Written | 2013-12 | Sawako Yoshina, Shohei Mitani |
Department of Physiology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan |
Identity |
HGNC (Hugo) | ADAMTS9 |
HGNC Alias symb | KIAA1312 |
HGNC Previous name | a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 9 |
LocusID (NCBI) | 56999 |
Atlas_Id | 577 |
Location | 3p14.1 [Link to chromosome band 3p14] |
Location_base_pair | Starts at 64515655 and ends at 64688000 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping ADAMTS9.png] |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
ADAMTS9 (3p14.1) / CHL1 (3p26.3) | ADAMTS9 (3p14.1) / SYNPR (3p14.2) | ADAMTS9 (3p14.1) / ULK4 (3p22.1) | |
ZNF619 (3p22.1) / ADAMTS9 (3p14.1) |
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. |
Protein |
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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 |
Note | |
Entity | 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 | 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 | 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 | 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 | 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 | 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 |
Expression of ADAMTS metalloproteinases in the retinal pigment epithelium derived cell line ARPE-19: transcriptional regulation by TNFalpha. |
Bevitt DJ, Mohamed J, Catterall JB, Li Z, Arris CE, Hiscott P, Sheridan C, Langton KP, Barker MD, Clarke MP, McKie N. |
Biochim Biophys Acta. 2003 Apr 15;1626(1-3):83-91. |
PMID 12697333 |
Variant 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, Gjesing AP, Grarup N, Rutanen J, Jansson PA, Hribal ML, Sesti G, Fritsche A, Stefan N, Staiger H, Haring H, Smith U, Laakso M, Pedersen O, Hansen T; EUGENE2 Consortium. |
PLoS One. 2009 Sep 30;4(9):e7236. doi: 10.1371/journal.pone.0007236. |
PMID 19789630 |
ADAMTS9, a novel member of the ADAM-TS/ metallospondin gene family. |
Clark ME, Kelner GS, Turbeville LA, Boyer A, Arden KC, Maki RA. |
Genomics. 2000 Aug 1;67(3):343-50. |
PMID 10936055 |
ADAMTS-9 is synergistically induced by interleukin-1beta and tumor necrosis factor alpha in OUMS-27 chondrosarcoma cells and in human chondrocytes. |
Demircan K, Hirohata S, Nishida K, Hatipoglu OF, Oohashi T, Yonezawa T, Apte SS, Ninomiya Y. |
Arthritis Rheum. 2005 May;52(5):1451-60. |
PMID 15880812 |
ADAMTS9 is a functional tumor suppressor through inhibiting AKT/mTOR pathway and associated with poor survival in gastric cancer. |
Du W, Wang S, Zhou Q, Li X, Chu J, Chang Z, Tao Q, Ng EK, Fang J, Sung JJ, Yu J. |
Oncogene. 2013 Jul 11;32(28):3319-28. doi: 10.1038/onc.2012.359. Epub 2012 Aug 20. |
PMID 22907434 |
Microarray identifies ADAM family members as key responders to TGF-beta1 in alveolar epithelial cells. |
Keating DT, Sadlier DM, Patricelli A, Smith SM, Walls D, Egan JJ, Doran PP. |
Respir Res. 2006 Sep 1;7:114. |
PMID 16948840 |
ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells. |
Koo BH, Coe DM, Dixon LJ, Somerville RP, Nelson CM, Wang LW, Young ME, Lindner DJ, Apte SS. |
Am J Pathol. 2010 Mar;176(3):1494-504. doi: 10.2353/ajpath.2010.090655. Epub 2010 Jan 21. |
PMID 20093484 |
Regulation of ADAMTS9 secretion and enzymatic activity by its propeptide. |
Koo BH, Longpre JM, Somerville RP, Alexander JP, Leduc R, Apte SS. |
J Biol Chem. 2007 Jun 1;282(22):16146-54. Epub 2007 Apr 2. |
PMID 17403680 |
Identification 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, Leung AC, Kwok CY, Cheung WS, Ko JM, Yang LC, Law S, Wang LD, Li J, Stanbridge EJ, Srivastava G, Tang JC, Tsao SW, Lung ML. |
Oncogene. 2007 Jan 4;26(1):148-57. Epub 2006 Jun 26. |
PMID 16799631 |
Extracellular protease ADAMTS9 suppresses esophageal and nasopharyngeal carcinoma tumor formation by inhibiting angiogenesis. |
Lo PH, Lung HL, Cheung AK, Apte SS, Chan KW, Kwong FM, Ko JM, Cheng Y, Law S, Srivastava G, Zabarovsky ER, Tsao SW, Tang JC, Stanbridge EJ, Lung ML. |
Cancer Res. 2010 Jul 1;70(13):5567-76. doi: 10.1158/0008-5472.CAN-09-4510. Epub 2010 Jun 15. |
PMID 20551050 |
Characterization of a novel epigenetically-silenced, growth-suppressive gene, ADAMTS9, and its association with lymph node metastases in nasopharyngeal carcinoma. |
Lung HL, Lo PH, Xie D, Apte SS, Cheung AK, Cheng Y, Law EW, Chua D, Zeng YX, Tsao SW, Stanbridge EJ, Lung ML. |
Int J Cancer. 2008 Jul 15;123(2):401-8. doi: 10.1002/ijc.23528. |
PMID 18449890 |
Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1. |
Somerville RP, Longpre JM, Jungers KA, Engle JM, Ross M, Evanko S, Wight TN, Leduc R, Apte SS. |
J Biol Chem. 2003 Mar 14;278(11):9503-13. Epub 2003 Jan 3. |
PMID 12514189 |
PPARG2 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, Bonetti S, Boselli ML, Miccoli R, Trabetti E, Malerba G, Pignatti PF, Bonora E, Del Prato S, Bonadonna RC. |
Acta Diabetol. 2013 Jun;50(3):401-8. doi: 10.1007/s00592-012-0443-9. Epub 2012 Nov 17. |
PMID 23161442 |
ADAMTS9 activation by interleukin 1 beta via NFATc1 in OUMS-27 chondrosarcoma cells and in human chondrocytes. |
Yaykasli KO, Oohashi T, Hirohata S, Hatipoglu OF, Inagawa K, Demircan K, Ninomiya Y. |
Mol Cell Biochem. 2009 Mar;323(1-2):69-79. doi: 10.1007/s11010-008-9965-4. Epub 2008 Dec 4. |
PMID 19052845 |
Identification of a novel ADAMTS9/GON-1 function for protein transport from the ER to the Golgi. |
Yoshina S, Sakaki K, Yonezumi-Hayashi A, Gengyo-Ando K, Inoue H, Iino Y, Mitani S. |
Mol Biol Cell. 2012 May;23(9):1728-41. doi: 10.1091/mbc.E11-10-0857. Epub 2012 Mar 14. |
PMID 22419820 |
Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. |
Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G, Ardlie K, Bostrom KB, Bergman RN, Bonnycastle LL, Borch-Johnsen K, Burtt NP, Chen H, Chines PS, Daly MJ, Deodhar P, Ding CJ, Doney AS, Duren WL, Elliott KS, Erdos MR, Frayling TM, Freathy RM, Gianniny L, Grallert H, Grarup N, Groves CJ, Guiducci C, Hansen T, Herder C, Hitman GA, Hughes TE, Isomaa B, Jackson AU, Jorgensen T, Kong A, Kubalanza K, Kuruvilla FG, Kuusisto J, Langenberg C, Lango H, Lauritzen T, Li Y, Lindgren CM, Lyssenko V, Marvelle AF, Meisinger C, Midthjell K, Mohlke KL, Morken MA, Morris AD, Narisu N, Nilsson P, Owen KR, Palmer CN, Payne F, Perry JR, Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW, Rees M, Roix JJ, Sandbaek A, Shields B, Sjogren M, Steinthorsdottir V, Stringham HM, Swift AJ, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tuomi T, Tuomilehto J, Walker M, Watanabe RM, Weedon MN, Willer CJ; Wellcome Trust Case Control Consortium, Illig T, Hveem K, Hu FB, Laakso M, Stefansson K, Pedersen O, Wareham NJ, Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI, Boehnke M, Altshuler D. |
Nat Genet. 2008 May;40(5):638-45. doi: 10.1038/ng.120. Epub 2008 Mar 30. |
PMID 18372903 |
High-resolution melting analysis of ADAMTS9 methylation levels in gastric, colorectal, and pancreatic cancers. |
Zhang C, Shao Y, Zhang W, Wu Q, Yang H, Zhong Q, Zhang J, Guan M, Yu B, Wan J. |
Cancer Genet Cytogenet. 2010 Jan 1;196(1):38-44. doi: 10.1016/j.cancergencyto.2009.08.016. |
PMID 19963134 |
Citation |
This paper should be referenced as such : |
Yoshina, S ; Mitani, S |
ADAMTS9 (ADAM metallopeptidase with thrombospondin type 1 motif, 9) |
Atlas Genet Cytogenet Oncol Haematol. 2014;18(7):497-499. |
Free journal version : [ pdf ] [ DOI ] |
Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ] |
ADAMTS9/SYNPR (3p14)
t(3;3)(p14;p22) ADAMTS9/ULK4 t(3;3)(p14;p26) ADAMTS9/CHL1 |
External links |
REVIEW articles | automatic search in PubMed |
Last year publications | automatic search in PubMed |
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