ADAMTS9 (ADAM metallopeptidase with thrombospondin type 1 motif, 9)

2013-12-01   Sawako Yoshina , Shohei Mitani 

Department of Physiology, Tokyo Womens Medical University School of Medicine, Tokyo, Japan

Identity

HGNC
LOCATION
3p14.1
LOCUSID
ALIAS
-
FUSION GENES

DNA/RNA

Description

The human ADAMTS9 gene is composed of 40 exons spanning a genomic region of about 172 kbp. The open reading frame of the coding region is 5808 bp.

Pseudogene

No pseudogene reported.

Proteins

Atlas Image
Diagram of the human ADAMTS9 protein.

Description

ADAMTS9 is composed of a signal peptide, a propeptide, a metalloproteinase domain, a disintegrin-like domain, thrombospondin type 1-like repeats, a cystein-rich domain, a spacer domain, and a unique C-terminal domain (Somerville et al., 2003). A unique C-terminal domain was named as GON domain. The GON domain functions in the ER for protein transport from the ER to the Golgi (Yoshina et al., 2012). N-linked glycosylation of ADAMTS9 propeptide is found to be essential for ADAMTS9 secretion (Koo et al., 2007). ADAMTS9 is processed by furin extracellularly but not in the secretory pathway (Koo et al., 2006). Following furin processing, mature ADAMTS9 is released from the cell surface (Koo et al., 2007).
ADAMTS9 is required for early mouse development. ADAMTS9 null mice die before gastrulation. ADAMTS9+/- mice develop anomalous eye such as corneal clouding, corneal neovascularisation, and adhesions of the lens and iris to the cornea (Koo et al., 2010).

Expression

ADAMTS9 is found in adult human ovary, pancreas, heart, kidney, lung, placenta, and skeletal muscle. ADAMTS9 is found in fetal brain, heart, kidney, lung, liver, skeletal muscle, spleen and thymus. According to northern blot analysis, the highest mRNA levels are found in heart, placenta, and skeletal muscle (Clark et al., 2000; Somerville et al., 2003). ADAMTS9 is expressed in microvascular endothelial cells (Koo et al., 2010).
Following stimulation with TNFalpha, ADAMTS9 mRNA expression was enhanced in a human retinal pigment epithelial cell line (ARPE-19) (Bevitt et al., 2003). In a human chondrosarcoma cell line (OUMS-27) and human chondrocytes, exposure to IL-1 beta or TNF alpha upregulate ADAMTS9 mRNA expression (Demircan et al., 2005). Induction of ADAMTS9 mRNA by IL-1beta was reported to occur via NFATc binding to the ADAMTS9 promoter in the OUMS-27 and in human chondrocyte (Yaykasli et al., 2009). In the human lung carcinoma epithelial cell line (A549), exposure to TGF- beta or IL-13 or Epstein-Barr virus infection led to enhanced ADAMTS9 mRNA expression. IL-4 exposure had no effect on the expression of ADAMTS9 in A549 (Keating et al., 2006).

Localisation

ADAMTS9 is present at the plasma membrane and the endoplasmic reticulum (Somerville et al., 2003; Yoshina et al., 2012).

Function

ADAMTS9 cleaves aggrecan and versican (Somerville et al., 2003). ADAMTS9 is involved in cell migration and inhibition of angiogenesis (Koo et al., 2010).
ADAMTS9 is implicated in the transport from the endoplasmic reticulum to the Golgi. This function is GON-domain dependent but protease activity independent (Yoshina et al., 2012).

Homology

ADAMTS9 and ADAMTS20 have the identical domain organization and exon structure and a similar primaly sequence. The unique C-terminal domain, GON domain, is highly similar in ADAMTS9 and ADAMTS20 (Somerville et al., 2003).

Mutations

Note

A downregulation of ADAMTS9 has been observed in some carcinoma that is induced by aberrant methylation of the gene.
The major C-risk allele of rs4607103 near ADAMTS9, conferring increased risk of type 2 diabetes.

Implicated in

Entity name
Esophageal squamous cell carcinoma
Note
Complete loss or downregulation of ADAMTS9 gene expression was found in 15 out of 16 esophageal carcinoma cell lines. Promoter hypermethylation was involved in gene downregulation. Downregulation of ADAMTS9 was also found in primary esophageal tumor tissues from Hong Kong and from the high-risk region of Henan (Lo et al., 2007). Downregulation of ADAMTS9 expression led to tumorigenesis. Overexpression of ADAMTS9 induced suppression of tumor formation and angiogenesis in esophageal carcinoma cell line (Lo et al., 2010).
Entity name
Nasopharyngeal carcinoma
Note
ADAMTS9 was downregulated in nasopharyngeal carcinoma cell lines. The mechanism of ADAMTS9 gene inactivation was attributed to promoter hypermethylation (Lung et al., 2008). Downregulation of ADAMTS9 expression led to tumorigenesis. Overexpression of ADAMTS9 induced suppression of tumor formation and angiogenesis in nasopharyngeal carcinoma cell line (Lo et al., 2010).
Entity name
Colorectal cancer
Note
The frequency of ADAMTS9 promoter methylation in primary colorectal cancers was significantly higher than in normal tissues (Zhang et al., 2010).
Entity name
Gastric cancer
Note
The frequency of ADAMTS9 promoter methylation in primary gastric cancers was significantly higher than in normal tissues (Zhang et al., 2010; Du et al., 2013). ADAMTS9 contributes to the suppression of tumorigenesis by decreasing cell proliferation, inducing cell apoptosis and inhibiting angiogenesis through regulating AKT/mTOR signaling pathway (Du et al., 2013).
Entity name
Pancreatic cancer
Note
The frequency of ADAMTS9 promoter methylation in primary pancreatic cancers was significantly higher than in normal tissues (Zhang et al., 2010).
Entity name
Type II diabetes
Note
Genome-wide assosiation studies (GWAS) linked a marker near the ADAMTS9 locus to type II diabetes (Zeggini et al., 2008). The major C allele of rs4607103, located upstream of ADAMTS9, was established as a diabetes risk variant in GWAS. rs4607103 is associated with a decrease in insulin sensitivity of peripheral tissues (Boesgaard et al., 2009; Trombetta et al., 2013).

Bibliography

Pubmed IDLast YearTitleAuthors
126973332003Expression of ADAMTS metalloproteinases in the retinal pigment epithelium derived cell line ARPE-19: transcriptional regulation by TNFalpha.Bevitt DJ et al
197896302009Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study.Boesgaard TW et al
109360552000ADAMTS9, a novel member of the ADAM-TS/ metallospondin gene family.Clark ME et al
158808122005ADAMTS-9 is synergistically induced by interleukin-1beta and tumor necrosis factor alpha in OUMS-27 chondrosarcoma cells and in human chondrocytes.Demircan K et al
229074342013ADAMTS9 is a functional tumor suppressor through inhibiting AKT/mTOR pathway and associated with poor survival in gastric cancer.Du W et al
169488402006Microarray identifies ADAM family members as key responders to TGF-beta1 in alveolar epithelial cells.Keating DT et al
200934842010ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells.Koo BH et al
174036802007Regulation of ADAMTS9 secretion and enzymatic activity by its propeptide.Koo BH et al
167996312007Identification of a tumor suppressive critical region mapping to 3p14.2 in esophageal squamous cell carcinoma and studies of a candidate tumor suppressor gene, ADAMTS9.Lo PH et al
205510502010Extracellular protease ADAMTS9 suppresses esophageal and nasopharyngeal carcinoma tumor formation by inhibiting angiogenesis.Lo PH et al
184498902008Characterization of a novel epigenetically-silenced, growth-suppressive gene, ADAMTS9, and its association with lymph node metastases in nasopharyngeal carcinoma.Lung HL et al
125141892003Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1.Somerville RP et al
231614422013PPARG2 Pro12Ala and ADAMTS9 rs4607103 as "insulin resistance loci" and "insulin secretion loci" in Italian individuals. The GENFIEV study and the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 4.Trombetta M et al
190528452009ADAMTS9 activation by interleukin 1 beta via NFATc1 in OUMS-27 chondrosarcoma cells and in human chondrocytes.Yaykasli KO et al
224198202012Identification of a novel ADAMTS9/GON-1 function for protein transport from the ER to the Golgi.Yoshina S et al
183729032008Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.Zeggini E et al
199631342010High-resolution melting analysis of ADAMTS9 methylation levels in gastric, colorectal, and pancreatic cancers.Zhang C et al

Other Information

Locus ID:

NCBI: 56999
MIM: 605421
HGNC: 13202
Ensembl: ENSG00000163638

Variants:

dbSNP: 56999
ClinVar: 56999
TCGA: ENSG00000163638
COSMIC: ADAMTS9

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000163638ENST00000295903Q9P2N4
ENSG00000163638ENST00000459780C9JWI2
ENSG00000163638ENST00000467257A0A087WTS1
ENSG00000163638ENST00000481060H0Y859
ENSG00000163638ENST00000498707Q9P2N4

Expression (GTEx)

0
10
20
30
40
50
60

Pathways

PathwaySourceExternal ID
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
O-linked glycosylationREACTOMER-HSA-5173105
O-glycosylation of TSR domain-containing proteinsREACTOMER-HSA-5173214
DiseaseREACTOMER-HSA-1643685
Diseases of glycosylationREACTOMER-HSA-3781865
Extracellular matrix organizationREACTOMER-HSA-1474244
Degradation of the extracellular matrixREACTOMER-HSA-1474228
Diseases associated with O-glycosylation of proteinsREACTOMER-HSA-3906995
Defective B3GALTL causes Peters-plus syndrome (PpS)REACTOMER-HSA-5083635

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
183729032008Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.829
209356292010Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.396
190203232008Genotype score in addition to common risk factors for prediction of type 2 diabetes.304
190203242008Clinical risk factors, DNA variants, and the development of type 2 diabetes.262
185913882008Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk.129
186949742008Predicting type 2 diabetes based on polymorphisms from genome-wide association studies: a population-based study.121
200751502010Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: Whitehall II prospective cohort study.95
125141892003Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1.92
198623252009PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 are associated with type 2 diabetes in a Chinese population.70
208898532011Genetic risk reclassification for type 2 diabetes by age below or above 50 years using 40 type 2 diabetes risk single nucleotide polymorphisms.65

Citation

Sawako Yoshina ; Shohei Mitani

ADAMTS9 (ADAM metallopeptidase with thrombospondin type 1 motif, 9)

Atlas Genet Cytogenet Oncol Haematol. 2013-12-01

Online version: http://atlasgeneticsoncology.org/gene/577/adamts9