Vazquez, F. et al. METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity. J. Biol. Chem. 274, 23349-23357

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


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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    • "It is also found that ADAMTS1 has some proteolytic activity and shows a certain substrate specificity among others with aggrecan, although the places of cleavages made by ADAMTS1 vary from other aggrecans (79). At the beginning of research, the inhibition of angiogenesis was specified as a basic function of ADAMTS1 (41). It was proved that this protein silences the proliferation signal caused by VEGF and FGF2 via the inhibition of VEGFR2 phosphorylation (80). "
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    ABSTRACT: The ADAM and ADAMTS families, also called adamalysins belong to an important group of extracellular matrix proteins. The ADAMs family belong to both the transmembrane and secreted proteins, while ADAMTS family only contains secreted forms. Adamalysins play an important role in the cell phenotype regulation via their activities in signaling pathways, cell adhesion and migration. The human proteome contains 21 ADAM, and 19 ADAMTS proteins, which are involved in extracellular matrix remodeling, shedding of various substrates such as: adhesion ligands, growth factors, their receptors and diverse cytokines. Recent studies provide evidence that adamalysins play a crucial role in colorectal cancer (CRC) etiopathogenesis. It seems possible that adamalysins might be used as CRC prediction markers or potential pharmaceutical targets. [BMB Reports 2013; 46(3): 139-150].
    Full-text · Article · Mar 2013 · BMB reports
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    • "Moreover, the involvement of Btg2 during fear conditioning was suggested by a behavioral experiment using the knock-out mice [26] and a genome-wide association study using a trait loci mapping method [27]. Adamts1 is the first member of ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) [28] and has been shown to display anti-angiogenic properties [29] and a role in the turnover of the extracellular matrix in the central nervous system [30]. It has been reported that the gene expression of Adamts1 was increased by an insult of ischemia in the hippocampus [31] and cerebral cortex [32,33] of rodents. "
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    ABSTRACT: Anxiety and stress-related disorders are among the most common psychiatric disorders. The hippocampus is a crucial brain area involved in the neural circuits of the pathophysiology of anxiety and stress-related disorders, and GABA is one of most important neurotransmitters related to these disorders. An anxiogenic drug and a pharmacological stressor, FG7142 (N-methyl-ß-carboline-3-carboxamide), produces anxiety in humans and experimental animals, acting at the benzodiazepine sites of the GABAA receptors as a partial inverse agonist. This drug as well as immobilization stress produced an increased mRNA in a number of genes, e.g., Btg2 and Adamsts1, in the cortex of rodents. The present study was carried out to clarify the effect of the anxiogenic drug on the gene expressions in the hippocampus and to obtain a new insight into the GABAergic system involved in the pathophysiology of the disorders. We examined the effects of FG7142 on the gene expression of Btg2 and Adamts1 in the hippocampus of mice using a quantitative RT-PCR method as well as an in situ hybridization method. The intraperitoneal administration of FG7142 at a dose of 20 mg/kg, but not 10 mg/kg, induced a statistically significant increase in the hippocampal mRNA of both genes in adult mice (postnatal days 56), being blocked by co-administrations of flumazenil (twice of 10 mg/kg, i.p.), an antagonist at the benzodiazepine binding site, while FG7142 failed to produce any change in the gene expressions in infant mice (postnatal days 8). In addition, the in situ hybridization experiment demonstrated an upregulation of the gene expressions restricted to the dentate gyrus of the hippocampus in adult mice. The present study suggests a functional coupling between the GABAergic system and the transcriptional regulation of the two genes (Btg2 and Adamsts1) in the hippocampus of adult mice, which may play a role in the brain function related to anxiety and stress such as memory of fear.
    Full-text · Article · Aug 2012 · Behavioral and Brain Functions
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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.
    Full-text · Article · Feb 2012 · International Journal of Experimental Pathology
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