Download Gene Section ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma))

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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)
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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)
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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
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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