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ADAM23 (ADAM metallopeptidase domain 23)

Written2007-07Marilia de Freitas Calmon, Paula Rahal
Laboratory of Genomics studies - Sao Paulo State University _ Departament of Biology _ Sao Jose do Rio Preto- SP- Brazil
Updated2014-09Erico T Costa, Anamaria A Camargo
Ludwig Institute for Cancer Research - at Hospital Sirio-Libanes, Sao Paulo - SP - Brazil

Abstract ADAM23 belongs to the ADAM (A Disintegrin And Metalloproteinase domain) family of proteins. Members of this family present a common structural organization including metalloprotease, disintegrin, cystein-rich, epidermal growth factor-like, transmembrane and cytoplasmatic domains and are structurally related to snake venom disintegrins. ADAM23 has close similarity to ADAM11 and ADAM22; is highly expressed in the CNS, and is crucial for normal brain development. Mice homozygous for an insertional mutation that inactivates the gene are smaller than normal littermates, show delayed lung development, are lethal by postnatal day 14, and display severe tremor and ataxia. ADAM23 does not present metalloprotease activity and probably plays its biological role through the disintegrin domain. ADAM23 is involved in cell-cell adhesion and communication and cell-matrix modulation. The ADAM23 gene is frequently silenced by DNA promoter methylation in different types of solid cancers and epigenetic inactivation is associated with cancer progression, increased tumor cell mobility and reduced tumor cell proliferation.

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Identity

Other namesMDC-3
MDC3
HGNC (Hugo) ADAM23
LocusID (NCBI) 8745
Atlas_Id 44041
Location 2q33.3
Location_base_pair Starts at 207308368 and ends at 207485854 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Fusion genes
(updated 2016)
ADAM23 (2q33.3) / ADAM23 (2q33.3)ADAM23 (2q33.3) / CERKL (2q31.3)ADAM23 (2q33.3) / PLPP1 (5q11.2)
ADAM23 (2q33.3) / SGOL2 (2q33.1)

DNA/RNA

 
  Genomic structure of ADAM23 human gene composed of 27 coding exons. Black boxes represent constitutive exons present in all splicing isoforms. Colored boxes represent alternatively spliced exons.
Description DNA contains 177488 bp composed of 27 coding exons (26 reported by RefSeq sequences).
Transcription 6236 bp mRNA transcribed (RefSeq NM_003812.3) in centromeric to telomeric orientation; 2499 bp open reading frame. There are three alternative splicing isoforms of the human ADAM23 gene: ADAM23-alpha (chosen as the 'canonical' sequence), ADAM23-beta and ADAM23-gamma. These splicing isoforms are generated by the mutually exclusive use or skipping of the exons 25 and/or 26, both of which coding for transmembrane domains with different aminoacid compositions. The ADAM23 proteins encoded by the alpha and beta splicing isoforms are anchored to the membrane by different transmembrane domains (encoded by exon 26 in the isoform alpha and by exon 25 in the isoform beta) and are predicted to have distinct membrane subdomain localizations. ADAM23-gamma is generated by exon skipping of exons 25 and 26 and therefore lacks the transmembrane domain and is predicted to be either a cytoplasmatic or a secreted isoform of the ADAM23 protein. ADAM23 mRNA is detected at high or medium expression levels in brain, testis and heart muscle (The Human Protein Atlas, ENSG00000114948).
Pseudogene No pseudogenes reported.

Protein

 
  Domain structure of ADAM23. Its deduced amino acid sequence lacks essential residues conserved in metalloproteinases (adapted from Cal et al., 2000).
Description ADAM23 is a non-catalytically active member of ADAM family and exhibits all the conserved protein domains, including: an N-terminal signal, a pro-domain, a metalloprotease and a disintegrin domains, a cysteine-rich region, an EGF-like domain, a transmembrane and a short cytoplasmic domains. Within the metalloprotease domain, ADAM23 lacks the conserved zinc-binding sequence HEXXHXXGXXH, which is critical for the proteinase activity. Interacts with LGI1, LGI3 and LGI4 (leucine-rich glioma inactivated family), alphav-beta3 integrins and PrPc proteins.
Size: 832 amino acid; 92 kDa predicted (RefSeq NP_003803).
Expression Detected at medium/high expression levels in 46 of 82 analyzed normal tissue types, including: brain, testis, lung, breast, colon, pancreas and kidney (according to The Human Protein Atlas).
Localisation Cell membrane; single-pass type I membrane protein (isoform ADAM23-alpha and ADAM23-beta). Secreted protein (predicted for ADAM23-gama isoform).
 
  Immunohistochemistry staining of ADAM23 protein in normal colon and normal breast tissues was carried out using the polyclonal antibody anti-ADAM23 (HPA012130, Sigma) (photograph courtesy of Dra. Gabriela F Barnabe from Ludwig Institute for Cancer Research - SP - Brazil).
Function ADAM23 was originally described to promote neuroblastoma and astrocytoma cell-cell adhesion via direct interaction with alphavbeta3 integrin. Following reports showed that the interaction between ADAM23 and alphavbeta3 integrin inhibits cell-matrix adhesion and negatively modulates alphavbeta3 activation during metastatic progression. Silencing of the ADAM23 gene promotes cell cycle arrest and terminal differentiation in P19 mice embryonic carcinoma cells and, in MDA-MB435 and SK-Mel37 tumor cell lines, promotes tumor cell migration and invasion and inhibits tumor cell proliferation.
Homology H. sapiens: ADAM23, P. troglodytes: ADAM23, C. lupus: LOC607871, M. musculus: ADAM23, R. novergicus: ADAM23, G. gallus: LOC424099.

Mutations

Note No mutations have been reported for ADAM23 gene.
Epigenetics Epigenetic silencing of the ADAM23 have been frequently reported in different types of solid tumors.
Germinal No germline mutations have been reported for the ADAM23 gene (OMIM603710).
Somatic No somatic point mutations and CNVs have been reported.

Implicated in

Note
Entity Breast carcinoma
Note ADAM23 expression is downregulated by promoter hypermethylation during breast cancer progression and hypermethylation was significantly associated with a higher incidence of distant metastasis and reduced overall survival. Recently, ADAM23 epigenetic silencing during tumor progression was shown to generate genetic and functional heterogeneity in invasive breast tumors. ADAM23-intratumoral heterogeneity (ADAM23-ITH) was observed in topographically distinct areas of undifferentiated breast invasive ductal carcinomas, with invasive components being frequently composed by mosaic clusters of ADAM23-positive tumor cells coexisting in close proximity with ADAM23-silenced cells. Most importantly, it was demonstrated that ADAM23-ITH promotes tumor growth and metastasis by establishing a crosstalk between ADAM23-positives and ADAM23-negatives tumor cells in which ADAM23-negative cells promote tumor growth and metastasis by enhancing the proliferation and invasion of adjacent ADAM23-positive cells through the production of the ADAM23-ligant LGI4 (leucine-rich glioma Inactivated gene 4) and pro-migratory levels of nitric oxide (NO).
  
Entity Lung carcinoma
Note ADAM23 protein levels is lower in non-small-cell lung carcinoma (NSCLC) compared to corresponding normal tissues and benign pulmonary lesions, and a decrease in ADAM23 protein expression was observed during NSCLC progression. Hypermethylation of ADAM23 promoter region was observed in 40% of NSCLC but in only 7.6% of the adjacent normal tissues.
  
Entity Gastric tumors
Note ADAM23 promoter hypermethylation is frequently observed in gastric dysplasia (90%) and gastric tumors (29-55%) but is rarely observed in normal mucosa (9%). The frequency of ADAM23 methylation is higher in metastatic lesions compared to paired primary tumors. Homozygous loss of ADAM23 was also reported for gastric tumors but at a lower frequency (~3%).
  
Entity Pancreatic tumors
Note ADAM23 promoter methylation was detected in 7 out of 24 (29%) primary invasive pancreatic ductal adenocarcinomas.
  
Entity Head and neck cancer
Note ADAM23 promoter hypermethylation was detected in 18 out of 43 head and neck tumors (42%) and a significant association between ADAM23 hypermethylation and advanced stages (T3-T4) was observed larynx tumors.
  
Entity Multiple myeloma
Note ADAM23 mRNA expression is absent in normal bone marrow plasma cells, but is aberrantly expressed in 2/131 (1,5%) patients with newly diagnosed multiple myeloma. In two independent cohorts of patients with primary multiple myeloma, 24 out of 557 patients (4%) showed increased levels of ADAM23 mRNA expression, which was significantly associated with poor overall survival.
  

Bibliography

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ADAM 23/MDC3, a human disintegrin that promotes cell adhesion via interaction with the alphavbeta3 integrin through an RGD-independent mechanism.
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Mol Biol Cell. 2000 Apr;11(4):1457-69.
PMID 10749942
 
Epigenetic silencing of the adhesion molecule ADAM23 is highly frequent in breast tumors.
Costa FF, Verbisck NV, Salim AC, Ierardi DF, Pires LC, Sasahara RM, Sogayar MC, Zanata SM, Mackay A, O'Hare M, Soares F, Simpson AJ, Camargo AA.
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Identification of 27 5' CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers.
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Oncogene. 2004 Nov 11;23(53):8705-10.
PMID 15467763
 
Two novel isoforms of Adam23 expressed in the developmental process of mouse and human brains.
Sun YP, Deng KJ, Wang F, Zhang J, Huang X, Qiao S, Zhao S.
Gene. 2004 Jan 21;325:171-8.
PMID 14697522
 
ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation.
Takada H, Imoto I, Tsuda H, Nakanishi Y, Ichikura T, Mochizuki H, Mitsufuji S, Hosoda F, Hirohashi S, Ohki M, Inazawa J.
Oncogene. 2005 Dec 1;24(54):8051-60.
PMID 16103878
 
Methylation profile of genes CDKN2A (p14 and p16), DAPK1, CDH1, and ADAM23 in head and neck cancer.
Calmon MF, Colombo J, Carvalho F, Souza FP, Filho JF, Fukuyama EE, Camargo AA, Caballero OL, Tajara EH, Cordeiro JA, Rahal P.
Cancer Genet Cytogenet. 2007 Feb;173(1):31-7.
PMID 17284367
 
ADAM23 plays multiple roles in neuronal differentiation of P19 embryonal carcinoma cells.
Sun Y, Wang Y, Zhang J, Tao J, Wang C, Jing N, Wu C, Deng K, Qiao S.
Neurochem Res. 2007 Jul;32(7):1217-23. Epub 2007 Feb 9.
PMID 17333391
 
Comparative analysis of DNA methylation between primary and metastatic gastric carcinoma.
Kim JH, Jung EJ, Lee HS, Kim MA, Kim WH.
Oncol Rep. 2009 May;21(5):1251-9.
PMID 19360301
 
Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes.
Watanabe Y, Kim HS, Castoro RJ, Chung W, Estecio MR, Kondo K, Guo Y, Ahmed SS, Toyota M, Itoh F, Suk KT, Cho MY, Shen L, Jelinek J, Issa JP.
Gastroenterology. 2009 Jun;136(7):2149-58. doi: 10.1053/j.gastro.2009.02.085. Epub 2009 Apr 16.
PMID 19375421
 
Gene expression profile of ADAMs and ADAMTSs metalloproteinases in normal and malignant plasma cells and in the bone marrow environment.
Bret C, Hose D, Reme T, Kassambara A, Seckinger A, Meissner T, Schved JF, Kanouni T, Goldschmidt H, Klein B.
Exp Hematol. 2011 May;39(5):546-557.e8. doi: 10.1016/j.exphem.2011.02.002. Epub 2011 Mar 3.
PMID 21316416
 
The expression of ADAM23 and its correlation with promoter methylation in non-small-cell lung carcinoma.
Hu C, Lv H, Pan G, Cao H, Deng Z, Hu C, Wen J, Zhou J.
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PMID 21429053
 
ADAM23 knockdown promotes neuronal differentiation of P19 embryonal carcinoma cells by up-regulating P27KIP1 expression.
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PMID 22973984
 
Restoration of the methylation status of hypermethylated gene promoters by microRNA-29b in human breast cancer: A novel epigenetic therapeutic approach.
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Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals.
Costa ET, Barnabe GF, Li M, Dias AA, Machado TR, Asprino PF, Cavalher FP, Ferreira EN, Del Mar Inda M, Nagai MH, Malnic B, Duarte ML, Leite KR, de Barros AC, Carraro DM, Chammas R, Armelin HA, Cavenee W, Furnari F, Camargo AA.
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PMID 24662834
 

Citation

This paper should be referenced as such :
Costa ET, Camargo AA
ADAM23 (ADAM metallopeptidase domain 23);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/ADAM23ID44041ch2q33.html
History of this paper:
Marilia, de Freitas C ; Rahal, P. ADAM23 (ADAM metallopeptidase domain 23). Atlas Genet Cytogenet Oncol Haematol. 2008;12(1):17-19.
http://documents.irevues.inist.fr/bitstream/handle/2042/38466/07-2007-ADAM23ID44041ch2q33.pdf


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 0 ]
  Lung: Translocations in Adenocarcinoma

External links

Nomenclature
HGNC (Hugo)ADAM23   202
Cards
AtlasADAM23ID44041ch2q33
Entrez_Gene (NCBI)ADAM23  8745  ADAM metallopeptidase domain 23
GeneCards (Weizmann)ADAM23
Ensembl hg19 (Hinxton)ENSG00000114948 [Gene_View]  chr2:207308368-207485854 [Contig_View]  ADAM23 [Vega]
Ensembl hg38 (Hinxton)ENSG00000114948 [Gene_View]  chr2:207308368-207485854 [Contig_View]  ADAM23 [Vega]
ICGC DataPortalENSG00000114948
TCGA cBioPortalADAM23
AceView (NCBI)ADAM23
Genatlas (Paris)ADAM23
WikiGenes8745
SOURCE (Princeton)ADAM23
Genomic and cartography
GoldenPath hg19 (UCSC)ADAM23  -     chr2:207308368-207485854 +  2q33   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)ADAM23  -     2q33   [Description]    (hg38-Dec_2013)
EnsemblADAM23 - 2q33 [CytoView hg19]  ADAM23 - 2q33 [CytoView hg38]
Mapping of homologs : NCBIADAM23 [Mapview hg19]  ADAM23 [Mapview hg38]
OMIM603710   
Gene and transcription
Genbank (Entrez)AB009672 AF052115 AJ005580 AK091800 AK129906
RefSeq transcript (Entrez)NM_003812
RefSeq genomic (Entrez)NC_000002 NC_018913 NG_029874 NT_005403 NW_004929305
Consensus coding sequences : CCDS (NCBI)ADAM23
Cluster EST : UnigeneHs.591643 [ NCBI ]
CGAP (NCI)Hs.591643
Alternative Splicing GalleryENSG00000114948
Gene ExpressionADAM23 [ NCBI-GEO ]   ADAM23 [ EBI - ARRAY_EXPRESS ]   ADAM23 [ SEEK ]   ADAM23 [ MEM ]
Gene Expression Viewer (FireBrowse)ADAM23 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8745
GTEX Portal (Tissue expression)ADAM23
Protein : pattern, domain, 3D structure
UniProt/SwissProtO75077 (Uniprot)
NextProtO75077  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO75077
Splice isoforms : SwissVarO75077 (Swissvar)
PhosPhoSitePlusO75077
Domaine pattern : Prosite (Expaxy)ADAM_MEPRO (PS50215)    DISINTEGRIN_2 (PS50214)    EGF_1 (PS00022)    EGF_3 (PS50026)   
Domains : Interpro (EBI)ADAM_Cys-rich    Disintegrin_dom    EGF-like_CS    EGF-like_dom    MetalloPept_cat_dom    Peptidase_M12B    Peptidase_M12B_N   
Domain families : Pfam (Sanger)ADAM_CR (PF08516)    Disintegrin (PF00200)    Pep_M12B_propep (PF01562)    Reprolysin (PF01421)   
Domain families : Pfam (NCBI)pfam08516    pfam00200    pfam01562    pfam01421   
Domain families : Smart (EMBL)ACR (SM00608)  DISIN (SM00050)  EGF (SM00181)  
DMDM Disease mutations8745
Blocks (Seattle)ADAM23
SuperfamilyO75077
Human Protein AtlasENSG00000114948
Peptide AtlasO75077
HPRD04752
IPIIPI00021903   IPI00478084   IPI00477723   IPI00979515   IPI01018829   
Protein Interaction databases
DIP (DOE-UCLA)O75077
IntAct (EBI)O75077
FunCoupENSG00000114948
BioGRIDADAM23
STRING (EMBL)ADAM23
ZODIACADAM23
Ontologies - Pathways
QuickGOO75077
Ontology : AmiGOmetalloendopeptidase activity  integrin binding  protein binding  extracellular region  plasma membrane  integral component of plasma membrane  proteolysis  cell adhesion  central nervous system development  metallopeptidase activity  zinc ion binding  
Ontology : EGO-EBImetalloendopeptidase activity  integrin binding  protein binding  extracellular region  plasma membrane  integral component of plasma membrane  proteolysis  cell adhesion  central nervous system development  metallopeptidase activity  zinc ion binding  
REACTOMEO75077 [protein]
REACTOME PathwaysR-HSA-5682910 LGI-ADAM interactions [pathway]
NDEx Network
Atlas of Cancer Signalling NetworkADAM23
Wikipedia pathwaysADAM23
Orthology - Evolution
OrthoDB8745
GeneTree (enSembl)ENSG00000114948
Phylogenetic Trees/Animal Genes : TreeFamADAM23
Homologs : HomoloGeneADAM23
Homology/Alignments : Family Browser (UCSC)ADAM23
Gene fusions - Rearrangements
Fusion : MitelmanADAM23/CERKL [2q33.3/2q31.3]  
Fusion : MitelmanADAM23/PPAP2A [2q33.3/5q11.2]  [t(2;5)(q33;q11)]  
Fusion : MitelmanADAM23/SGOL2 [2q33.3/2q33.1]  [t(2;2)(q33;q33)]  
Fusion: TCGAADAM23 2q33.3 CERKL 2q31.3 LUSC
Fusion: TCGAADAM23 2q33.3 PPAP2A 5q11.2 HNSC
Polymorphisms : SNP, variants
NCBI Variation ViewerADAM23 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ADAM23
dbVarADAM23
ClinVarADAM23
1000_GenomesADAM23 
Exome Variant ServerADAM23
ExAC (Exome Aggregation Consortium)ADAM23 (select the gene name)
Genetic variants : HAPMAP8745
Genomic Variants (DGV)ADAM23 [DGVbeta]
Mutations
ICGC Data PortalADAM23 
TCGA Data PortalADAM23 
Broad Tumor PortalADAM23
OASIS PortalADAM23 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICADAM23 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch ADAM23
DgiDB (Drug Gene Interaction Database)ADAM23
DoCM (Curated mutations)ADAM23 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ADAM23 (select a term)
intoGenADAM23
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)2:207308368-207485854  ENSG00000114948
CONAN: Copy Number AnalysisADAM23 
Mutations and Diseases : HGMDADAM23
OMIM603710   
MedgenADAM23
Genetic Testing Registry ADAM23
NextProtO75077 [Medical]
TSGene8745
GENETestsADAM23
Huge Navigator ADAM23 [HugePedia]
snp3D : Map Gene to Disease8745
BioCentury BCIQADAM23
ClinGenADAM23
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD8745
Chemical/Pharm GKB GenePA24519
Clinical trialADAM23
Miscellaneous
canSAR (ICR)ADAM23 (select the gene name)
Probes
Litterature
PubMed28 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineADAM23
EVEXADAM23
GoPubMedADAM23
iHOPADAM23
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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