ADAM23 (ADAM metallopeptidase domain 23)

2014-09-01 Erico T Costa , Anamaria A Camargo Affiliation

Identity

HGNC

ADAM23

LOCATION

2q33.3

LOCUSID

8745

ALIAS

MDC-3,MDC3

FUSION GENES

Show Gene Fusions

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.

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.

Proteins

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.

Germinal

No germline mutations have been reported for the ADAM23 gene (OMIM603710).

Somatic

No somatic point mutations and CNVs have been reported.

Epigenetics

Epigenetic silencing of the ADAM23 have been frequently reported in different types of solid tumors.

Implicated in

Entity name

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 name

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 name

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 name

Pancreatic tumors

Note

ADAM23 promoter methylation was detected in 7 out of 24 (29%) primary invasive pancreatic ductal adenocarcinomas.

Entity name

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 name

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

Pubmed ID	Last Year	Title	Authors
21316416	2011	Gene expression profile of ADAMs and ADAMTSs metalloproteinases in normal and malignant plasma cells and in the bone marrow environment.	Bret C et al
10749942	2000	ADAM 23/MDC3, a human disintegrin that promotes cell adhesion via interaction with the alphavbeta3 integrin through an RGD-independent mechanism.	Cal S et al
17284367	2007	Methylation profile of genes CDKN2A (p14 and p16), DAPK1, CDH1, and ADAM23 in head and neck cancer.	Calmon MF et al
24662834	2015	Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals.	Costa ET et al
14661055	2004	Epigenetic silencing of the adhesion molecule ADAM23 is highly frequent in breast tumors.	Costa FF et al
15467763	2004	Identification of 27 5' CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers.	Hagihara A et al
21429053	2011	The expression of ADAM23 and its correlation with promoter methylation in non-small-cell lung carcinoma.	Hu C et al
19360301	2009	Comparative analysis of DNA methylation between primary and metastatic gastric carcinoma.	Kim JH et al
10524237	1999	The identification of seven metalloproteinase-disintegrin (ADAM) genes from genomic libraries.	Poindexter K et al
9693107	1998	Metalloproteinase-like, disintegrin-like, cysteine-rich proteins MDC2 and MDC3: novel human cellular disintegrins highly expressed in the brain.	Sagane K et al
23961262	2013	Restoration of the methylation status of hypermethylated gene promoters by microRNA-29b in human breast cancer: A novel epigenetic therapeutic approach.	Starlard-Davenport A et al
17333391	2007	ADAM23 plays multiple roles in neuronal differentiation of P19 embryonal carcinoma cells.	Sun Y et al
14697522	2004	Two novel isoforms of Adam23 expressed in the developmental process of mouse and human brains.	Sun YP et al
16103878	2005	ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation.	Takada H et al
22973984	2012	ADAM23 knockdown promotes neuronal differentiation of P19 embryonal carcinoma cells by up-regulating P27KIP1 expression.	Wang Y et al
19375421	2009	Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes.	Watanabe Y et al

Other Information

Locus ID:

NCBI: 8745
MIM: 603710
HGNC: 202
Ensembl: ENSG00000114948

Variants:

dbSNP: 8745
ClinVar: 8745
TCGA: ENSG00000114948
COSMIC: ADAM23

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000114948	ENST00000264377	O75077
ENSG00000114948	ENST00000264377	A0A024R3W8
ENSG00000114948	ENST00000374415	E7EWD3
ENSG00000114948	ENST00000444281	H7C2M6

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Developmental Biology	REACTOME	R-HSA-1266738
LGI-ADAM interactions	REACTOME	R-HSA-5682910

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
20379614	2010	Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.	62
19549921	2009	ADAM23 negatively modulates alpha(v)beta(3) integrin activation during metastasis.	19
16103878	2005	ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation.	15
25620615	2015	CXCL12 and ADAM23 hypermethylation are associated with advanced breast cancers.	12
25740824	2015	Epigenetic clustering of gastric carcinomas based on DNA methylation profiles at the precancerous stage: its correlation with tumor aggressiveness and patient outcome.	12
19089928	2009	Promoter hypermethylation of the ADAM23 gene in colorectal cancer cell lines and cancer tissues.	9
24662834	2015	Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals.	7
26800504	2016	ADAM23 is downregulated in side population and suppresses lung metastasis of lung carcinoma cells.	7
21429053	2011	The expression of ADAM23 and its correlation with promoter methylation in non-small-cell lung carcinoma.	6
15862898	2005	ADAM23 methylation and expression analysis in brain tumors.	5

Citation

Erico T Costa ; Anamaria A Camargo

ADAM23 (ADAM metallopeptidase domain 23)

Atlas Genet Cytogenet Oncol Haematol. 2014-09-01

Online version: http://atlasgeneticsoncology.org/gene/44041/adam23-(adam-metallopeptidase-domain-23)

Historical Card

2007-07-01 ADAM23 (ADAM metallopeptidase domain 23) by Marilia de Freitas Calmon,Paula Rahal Affiliation

Laboratory of Genomics studies - Sao Paulo State University _ Departament of Biology _ Sao Jose do Rio Preto- SP- Brazil