Gene : 1 --> 4670
Exon : 1 --> 1185
CDS : 456 --> 3359
Signal peptide : 456 --> 602
Proprotein: 603 --> 3356
Mature peptide : 1212 --> 3356
Human ADAMTS1 DNA spans 4,649 bps. Its sequence is composed of 9 exons.

The ADAMTS1 gene is composed of nine exons, all of which are present within the 9.2-kb genomic region. Sequence analysis shows that the open reading frame of ADAMTS1 codes for a protein of 950 amino acids (Vazquez et al., 1999). Among these exons, exons 2 to 8 range from 133 to 347 bp in size. The first and the last exons are longer than the others. There are 4 polyadenylation signals in the untranslated region of exon 9. Exons 1, 5, and 6 encode a proprotein domain, a disintegrin-like domain and a TSP type I motif, respectively, of the ADAMTS1 protein. The metalloproteinase domain is encoded by the 3 exons: 2, 3 and 4. Exons 7 and 8 encode the spacer region (Kuno et al., 1997a).
ADAMTS1 is an IL-1 inducible gene since ADAMTS1 mRNA levels are enhanced 2 h after IL-1 stimulation (Kuno et al., 1997a). Moreover, ADAMTS1 mRNA expression is significantly enhanced in heart and kidney after lipopolysaccharide (LPS) treatment. These data indicate that the ADAMTS1 gene is an inflammation-associated gene.

No pseudogenes reported.

ADAMTS1 precursor: 967 amino acids; 105358 Da.

There are many cysteine residues, especially from residues 346 to 950, and four putative N-glycosylation sites in the ADAMTS1 protein. Comparison of the deduced amino acid sequence of ADAMTS1 protein with the data base (Human Genome Center, Institute of Medical Science, University of Tokyo) reveales that the middle part (519-615 amino acids) of the ADAMTS1 gene product shows about 40% homology with thrombospondin-1 and thrombospondin-2 (Kuno et al., 1997b). The TSP type I motifs present in the C-terminal half of ADAMTS1 are functional for binding to heparin. Moreover, analyses of deletion mutants have revealed that the carboxyl-terminal spacing region as well as three TSP type I motifs are responsible for the anchoring to the extracellular matrix (Kuno and Matsushima, 1998).
The proteinase domain of ADAMTS1 is capable of forming a covalent complex with alpha2-macroglobulin, a plasma proteolytic enzyme inhibitor that binds various types of proteinases, revealing that ADAMTS1 is an active metalloproteinase. The finding that a mutation of the zinc-binding motif of ADAMTS1 abrogates its capacity to bind to alpha2-macroglobulin confirmes the notion of an active proteinase (Kuno et al., 1999). However, in the potential zinc-binding motif of ADAMTS1, the Gly residue of the consensus sequence (HEXXHXXGXXH) is not conserved. Since ADAMTS1 is an active metalloproteinase, it is likely that the conserved Gly residue of the zinc-binding motif is functionally interchangeable with Asn (Kuno et al., 1999).
Studies have demonstrated that ADAMTS1 and fibulin-1 are colocalized in vivo. Interestingly, fibulin-1 has been found to enhance the capacity of ADAMTS1 to cleave aggrecan. Fibulin-1 seems therefore to be a new regulator of ADAMTS1-mediated proteoglycan proteolysis and may play an important role in proteoglycan turnover in tissues where there is overlapping expression (Lee et al., 2005).

To date, studies analyzing the expression of ADAMTS1 in normal tissues have leaded to controversial data. Tissue distribution of ADAMTS1 mRNA has been examined by Northern blot analysis by several research groups. While some research groups describe a very weak signal for ADAMTS1 mRNA in the heart and kidney and no ADAMTS1 mRNA expression in other organs including lung, liver, brain, and muscle, other groups describe an ADAMTS1 expression in every tissues analyzed, with abundant ADAMTS1 mRNA expression in adrenal, heart, and placenta, skeletal muscle, thyroid, and stomach. Of the embryonic tissues analyzed, kidney has showed the highest expression of ADAMTS1 mRNA. ADAMTS1 mRNA has been detected in dermal fibroblasts and at lower levels in vascular smooth muscle cells, endometrial stromal cells and in some endothelial cells (Vazquez et al., 1999).
Since the ADAMTS1 gene is activated by IL-1 stimulation in vitro, LPS has been administered intravenously into mice for induction of systemic inflammation. ADAMTS1 mRNA levels are significantly enhanced in heart and kidney after LPS treatment, but not in other organs (evaluated by Northern blot analysis). This result indicates that the ADAMTS1 gene is an inflammation-associated gene (Kuno et al., 1997b).
ADAMTS1 mRNA has been detected in the ischemic myocardium. Endothelial cells, which weakly express ADAMTS1 mRNA in the normal heart, have shown increased expression of ADAMTS1 mRNA immediately after myocardial infarction concomitant with VEGF expression (Nakamura et al., 2004).
Increased ADAMTS1 mRNA expression has been observed in the kidney by in situ hybridization after induction of unilateral ureteral obstruction (Nakamura et al., 2007).
In granulosa cells, progesterone receptor appears to play the role of an inducible coregulator of the ADAMTS1 gene (Doyle et al., 2004).

Extracellular localization, anchored to the extracellular matrix through C-terminal spacing region and thrombospondin type I motifs.

ADAMTS1 is a catalytic active protein and identified substrates of ADAMTS1 are principally proteoglycans such as aggrecan and versican (Kuno et al., 2000; Rodriguez-Manzaneque et al., 2002).
ADAMTS1 is able to cleave ligands of the EGF (Epidermal Growth Factor) receptor such as pro-HBEGF (Heparin-binding EGF-like Growth Factor) or pro-amphiregulin (Liu et al., 2006).
Two new substrates of ADAMTS1 have been identified recently: thrombospondin-1 and thrombospondin-2 (Lee et al., 2006).
Like many members of the ADAM and ADAMTS subfamilies, ADAMTS1 shares many physiological and pathological functions. Studies using ADAMTS1-knock-out mice showed that this proteinase is important for normal growth, organogenesis and fertility (Mittaz et al., 2004).
ADAMTS1 is implicated in inflammatory processes since a treatment of mice with LPS enhances ADAMTS1 expression in tissues (Kuno et al., 1997b).

Comparison of the human and mouse sequences of ADAMTS1 reveals highly conservation (83.4% amino acid identity). The overall amino acid sequence identity between ADAMTS1 and ADAMTS-8 is 51.7% (Vazquez et al., 1999).

A down-regulation of ADAMTS1 has been observed in some non small cell lung cancer (NSCLC) cell lines and is concordant with an aberrant methylation of the gene. In NSCLC tumours, aberrant methylation of the gene has been observed in 31.6% of samples, while it was found in only 7.1% of nonmalignant tissues (Choi et al., 2008).
In colorectal tumors, ADAMTS1 gene is associated to a cancer-specific hypermethylation. Among 20 colon cancer cell lines, hypermethylation of the ADAMTS1 gene was identified in 85% of cell lines. The methylation status of ADAMTS1 has also been investigated in colorectal adenomas and carcinomas. 37% of adenomas as well as 71% of carcinomas showed hypermethylation for the ADAMTS1 gene. However, ADAMTS1 is unmethylated in tumors from three other organs, prostate, testis, and kidney (Lind et al., 2006).