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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Shian-Ying Sung Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung, Taiwan (SYS) Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/ADAM9ID573ch8p11.html DOI: 10.4267/2042/44708 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology mitotic arrest deficient 2beta. ADAM9 has implicated mediated by stress, such as oxidation during inflammation and cancer progression. Identity Other names: MDC9; Meltrin-gamma; MLTNG; MCMP; KIAA0021 HGNC (Hugo): ADAM9 Location: 8p11.23 Local order: TACC1 - PLEKHA2 - HTRA4 - TM2D2 - ADAM9 - ADAM32 - ADAM5p - ADAM3A ADAM18 - ADAM2; TACC1; 8P11; Transforming, acidic coiled-coil containing protein 1; PLEKHA2; 8P11.23; Pleckstrin homology domain containing, family A member 2; HTRA4; 8P11.23; HtrA serine peptidase 4; TM2D2; 8P11.23; TM2 domain containing 2; ADAM9; 8P11.23; a disintegrin and metalloproteinase domain 9; ADAM32; 8p11.23; ADAM metalloproteinase domain 32; ADAM5P; 8p11.23; ADAM metallopeptidase domain 5 pseudogene; ADAM3A; 8p11.23; ADAM metallopeptidase domain 3A (Cyritestin 1); ADAM18; 8p11.22; ADAM metallopeptidase domain 18; ADAM2; 8p11.22; ADAM metallopeptidase domain 2. Note The ADAM9 gene, a member of the ADAM superfamily has metalloprotease, integrin binding and cell adhesion capacities. It shown the metallo-protease domain cleaves insulin beta-chain, TNF-alpha, gelatin, beta-casein, fibronectin, as well as shedding of EGF, HB-EGF and FGFR2IIIB. The integrin domain mediates cellular adhesion through alpha6beta1 and alphavbeta5 integrins. The cytoplasmic tail of ADAM9 has been reported to interact with endophilin 1 (SH3GL2), SH3PX1 and Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) DNA/RNA Note The ADAM9 gene transcript 2 isoforms of mRNA with altered splicing results the lost of exon 18 in the second isoform of ADAM9 mRNA and early stop codon. Description ADAM9 gene extends 108,276 base pairs with 22 exons which gives rise to 2 different ADAM9 transcripts with differential splicing. The mRNA of ADAM9 isoform 1 is 4111 base pair and isoform 2 is 4005. ADAM9 isoform 2 lacks exon 18 of iso-form 1 in the coding region, which results in a frameshift and an early stop codon. The isoform 2 lacks the c-terminal transmembrane and cyto-plasmic domains and is a secreted form. Transcription Isoform 1 mRNA of ADAM9 (NM_003816) has a size of 4111 bp, isoform 2 mRNA (NM_001005845) has a size of 4005 bp. ADAM9 mRNA is equally expressed in many tissue. Among cancer progression, ADAM9 mRNA is relatively highly expressed in prostate cancer and breast cancer. However, little is known of differential expression between different isoform of ADAM9. Pseudogene No pseudogene has reported for ADAM9. 270 ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY ADAM9 gene is located on chromosome 8p11.23 spread out on 108,276 deoxynucleotides contained 22 exons. The coding sequence of ADAM9 is 2460 nucleotides. Two isoforms reported, isoform 1 of ADAM9 carried full-length membrane bond ADAM9 and isoform 2 carried soluble form of ADAM9 (sADAM9). The sADAM9 is due to alternative splicing in which lost of exon 18 and results in early stop translation in exon 19. alteration and lost of exon 18 of ADAM9 causes lost of transmembrane domain and early stop in soluble form of ADAM9. Protein Note Two different isoform of ADAM9 was reported, the full length and soluble form of ADAM9. Recent report suggests promoter polymorphisms regulated ADAM9 transcription that plays a protective role against Alzheimer's disease. Localisation Full length has N-terminal signal peptide and a single hydrophobic region predicted to be transmembrane domain. Hence, the full length of ADAM9 is localized to the plasma membrane. Soluble ADAM9 lack the transmembrane domain and cytoplasmic domain and to be released out of cell. Description The predicted molecular mass of ADAM9 is about 84 KDa. ADAM9 contained coding sequence of 2460 nucleotides which encoding amino acid of 819 residues. The full length of active ADAM9 contained several functional regions including metalloproteinase, disintegrin, cystein rich, EGF-like, transmembrane and cytoplasmic domains. The pro-domain of ADAM9 was removed by furin-type convertase during ADAM9 translocated onto membrane and become active form. Recent reports indicated soluble form of ADAM9 cloned from human cDNA library that showed increased of cancer invasion in malignant progression. Function 1. Ectodomain shedding: Metalloproteinase domain of ADAM9 is zinc dependent. Metallo-proteinase has been showed to involve ectodomain shedding (see table below). One such protein is the heparin-binding EGFlike growth factor (HB-EGF) and amyloid precursor protein (APP). 2. Matrix Degradation: purified metalloproteinase domain of ADAM9 showed the ability to digest fibronectin, gelatin and beta-casein. Secreted form of ADAM9 showed the ability to digest laminin and promote cancer invasion. 3. Cell contact: ADAM9 specifically bind to integrin alpha6beta1, a laminin receptor, via disintegrin region of ADAM9 through non-RGD mechanism. ADAM9 also have been implicated in binding of avbeta5 in divalent cation dependent condition, suggests ADAM9 can function as adhesion molecule for cell-cell and cellmartrix interaction. Secreted form of ADAM9 binds directly to alpha6beta4 and alpha2beta1 integrin and Expression ADAM9 is ubiquitously expressed. SAGE analyses of ADAM9 expression demonstrated that ADAM9 is expressed in the bone marrow, lymph node, brain, retina, heart, skin, muscle, lung, prostate, breast and placenta. Increased expression of ADAM9 was reported in several cancers, including gastric, breast, prostate, colon, and pancreatic cancers. Splicing Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 271 ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY Two isoforms of ADAM9 with their specific function. Soluble form of ADAM9 has function to active APP either on the same cell or neighbor cell. ability to cleave laminin and promote cancer progression. 4. Cysteine-Rich domain: The ADAM Cysteine-rich domain is not found in other organisms, such as virus, archaeal, bacterial or plant. The function of cysteinerich domain might involved in complement the binding ability of disintegrin-mediated interactions. Homology The table below gives homology between the human ADAM9 and others organisms. Mutations Note Single nucleotide polymorphosim analyses of chromosome 8 demonstrated about 356 SNP in the chromosome 8p11.23. Most of them are located in intron of ADAM9. No mutation was reported in ADAM9 coding sequence. Recent evidence sug-gests promoter polymorphisms that may upregulate ADAM9 transcription, such as -1314C has higher of transcription activities. TABLE: Substrate and Peptide Sequence Cleaved. Substrate Peptide sequence cleaved (*: cleave site) Amyloid precursor protein EVHH*QKLVFFAE TNF-a SPLA*QAVRS*SSR P75 TNF SMAPGAVH*LPQP receptor c-kit ligand Insulin Chain HB-EGF LPPVA*A*S*SLRND B LVEALY*LVCGERGFFY*TPKA GLSLPVE*NRLYTYD Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 272 ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY ADAM9 gene promoter region contained 4 polymorphisms: -542C/T, -600A/C, -963A/G and -1314T/C. 1314C showed higher ADAM9 transcription compared to 1314T. blot studies demonstrated multiform of ADAM9 were expressed in breast carcinoma. In addition, recent study demonstrated copy number abnormalities occurred in ADAM9 gene. Implicated in Prostate cancer Note ADAM9 has been implicated in prostate cancer progression and the production of reactive oxygen species. Large cohort of clinic evaluation demonstrated ADAM9 is upregulated in prostate cancer in both mRNA and protein level. ADAM9 protein expression can be upregulated by androgen in AR-positive but not in AR-negative prostate cancer cells that is through downstream ROS as mediator to induce ADAM9 expression. ADAM9 protein expression is associated with shortened PSA-relapse-free survival in clinic evaluation. Lung cancer Note The increased of ADAM9 expression in lung cancer enhanced cell adhesion and invasion of non-small cell lung cancer through change adhesion properties and sensitivity to growth factors, and increase its capacity of brain metastasis. Renal cell carcinoma Note ADAM9 was implicated increased expression in renal cell carcinoma and associated with tumor progression. It also showed higher of ADAM9 expression is associated with shorten patient survival rate. Pancreatic cancer Note Pancreatic ductal adenocarcinomas showing increased of ADAM9 expression in microarray analyses and clinic evaluation that correlated with poor tumor differentiation and shorter overall survival rate. Alzheimer's disease Note The amyloid precursor protein (APP) of Alzheimer's disease is a transmembrane protein processed via either the non-amyloidogenic or amyloidogenic pathways. In the non-amyloidogenic pathway, alpha-secretase cleaves APP within the Abeta peptide region releasing a large soluble fragment sAPPalpha that has Breast cancer Note ADAM9 expression is 24% positive in normal breast tissue and 66% positive in breast carcinomas. Western Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 273 ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY carcinoma invasion through tumor-stromal interactions. Cancer Res. 2005 Jun 1;65(11):4728-38 neuroprotective properties. In the amyloidogenic pathway, beta-secretase and gamma-secretase sequentially cleave APP to generate the intact Abeta peptide, which is neurotoxic. In ADAM9 expression analyses showed increase in production of sAPPalpha upon phorbol ester treatment of cell that co-express of ADAM9 and APP. ADAM9 did not cleave at the Lys16-Leu17 bone but at the His14-Gln15 bone in the Abeta domain of APP cleave site. Hence, ADAM9 might play role in protective against sporadic Alzheimer's disease. Peduto L, Reuter VE, Shaffer DR, Scher HI, Blobel CP. Critical function for ADAM9 in mouse prostate cancer. Cancer Res. 2005 Oct 15;65(20):9312-9 Chin K, DeVries S, Fridlyand J, Spellman PT, et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell. 2006 Dec;10(6):529-41 Hirao T, Nanba D, Tanaka M, Ishiguro H, Kinugasa Y, Doki Y, Yano M, Matsuura N, Monden M, Higashiyama S. Overexpression of ADAM9 enhances growth factor-mediated recycling of E-cadherin in human colon cancer cell line HT29 cells. Exp Cell Res. 2006 Feb 1;312(3):331-9 References Sung SY, Kubo H, Shigemura K, Arnold RS, Logani S, et al. Oxidative stress induces ADAM9 protein expression in human prostate cancer cells. Cancer Res. 2006 Oct 1;66(19):9519-26 Shuttleworth A. Violence to healthcare staff must be tackled nationally. Prof Nurse. 1992 Jun;7(9):560 Mochizuki S, Okada Y. ADAMs in cancer cell proliferation and progression. Cancer Sci. 2007 May;98(5):621-8 Izumi Y, Hirata M, Hasuwa H, Iwamoto R, Umata T, et al. A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 1998 Dec 15;17(24):7260-72 Shigemura K, Sung SY, Kubo H, Arnold RS, Fujisawa M, Gotoh A, Zhau HE, Chung LW. Reactive oxygen species mediate androgen receptor- and serum starvation-elicited downstream signaling of ADAM9 expression in human prostate cancer cells. Prostate. 2007 May 15;67(7):722-31 Nelson KK, Schlöndorff J, Blobel CP. Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2beta. Biochem J. 1999 Nov 1;343 Pt 3:673-80 Fritzsche FR, Jung M, Tölle A, Wild P, Hartmann A, et al. ADAM9 expression is a significant and independent prognostic marker of PSA relapse in prostate cancer. Eur Urol. 2008 Nov;54(5):1097-106 Cao Y, Kang Q, Zhao Z, Zolkiewska A. Intracellular processing of metalloprotease disintegrin ADAM12. J Biol Chem. 2002 Jul 19;277(29):26403-11 Fritzsche FR, Wassermann K, Jung M, Tölle A, Kristiansen I, Lein M, Johannsen M, Dietel M, Jung K, Kristiansen G. ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression. BMC Cancer. 2008 Jun 26;8:179 Hotoda N, Koike H, Sasagawa N, Ishiura S. A secreted form of human ADAM9 has an alpha-secretase activity for APP. Biochem Biophys Res Commun. 2002 May 3;293(2):800-5 Boelens MC, Kok K, van der Vlies P, van der Vries G, Sietsma H, Timens W, Postma DS, Groen HJ, van den Berg A. Genomic aberrations in squamous cell lung carcinoma related to lymph node or distant metastasis. Lung Cancer. 2009 Dec;66(3):372-8 Grützmann R, Foerder M, Alldinger I, Staub E, Brümmendorf T, Röpcke S, Li X, Kristiansen G, Jesnowski R, Sipos B, Löhr M, Lüttges J, Ockert D, Klöppel G, Saeger HD, Pilarsky C. Gene expression profiles of microdissected pancreatic ductal adenocarcinoma. Virchows Arch. 2003 Oct;443(4):508-17 Dijkstra A, Postma DS, Noordhoek JA, Lodewijk ME, Kauffman HF, ten Hacken NH, Timens W. Expression of ADAMs ("a disintegrin and metalloprotease") in the human lung. Virchows Arch. 2009 Apr;454(4):441-9 Fischer OM, Hart S, Gschwind A, Prenzel N, Ullrich A. Oxidative and osmotic stress signaling in tumor cells is mediated by ADAM proteases and heparin-binding epidermal growth factor. Mol Cell Biol. 2004 Jun;24(12):5172-83 Guaiquil V, Swendeman S, Yoshida T, Chavala S, Campochiaro PA, Blobel CP. ADAM9 is involved in pathological retinal neovascularization. Mol Cell Biol. 2009 May;29(10):2694-703 Grützmann R, Lüttges J, Sipos B, Ammerpohl O, Dobrowolski F, Alldinger I, Kersting S, Ockert D, Koch R, Kalthoff H, Schackert HK, Saeger HD, Klöppel G, Pilarsky C. ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma. Br J Cancer. 2004 Mar 8;90(5):1053-8 Klessner JL, Desai BV, Amargo EV, Getsios S, Green KJ. EGFR and ADAMs cooperate to regulate shedding and endocytic trafficking of the desmosomal cadherin desmoglein 2. Mol Biol Cell. 2009 Jan;20(1):328-37 Shintani Y, Higashiyama S, Ohta M, Hirabayashi H, Yamamoto S, Yoshimasu T, Matsuda H, Matsuura N. Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis. Cancer Res. 2004 Jun 15;64(12):4190-6 Nakagawa M, Nabeshima K, Asano S, Hamasaki M, Uesugi N, Tani H, Yamashita Y, Iwasaki H. Up-regulated expression of ADAM17 in gastrointestinal stromal tumors: coexpression with EGFR and EGFR ligands. Cancer Sci. 2009 Apr;100(4):654-62 Asayesh A, Alanentalo T, Khoo NK, Ahlgren U. Developmental expression of metalloproteases ADAM 9, 10, and 17 becomes restricted to divergent pancreatic compartments. Dev Dyn. 2005 Apr;232(4):1105-14 Singh B, Schneider M, Knyazev P, Ullrich A. UV-induced EGFR signal transactivation is dependent on proligand shedding by activated metalloproteases in skin cancer cell lines. Int J Cancer. 2009 Feb 1;124(3):531-9 Carl-McGrath S, Lendeckel U, Ebert M, Roessner A, Röcken C. The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer. Int J Oncol. 2005 Jan;26(1):17-24 This article should be referenced as such: Sung SY. ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):270-274. Mazzocca A, Coppari R, De Franco R, Cho JY, Libermann TA, Pinzani M, Toker A. A secreted form of ADAM9 promotes Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 274