Molecular Cloning of a Gene Encoding a New Type of Metalloproteinase-disintegrin Family Protein with Thrombospondin Motifs as an Inflammation Associated Gene

Abstract

A cellular disintegrin and metalloproteinase (ADAM) is a new family of genes with structural homology to the snake venom metalloproteinases and disintegrins. We screened genes which were selectively expressed in the cachexigenic colon 26 adenocarcinoma subline in vivo. It was found that one novel cDNA clone, identified as a cachexigenic tumor selective gene, encodes a cysteinerich protein which shows a sequence similarity to that of both the snake venom metalloproteinases and thrombospondins. We named this cDNA clone A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-1). ADAMTS1 consists of six domains, 1) a proand 2) a metalloproteinase, 3) a disintegrin-like, 4) a thrombospondin (TSP) homologous domain containing TSP type I motif, 5) a spacer region, and 6) COOH-terminal TSP submotifs. Unlike other ADAMs, ADAMTS-1 does not possess a transmembrane domain and is a putative secretory protein. Therefore, ADAMTS-1 is a new type of ADAM family protein with TSP type I motifs. We demonstrated that the TSP homologous domain containing the TSP type I motif of ADAMTS-1 is functional for binding to heparin. ADAMTS-1 mRNA could be induced by stimulating colon 26 cells with an inflammatory cytokine, interleukin-1, in vitro. Moreover, intravenous administration of lipopolysaccharide in mice selectively induced ADAMTS-1 mRNA in kidney and heart. These data suggest that ADAM-TS-1 may be a gene whose expression is associated with various inflammatory processes as well as development of cancer cachexia.

Tissue-specific induction of ADAMTS2 in monocytes and macrophages by glucocorticoids

“…All of the selected genes showed only a moderate induction between 4-and 13-fold, which is low compared to ADAMTS2 which was induced 150-fold in the same experiments. In the original description, ADAMTS1 was shown to be induced by interleukin-1 and lipopolysaccharide suggesting a role in inflammatory processes [39]. Therefore, a modulation by GC treatment could have been expected, but the effect seen was only a 4-fold induction in GC-treated MDM (Fig.…”

Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC)

“…It plays significant roles in organogenesis, inhibition of VEGF and fibroblast growth factor (FGF-2)-induced angiogenesis (IruelaArispe et al, 2003) and is associated with IL-1 and LPS-induced inflammation (Kuno et al, 1997). ADAMTS-1 has been shown to bind VEGF-A 165 and to inhibit VEGF-A 165 -stimulated VEGF-R2 phosphorylation .…”

“…Monocytes from lung cancer patients produce elevated levels of mature TNF-a (Trejo et al, 2001) which could result from the shedding of pro-TNF-a by ADAM-17 (TACE) (Black et al, 1997). ADAM with TS-like motifs-1 (ADAMTS-1) is expressed in colon cancer cells (Kuno et al, 1997).…”

Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively

“…ADAMTS-1 has a unique domain organization, being composed of the propeptide, metalloproteinase, disintegrin, and cysteine-rich (Cys-rich) domains, domains containing thrombospondin type I-like (TSP-1) motifs, and a spacer region (Kuno et al, 1997;Vazquez et al, 1999;Cal et al, 2002;Figure 1A). There are at least 19 members of the ADAMTS family, of which ADAMTS-1 was the first to be identified.…”