ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma))

2009-04-01   Shian-Ying Sung 

Center for Molecular Medicine, Graduate Institute of Cancer Biology, China Medical University, Hospital, Taichung, Taiwan





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.
Atlas Image
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.


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 isoform 1 in the coding region, which results in a frameshift and an early stop codon. The isoform 2 lacks the c-terminal transmembrane and cytoplasmic domains and is a secreted form.


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.


No pseudogene has reported for ADAM9.



Two different isoform of ADAM9 was reported, the full length and soluble form of ADAM9. Recent report suggests promoter polymorphisms regulated ADAM9 transcription that play a protective role against Alzheimers disease.
Atlas Image
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.


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.


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 alteration and lost of exon 18 of ADAM9 causes lost of transmembrane domain and early stop in soluble form of ADAM9.


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.


1. Ectodomain shedding: Metalloproteinase domain of ADAM9 is zinc dependent. Metalloproteinase has been showed to involve ectodomain shedding (see table below). One such protein is the heparin-binding EGF-like growth factor (HB-EGF) and amyloid precursor protein (APP).
TABLE : Substrate and Peptide Sequence Cleaved
Substrate Peptide sequence cleaved (*: cleave site)
Amyloid precursor proteinEVHH*QKLVFFAE
c-kit ligandLPPVA*A*S*SLRND

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 cell-martrix interaction. Secreted form of ADAM9 binds directly to alpha6beta4 and alpha2beta1 integrin and 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 cysteine-rich domain might involved in complement the binding ability of disintegrin-mediated interactions.


The table below gives homology between the human ADAM9 and others organisms.
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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 suggests promoter polymorphisms that may upregulate ADAM9 transcription, such as -1314C has higher of transcription activities.
Atlas Image
ADAM9 gene promoter region contained 4 polymorphisms: -542C/T, -600A/C, -963A/G and -1314T/C. 1314C showed higher ADAM9 transcription compared to 1314T.

Implicated in

Entity name
Prostate cancer
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.
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Pancreatic cancer
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.
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Breast cancer
ADAM9 expression is 24% positive in normal breast tissue and 66% positive in breast carcinomas. Western blot studies demonstrated multiform of ADAM9 were expressed in breast carcinoma. In addition, recent study demonstrated copy number abnormalities occurred in ADAM9 gene.
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Lung cancer
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.
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Renal cell carcinoma
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.
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Alzheimers disease
The amyloid precursor protein (APP) of Alzheimers 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 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 Alzheimers disease.


Pubmed IDLast YearTitleAuthors
15983441992Violence to healthcare staff must be tackled nationally.Shuttleworth A et al
157392252005Developmental expression of metalloproteases ADAM 9, 10, and 17 becomes restricted to divergent pancreatic compartments.Asayesh A et al
193244462009Genomic aberrations in squamous cell lung carcinoma related to lymph node or distant metastasis.Boelens MC et al
120007442002Intracellular processing of metalloprotease disintegrin ADAM12.Cao Y et al
155862202005The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer.Carl-McGrath S et al
171577922006Genomic and transcriptional aberrations linked to breast cancer pathophysiologies.Chin K et al
192557802009Expression of ADAMs ("a disintegrin and metalloprotease") in the human lung.Dijkstra A et al
151698832004Oxidative and osmotic stress signaling in tumor cells is mediated by ADAM proteases and heparin-binding epidermal growth factor.Fischer OM et al
185823782008ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression.Fritzsche FR et al
149972072004ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma.Grützmann R et al
192735932009ADAM9 is involved in pathological retinal neovascularization.Guaiquil V et al
163369602006Overexpression of ADAM9 enhances growth factor-mediated recycling of E-cadherin in human colon cancer cell line HT29 cells.Hirao T et al
120545412002A secreted form of human ADAM9 has an alpha-secretase activity for APP.Hotoda N et al
98571831998A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor.Izumi Y et al
189873422009EGFR and ADAMs cooperate to regulate shedding and endocytic trafficking of the desmosomal cadherin desmoglein 2.Klessner JL et al
159302912005A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions.Mazzocca A et al
173552652007ADAMs in cancer cell proliferation and progression.Mochizuki S et al
192986002009Up-regulated expression of ADAM17 in gastrointestinal stromal tumors: coexpression with EGFR and EGFR ligands.Nakagawa M et al
105279481999Evidence 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.Nelson KK et al
162303932005Critical function for ADAM9 in mouse prostate cancer.Peduto L et al
173427492007Reactive oxygen species mediate androgen receptor- and serum starvation-elicited downstream signaling of ADAM9 expression in human prostate cancer cells.Shigemura K et al
152053302004Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis.Shintani Y et al
190039952009UV-induced EGFR signal transactivation is dependent on proligand shedding by activated metalloproteases in skin cancer cell lines.Singh B et al
170186082006Oxidative stress induces ADAM9 protein expression in human prostate cancer cells.Sung SY et al

Other Information

Locus ID:

NCBI: 8754
MIM: 602713
HGNC: 216
Ensembl: ENSG00000168615


dbSNP: 8754
ClinVar: 8754
TCGA: ENSG00000168615


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Extracellular matrix organizationREACTOMER-HSA-1474244
Degradation of the extracellular matrixREACTOMER-HSA-1474228
Collagen degradationREACTOMER-HSA-1442490


Pubmed IDYearTitleCitations
125356682003Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase.77
220646522012MiR-126 acts as a tumor suppressor in pancreatic cancer cells via the regulation of ADAM9.60
195643382009Role of ADAMs in the ectodomain shedding and conformational conversion of the prion protein.54
152053302004Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis.39
170186082006Oxidative stress induces ADAM9 protein expression in human prostate cancer cells.37
234372502013miR-126&126* restored expressions play a tumor suppressor role by directly regulating ADAM9 and MMP7 in melanoma.33
194095192009Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice.32
127670592003Expression of ADAM-9 mRNA and protein in human breast cancer.31
248236972014MicroRNA-126 inhibits invasion in bladder cancer via regulation of ADAM9.31
149972072004ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma.29


Shian-Ying Sung

ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma))

Atlas Genet Cytogenet Oncol Haematol. 2009-04-01

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