
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    • "U343 cells treated with cisplatin also showed upregulated (ADAMTS1 and CDH13), and down-regulated genes (GNB1, TIMP2, RHOA and ING1) related to cell proliferation . ADAMTS1 negatively regulates tumor growth and metastasis (Vazquez et al., 1999; Luque et al., 2003; Choi et al., 2008) , whereas TIMP2 takes part in degrading ECM (extracellular matrix) and regulating the invasion process (Lu et al., 2004), considered the root cause of the high recurrent incidence in glioblastoma (Kong et al., 2007). TIMPs have also been shown to exert pluripotential effects on cell growth, apoptosis and differentiation (Baker et al., 2002; Jiang et al., 2002). "
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    Genetics and Molecular Biology 03/2010; 33(1):159-68. DOI:10.1590/S1415-47572010005000013 · 0.88 Impact Factor
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    • "Critical evaluations of MMPI performance concluded that this was at least in part due to their broad spectrum activity (Zucker et al., 2000; Coussens et al., 2002; Overall and Lopez-Otin, 2002; Turk, 2006). This resulted in blockade of important off-target cellular processes that were in fact anti-tumorigenic (Vazquez et al., 1999) as well as activation of pro-tumorigenic signalling pathways (Maquoi et al., 2002) or interference with unrelated functions producing detrimental side effects such as tendonitis-like musculoskeletal pain (Giavazzi et al., 1998). Selective inhibitors can be designed by exploiting unique structural features within the active site. "
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    ABSTRACT: The kallikreins and kallikrein-related peptidases are serine proteases that control a plethora of developmental and homeostatic phenomena, ranging from semen liquefaction to skin desquamation and blood pressure. The diversity of roles played by kallikreins has stimulated considerable interest in these enzymes from the perspective of diagnostics and drug design. Kallikreins already have well-established credentials as targets for therapeutic intervention and there is increasing appreciation of their potential both as biomarkers and as targets for inhibitor design. Here, we explore the current status of naturally occurring kallikrein protease-inhibitor complexes and illustrate how this knowledge can interface with strategies for rational re-engineering of bioscaffolds and design of small-molecule inhibitors.
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