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ADAM12 (ADAM metallopeptidase domain 12 (meltrin alpha))

Identity

Other namesADAM-12
MCMP
MCMPMltna
MLTN
MLTNA
Meltrin-alpha
Mltna
HGNC (Hugo) ADAM12
LocusID (NCBI) 8038
Location 10q26.2
Location_base_pair Starts at 127702902 and ends at 128077127 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description Human ADAM-12L DNA spans 373186 bp and ADAM-12S DNA spans 347114 bp. Both sequences are composed of 19 exons.
Transcription The full-length ADAM-12L cDNA spans 5048 nucleotides, including a 311- nucleotides 5'-untranslated region, an open reading frame of 2727 nucleotides encoding 909 aa, a TGA stop codon, and a 3'-untranslated region of 2006 nucleotides. Full-length ADAM-12S cDNA has a 2214 nucleotides open reading frame that is identical to ADAM-12L up to nucleotide 2426, whereupon it diverges. The final 102 nucleotides of the ADAM-12S open reading frame encode a 34-aa carboxyl terminus, followed by a TGA stop codon and a 3'-end untranslated region of 788 nucleotides. The 3'-untranslated regions are different in the two human ADAM-12 forms.
Pseudogene ADAM-12 seems to be encoded by a single copy gene which is located on chromosome 10q26. No pseudogenes reported.

Protein

Note Full-length ADAM-12L: 909 amino acids; Mr: 99,641. There are two isoforms of ADAM-12 resulting from an alternative splicing: mature membrane-bound ADAM-12 (ADAM-12L) (881 amino acids, Mr: 96,917) and a secreted form (ADAM-12S) (718 amino acids, Mr: 77,775).
 
  Structure of ADAM proteinase. ADAM-12 is composed of a propeptide (Pro), a metalloproteinase (Metallo), a disintegrin (Dis), a cystein-rich (Cysrich) domain followed by an EGF-like (EGF), a transmembrane (TM) and a cytoplasmic domain. ADAM-12 proteinase contains in addition a sequence recognized by furin-like enzymes (FU) (Rocks et al, 2008b).
Description The open reading frame begins at the translation initiation codon ATG at nucleotide 312. Residues 1-28 encode the signal peptide. The mature human ADAM-12L contains 881 aa with an Mr of about 96,9 and that of ADAM-12S contains 718 aa with an Mr of 77,8. Five potential N-linked glycosylation sites are present. These five sites are also found at the same position in mouse ADAM-12, whereas three additional sites present in mouse are not found in human ADAM-12. The human ADAM-12 metalloproteinase domain contains the highly conserved zinc-binding motif HEXGHXXGXXHD which is regulated by a potential "cysteine switch" in the prodomain.
Expression Highly expressed in placenta and in lower amounts in skeletal muscle, heart, prostate, uterus, colon, small intestine, bladder, stomach. In prostate, uterus, colon, small intestine, bladder, stomach, the source of ADAM-12 may be the smooth muscle cells. ADAM-12 is also expressed by activated hepatic stellate cells (LePabic et al, 2003). ADAM-12 is present in higher amounts in maternal serum during pregnancy (Laigaard et al, 2006).
Localisation Membrane-bound for ADAM-12L, extracellular localization for ADAM-12S.
Function ADAM-12 is a catalytic active protein and functions ascribed to ADAM-12 in the literature are mostly related to its catalytic activity. Indeed, ADAM-12 is able to cleave Insulin-like Growth Factor Binding Protein-3 and-5 (IGFBP-3 and IGFBP-5). The release of increasing concentrations of bioavailable IGF through IGFBP cleavage is important during pregnancy for foetal growth (Laigaard et al, 2006). ADAM-12 is also able to cleave membrane-bound Heparin-binding EGF-like Growth Factor (HB-EGF) (Asakura et al, 2002).
Homology Human version of ADAM-12 shares 84% overall amino acid identity with its mouse homolog. Homology is highest in cysteine-rich, metalloproteinase, and disintegrin domains and lower in the pro- and cytoplasmic domains. Human ADAM-12 shares about 83% with the rat homolog, 68% with zebra fish ADAM-12 and 99% with chimpanzees. Human ADAM-12 shares 45% overall amino acid similarity with ADAM-8, ADAM-9 and ADAM-15.

Mutations

Note Three somatic mutations in ADAM-12 have been observed at significant frequencies in breast cancers (Dyczynska et al, 2008).
Somatic D301H, G479E and L792F: the first two mutations involve highly conserved residues in ADAM-12 which inhibit its proteolytic processing and activation. These mutants are retained inside of the cell and are not transported to the cell surface (Dyczynska et al, 2008).

Implicated in

Entity Lung cancer
Note ADAM-12 mRNA and protein levels are elevated in biopsies of non small cell lung cancer compared to non cancerous lung tissues (Rocks et al, 2006).
Prognosis Not determined
Cytogenetics Not determined
Hybrid/Mutated Gene Not determined
Abnormal Protein Not determined
Oncogenesis Contributes to enhance proliferation of bronchial epithelial cells through enhancement of membrane-bound HB-EGF shedding and activation of downstream HB-EGF / EGFR pathway. This cleavage also protects lung epithelial cells from etoposide-induced apoptosis (Rocks et al, 2008a).
  
Entity Breast cancer
Note Western Blots and immunoreactivity to ADAM-12 reveals that most of the malignant breast tissues exhibit ADAM-12 expression when compared to non-malignant breast lesions.
Prognosis Urine of the majority of breast cancer patients is positive for ADAM-12 compared with urine from control patients in which ADAM-12 levels are significantly lower. Moreover, median levels of ADAM-12 in urine increase with disease progression (Roy et al, 2004).
Cytogenetics Not determined
Hybrid/Mutated Gene Not determined
Abnormal Protein Not determined
Oncogenesis Overexpression of ADAM-12 accelerates tumor development and increases tumor burden. ADAM-12 overexpressing tumours display lower tumor cell apoptosis and higher apoptosis rates in stromal cells (Kveiborg et al, 2005).
  
Entity Bladder cancer
Note ADAM-12 mRNA levels are upregulated in bladder cancer as determined by microarray analysis and RT-PCR as compared to control samples. ADAM-12 protein levels correlate with tumor stage and grade.
Prognosis ADAM-12 levels are upregulated in urine of patients with bladder cancer compared with urine from healthy individuals. After removal of the tumor by surgery, levels of ADAM-12 in urine decrease. ADAM-12 is therefore an interesting biomarker of bladder cancer (Frohlich et al, 2006).
Cytogenetics Not determined
Hybrid/Mutated Gene Not determined
Abnormal Protein Not determined
Oncogenesis Not determined
  
Entity Hepatic cancer
Note Northern Blots show that ADAM-12 is expressed in human activated hepatic stellate cells. Hepatocellular carcinomas and liver metastases display higher ADAM-12 than normal liver and benign tumors. ADAM-12 expression is also correlated with tumor aggressiveness and progression (LePabic et al, Hepatology, 2003).
Prognosis Not determined
Cytogenetics Not determined
Hybrid/Mutated Gene Not determined
Abnormal Protein Not determined
Oncogenesis ADAM-12 expression is induced by Transforming Growth Factor (TGF)-β in activated hepatic stellate cells through both PI3K / p70S6K and MEK / ERK pathways (LePabic et al, 2005).
  
Entity Glioblastoma
Note Membrane-anchored ADAM-12 is overexpressed in glioblastomas compared to non-neoplastic brain tissues. In situ hybridization shows that glioblastoma cells are responsible for this gene expression (Kodama et al, 2004).
Prognosis Not determined
Cytogenetics Not determined
Hybrid/Mutated Gene Not determined
Abnormal Protein Not determined
Oncogenesis There is a relation between ADAM-12 mRNA expression and proliferative activity of gliomas. This enhanced proliferation might be related to an increase of membrane-bound pro-HB-EGF shedding.
  
Entity Intrauterine growth
Note ADAM-12 is able to cleave Insulin-like Growth Factor Binding Proteins (IGFBP) and thereby regulates the amount of free bioactive Insulin-like Growth Factor (IGF). The proposed role of ADAM-12 is the promotion of growth and development by breaking down IGFBPs, releasing IGF for uptake into cells to promote growth (Cowans et al, 2007).
Prognosis In cases of poor foetal growth, Down syndrome, trisomy 18 pregnancies or in women who later develop preeclampsia, levels of ADAM-12 during early pregnancy are significantly lower than in normal pregnancies. The lower ADAM-12 levels result in less free IGF available for cell uptake and foetal growth promotion (Laigaard et al, 2005b; Laigaard et al, 2005a; Laigaard et al, 2003).
Cytogenetics Not determined
Hybrid/Mutated Gene Not determined
Abnormal Protein Not determined
  
Entity Bone growth
Note ADAM-12S stimulates bone growth in ADAM-12S transgenic mice by modulating chondrocyte proliferation. Interestingly, the proteinase activity of ADAM-12 is necessary for the increased growth of bone tissues since mice expressing a truncated form of ADAM-12 lacking the pro- and metalloproteinase domains did not show an alteration in bone growth (Kveiborg et al, 2006).
Prognosis Not determined
Cytogenetics Not determined
Hybrid/Mutated Gene Not determined
Abnormal Protein Not determined
  
Entity Adipogenesis and myogenesis
Note Involvement of ADAM-12 in adipogenesis and myogenesis through the shedding of membrane-bound HB-EGF (Kurisaki et al, 2003; Gilpin et al, 1998).
Prognosis Not determined
Cytogenetics Not determined
Hybrid/Mutated Gene Not determined
Abnormal Protein Not determined
  

External links

Nomenclature
HGNC (Hugo)ADAM12   190
Cards
AtlasADAM12ID44084ch10q26
Entrez_Gene (NCBI)ADAM12  8038  ADAM metallopeptidase domain 12
GeneCards (Weizmann)ADAM12
Ensembl (Hinxton)ENSG00000148848 [Gene_View]  chr10:127702902-128077127 [Contig_View]  ADAM12 [Vega]
ICGC DataPortalENSG00000148848
cBioPortalADAM12
AceView (NCBI)ADAM12
Genatlas (Paris)ADAM12
WikiGenes8038
SOURCE (Princeton)NM_003474 NM_021641
Genomic and cartography
GoldenPath (UCSC)ADAM12  -  10q26.2   chr10:127702902-128077127 -  10q26   [Description]    (hg19-Feb_2009)
EnsemblADAM12 - 10q26 [CytoView]
Mapping of homologs : NCBIADAM12 [Mapview]
OMIM602714   
Gene and transcription
Genbank (Entrez)AF023476 AF023477 AK127856 AK291629 AY358878
RefSeq transcript (Entrez)NM_003474 NM_021641
RefSeq genomic (Entrez)AC_000142 NC_000010 NC_018921 NG_029050 NT_030059 NW_001838010 NW_004929376
Consensus coding sequences : CCDS (NCBI)ADAM12
Cluster EST : UnigeneHs.594351 [ NCBI ]
CGAP (NCI)Hs.594351
Alternative Splicing : Fast-db (Paris)GSHG0004441
Alternative Splicing GalleryENSG00000148848
Gene ExpressionADAM12 [ NCBI-GEO ]     ADAM12 [ SEEK ]   ADAM12 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO43184 (Uniprot)
NextProtO43184  [Medical]
With graphics : InterProO43184
Splice isoforms : SwissVarO43184 (Swissvar)
Catalytic activity : Enzyme3.4.24.- [ Enzyme-Expasy ]   3.4.24.-3.4.24.- [ IntEnz-EBI ]   3.4.24.- [ BRENDA ]   3.4.24.- [ KEGG ]   
Domaine pattern : Prosite (Expaxy)ADAM_MEPRO (PS50215)    DISINTEGRIN_1 (PS00427)    DISINTEGRIN_2 (PS50214)    EGF_1 (PS00022)    EGF_2 (PS01186)    EGF_3 (PS50026)    ZINC_PROTEASE (PS00142)   
Domains : Interpro (EBI)ADAM_Cys-rich [organisation]   Blood-coag_inhib_Disintegrin [organisation]   Disintegrin_CS [organisation]   EG-like_dom [organisation]   MetalloPept_cat_dom [organisation]   Peptidase_M12B [organisation]   Peptidase_M12B_N [organisation]  
Related proteins : CluSTrO43184
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)  
DMDM Disease mutations8038
Blocks (Seattle)O43184
Human Protein AtlasENSG00000148848 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasO43184
HPRD04092
IPIIPI00415037   IPI00884934   IPI01015126   IPI00415038   IPI00646614   
Protein Interaction databases
DIP (DOE-UCLA)O43184
IntAct (EBI)O43184
FunCoupENSG00000148848
BioGRIDADAM12
InParanoidO43184
Interologous Interaction database O43184
IntegromeDBADAM12
STRING (EMBL)ADAM12
Ontologies - Pathways
Ontology : AmiGOmetalloendopeptidase activity  protein binding  extracellular region  nucleus  nucleolus  mitochondrion  plasma membrane  proteolysis  cell adhesion  epidermal growth factor receptor signaling pathway  myoblast fusion  metallopeptidase activity  zinc ion binding  integral to membrane  SH3 domain binding  
Ontology : EGO-EBImetalloendopeptidase activity  protein binding  extracellular region  nucleus  nucleolus  mitochondrion  plasma membrane  proteolysis  cell adhesion  epidermal growth factor receptor signaling pathway  myoblast fusion  metallopeptidase activity  zinc ion binding  integral to membrane  SH3 domain binding  
Pathways : BIOCARTARole of EGF Receptor Transactivation by GPCRs in Cardiac Hypertrophy [Genes]   
Protein Interaction DatabaseADAM12
Wikipedia pathwaysADAM12
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)ADAM12
snp3D : Map Gene to Disease8038
SNP (GeneSNP Utah)ADAM12
SNP : HGBaseADAM12
Genetic variants : HAPMAPADAM12
Exome VariantADAM12
1000_GenomesADAM12 
ICGC programENSG00000148848 
Somatic Mutations in Cancer : COSMICADAM12 
CONAN: Copy Number AnalysisADAM12 
Mutations and Diseases : HGMDADAM12
Genomic VariantsADAM12  ADAM12 [DGVbeta]
dbVarADAM12
ClinVarADAM12
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM602714   
MedgenADAM12
GENETestsADAM12
Disease Genetic AssociationADAM12
Huge Navigator ADAM12 [HugePedia]  ADAM12 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneADAM12
Homology/Alignments : Family Browser (UCSC)ADAM12
Phylogenetic Trees/Animal Genes : TreeFamADAM12
Chemical/Protein Interactions : CTD8038
Chemical/Pharm GKB GenePA24507
Clinical trialADAM12
Cancer Resource (Charite)ENSG00000148848
Other databases
Probes
Litterature
PubMed114 Pubmed reference(s) in Entrez
CoreMineADAM12
iHOPADAM12

Bibliography

A novel, secreted form of human ADAM 12 (meltrin alpha) provokes myogenesis in vivo.
Gilpin BJ, Loechel F, Mattei MG, Engvall E, Albrechtsen R, Wewer UM.
J Biol Chem. 1998 Jan 2;273(1):157-66.
PMID 9417060
 
Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy.
Asakura M, Kitakaze M, Takashima S, Liao Y, Ishikura F, Yoshinaka T, Ohmoto H, Node K, Yoshino K, Ishiguro H, Asanuma H, Sanada S, Matsumura Y, Takeda H, Beppu S, Tada M, Hori M, Higashiyama S.
Nat Med. 2002 Jan;8(1):35-40.
PMID 11786904
 
Phenotypic analysis of Meltrin alpha (ADAM12)-deficient mice: involvement of Meltrin alpha in adipogenesis and myogenesis.
Kurisaki T, Masuda A, Sudo K, Sakagami J, Higashiyama S, Matsuda Y, Nagabukuro A, Tsuji A, Nabeshima Y, Asano M, Iwakura Y, Sehara-Fujisawa A.
Mol Cell Biol. 2003 Jan;23(1):55-61.
PMID 12482960
 
ADAM12: a novel first-trimester maternal serum marker for Down syndrome.
Laigaard J, Sorensen T, Frohlich C, Pedersen BN, Christiansen M, Schiott K, Uldbjerg N, Albrechtsen R, Clausen HV, Ottesen B, Wewer UM.
Prenat Diagn. 2003 Dec 30;23(13):1086-91.
PMID 14691998
 
ADAM12 in human liver cancers: TGF-beta-regulated expression in stellate cells is associated with matrix remodeling.
Le Pabic H, Bonnier D, Wewer UM, Coutand A, Musso O, Baffet G, Clement B, Theret N.
Hepatology. 2003 May;37(5):1056-66.
PMID 12717386
 
ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor.
Kodama T, Ikeda E, Okada A, Ohtsuka T, Shimoda M, Shiomi T, Yoshida K, Nakada M, Ohuchi E, Okada Y.
Am J Pathol. 2004 Nov;165(5):1743-53.
PMID 15509542
 
ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage.
Roy R, Wewer UM, Zurakowski D, Pories SE, Moses MA.
J Biol Chem. 2004 Dec 3;279(49):51323-30.
PMID 15381692
 
A role for ADAM12 in breast tumor progression and stromal cell apoptosis.
Kveiborg M, Frohlich C, Albrechtsen R, Tischler V, Dietrich N, Holck P, Kronqvist P, Rank F, Mercurio AM, Wewer UM.
Cancer Res. 2005 Jun 1;65(11):4754-61.
PMID 15930294
 
The level of ADAM12-S in maternal serum is an early first-trimester marker of fetal trisomy 18.
Laigaard J, Christiansen M, Frohlich C, Pedersen BN, Ottesen B, Wewer UM.
Prenat Diagn. 2005 Jan;25(1):45-6.
PMID 15662668
 
Reduction of the disintegrin and metalloprotease ADAM12 in preeclampsia.
Laigaard J, Sorensen T, Placing S, Holck P, Frohlich C, Wojdemann KR, Sundberg K, Shalmi AC, Tabor A, Norgaard-Pedersen B, Ottesen B, Christiansen M, Wewer UM.
Obstet Gynecol. 2005 Jul;106(1):144-9.
PMID 15994630
 
Involvement of the serine/threonine p70S6 kinase in TGF-beta1-induced ADAM12 expression in cultured human hepatic stellate cells.
Le Pabic H, L'Helgoualc'h A, Coutant A, Wewer UM, Baffet G, Clement B, Theret N.
J Hepatol. 2005 Dec;43(6):1038-44.
PMID 16139919
 
Molecular profiling of ADAM12 in human bladder cancer.
Frohlich C, Albrechtsen R, Dyrskjot L, Rudkjaer L, Orntoft TF, Wewer UM.
Clin Cancer Res. 2006 Dec 15;12(24):7359-68.
PMID 17189408
 
ADAM12-S stimulates bone growth in transgenic mice by modulating chondrocyte proliferation and maturation.
Kveiborg M, Albrechtsen R, Rudkjaer L, Wen G, Damgaard-Pedersen K, Wewer UM.
J Bone Miner Res. 2006 Aug;21(8):1288-96.
PMID 16869727
 
ADAM 12 as a first-trimester maternal serum marker in screening for Down syndrome.
Laigaard J, Spencer K, Christiansen M, Cowans NJ, Larsen SO, Pedersen BN, Wewer UM.
Prenat Diagn. 2006 Oct;26(10):973-9.
PMID 16892462
 
Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC).
Rocks N, Paulissen G, Quesada CF, Polette M, Gueders M, Munaut C, Foidart JM, Noel A, Birembaut P, Cataldo D.
Br J Cancer. 2006 Mar 13;94(5):724-30.
PMID 16495931
 
First-trimester ADAM12 and PAPP-A as markers for intrauterine fetal growth restriction through their roles in the insulin-like growth factor system.
Cowans NJ, Spencer K.
Prenat Diagn. 2007 Mar;27(3):264-71.
PMID 17278174
 
Breast cancer-associated mutations in metalloprotease disintegrin ADAM12 interfere with the intracellular trafficking and processing of the protein.
Dyczynska E, Syta E, Sun D, Zolkiewska A.
Int J Cancer. 2008 Jun 1;122(11):2634-40.
PMID 18241035
 
The metalloproteinase ADAM-12 regulates bronchial epithelial cell proliferation and apoptosis.
Rocks N, Estrella C, Paulissen G, Quesada Calvo F, Gilles C, Gueders M, Crahay C, Foidart JM, Gosset P, Noel A, Cataldo D.
Cell Prolif. 2008;in press.
 
Emerging roles of ADAM and ADAMTS metalloproteinases in cancer.
Rocks N, Paulissen G, El Hour M, Quesada F, Crahay C, Gueders M, Foidart JM, Noel A, Cataldo D.
Biochimie. 2008 Feb;90(2):369-79 (REVIEW).
PMID 17920749
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written05-2008Natacha Rocks, Didier Cataldo
Laboratory of Pneumology, Laboratory of Tumor and Developmental Biology, GIGA-research, CHU Sart-Tilman, B-4000 Liège, Belgique

Citation

This paper should be referenced as such :
Rocks, N ; Cataldo, D
ADAM12 (ADAM metallopeptidase domain 12 (meltrin alpha))
Atlas Genet Cytogenet Oncol Haematol. 2009;13(4):249-252.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/ADAM12ID44084ch10q26.html

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