*605175	Links
A DISINTEGRIN-LIKE AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 8; ADAMTS8

Alternative titles; symbols

METH2

Gene map locus 11q25

TEXT

Thrombospondin-1 (THBS1; 188060) associates with the extracellular matrix and inhibits angiogenesis in vivo. In vitro, THBS1 blocks capillary-like tube formation and endothelial cell proliferation. The antiangiogenic activity is mediated by a region that contains 3 type 1 (properdin or thrombospondin) repeats. By searching an EST database for sequences containing the antiangiogenic motif of THBS1, Vazquez et al. (1999) identified heart and lung cDNAs encoding ADAMTS1 (605174) and ADAMTS8, which they called METH1 and METH2, respectively. Sequence analysis predicted that the 890-amino acid ADAMTS8 protein shares 52% amino acid identity with ADAMTS1. ADAMTS8 is a secreted protein that has an N-terminal signal peptide, a zinc metalloprotease domain containing a zinc-binding site, and a cysteine-rich region containing 2 putative disintegrin loops. The C terminus of ADAMTS8 has 2 heparin-binding thrombospondin repeats with 6 cys and 3 trp residues. Southern blot analysis showed that ADAMTS8 is a single-copy gene distinct from that encoding ADAMTS1. Northern blot analysis detected highest expression of a 3.7-kb ADAMTS8 transcript in adult and fetal lung, with lower expression in brain, placenta, heart, and stomach, as well as fetal brain and kidney. Expression was also detected in a colon carcinoma cell line. SDS-PAGE analysis demonstrated that ADAMTS8 is expressed as a 98-kD protein, a 79-kD protein after cleavage at the subtilisin site, or as a 64-kD protein, which is most abundant, generated by an additional processing event. Functional analysis determined that ADAMTS8 disrupts angiogenesis in vivo and in vitro more efficiently than THBS1 or endostatin (120328) but somewhat less efficiently than ADAMTS1.

By interspecific backcross analysis, Georgiadis et al. (1999) mapped the mouse Adamts8 gene to chromosome 9 in a region showing homology of synteny with human 11q23-qter. They mapped the human ADAMTS8 gene to 11q25 by PCR analysis of a radiation hybrid mapping panel. The authors noted that a number of disorders have been mapped in the vicinity of the ADAMTS8 gene in mice and humans, most notably, given the expression and functional analyses, lung neoplasms.

REFERENCES

1. Georgiadis, K. E.; Hirohata, S.; Seldin, M. F.; Apte, S. S. :

ADAM-TS8, a novel metalloprotease of the ADAM-TS family located on mouse chromosome 9 and human chromosome 11. Genomics 62: 312-315, 1999.
PubMed ID : 10610729

2. Vazquez, F.; Hastings, G.; Ortega, M.-A.; Lane, T. F.; Oikemus, S.; Lombardo, M.; Iruela-Arispe, M. L. :

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, 1999.
PubMed ID : 10438512

CREATION DATE

Paul J. Converse : 7/27/2000

EDIT HISTORY

mgross : 7/27/2000

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