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ADAM12 (ADAM metallopeptidase domain 12 (meltrin alpha))

Written2008-05Natacha Rocks, Didier Cataldo
Laboratory of Pneumology, Laboratory of Tumor, Developmental Biology, GIGA-research, CHU Sart-Tilman, B-4000 Liège, Belgique

(Note : for Links provided by Atlas : click)


Alias (NCBI)ADAM-12
HGNC (Hugo) ADAM12
HGNC Alias symbMCMPMltna
HGNC Alias namemeltrin alpha
HGNC Previous namea disintegrin and metalloproteinase domain 12 (meltrin alpha)
LocusID (NCBI) 8038
Atlas_Id 44084
Location 10q26.2  [Link to chromosome band 10q26]
Location_base_pair Starts at 126041344 and ends at 126388477 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ADAM12.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ADAM12 (10q26.2)::ACIN1 (14q11.2)ADAM12 (10q26.2)::ADAM12 (10q26.2)ADAM12 (10q26.2)::CLIP1 (12q24.31)
ADAM12 (10q26.2)::FLNA (Xq28)ADAM12 (10q26.2)::GPRC5C (17q25.1)ADAM12 (10q26.2)::NUMA1 (11q13.4)
ADAM12 (10q26.2)::PACSIN2 (22q13.2)ADAM12 (10q26.2)::PAPPA2 (1q25.2)ADAM12 (10q26.2)::PARP14 (3q21.1)
ADAM12 (10q26.2)::PPP2R1A (19q13.41)ADAM12 (10q26.2)::RTN4 (2p16.1)ADAM12 (10q26.2)::ST6GALNAC3 (1p31.1)
AFF1 (4q21.3)::ADAM12 (10q26.2)CTBP2 (10q26.13)::ADAM12 (10q26.2)EFHD1 (2q37.1)::ADAM12 (10q26.2)
ELMO1 (7p14.2)::ADAM12 (10q26.2)FER1L4 (20q11.22)::ADAM12 (10q26.2)GIPC1 (19p13.12)::ADAM12 (10q26.2)
LRPPRC (2p21)::ADAM12 (10q26.2)MYO9B (19p13.11)::ADAM12 (10q26.2)PDIA3 (15q15.3)::ADAM12 (10q26.2)


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.


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.


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


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
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
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
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
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
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-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
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
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
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


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 journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(11;19)(q13;p13) FSTL3::CCND1

External links


HGNC (Hugo)ADAM12   190
Entrez_Gene (NCBI)ADAM12    ADAM metallopeptidase domain 12
AliasesADAM12-OT1; CAR10; MCMP; MCMPMltna; 
GeneCards (Weizmann)ADAM12
Ensembl hg19 (Hinxton)ENSG00000148848 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000148848 [Gene_View]  ENSG00000148848 [Sequence]  chr10:126041344-126388477 [Contig_View]  ADAM12 [Vega]
ICGC DataPortalENSG00000148848
TCGA cBioPortalADAM12
AceView (NCBI)ADAM12
Genatlas (Paris)ADAM12
SOURCE (Princeton)ADAM12
Genetics Home Reference (NIH)ADAM12
Genomic and cartography
GoldenPath hg38 (UCSC)ADAM12  -     chr10:126041344-126388477 -  10q26.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ADAM12  -     10q26.2   [Description]    (hg19-Feb_2009)
GoldenPathADAM12 - 10q26.2 [CytoView hg19]  ADAM12 - 10q26.2 [CytoView hg38]
Genome Data Viewer NCBIADAM12 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AF023476 AF023477 AK055628 AK127856 AK291629
RefSeq transcript (Entrez)NM_001288973 NM_001288974 NM_001288975 NM_003474 NM_021641
Consensus coding sequences : CCDS (NCBI)ADAM12
Gene ExpressionADAM12 [ NCBI-GEO ]   ADAM12 [ EBI - ARRAY_EXPRESS ]   ADAM12 [ SEEK ]   ADAM12 [ MEM ]
Gene Expression Viewer (FireBrowse)ADAM12 [ Firebrowse - Broad ]
GenevisibleExpression of ADAM12 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8038
GTEX Portal (Tissue expression)ADAM12
Human Protein AtlasENSG00000148848-ADAM12 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO43184   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO43184  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO43184
Catalytic activity : Enzyme3.4.24.- [ Enzyme-Expasy ]   3.4.24.-3.4.24.- [ IntEnz-EBI ]   3.4.24.- [ BRENDA ]   3.4.24.- [ KEGG ]   [ MEROPS ]
Domaine pattern : Prosite (Expaxy)ADAM_MEPRO (PS50215)    DISINTEGRIN_1 (PS00427)    DISINTEGRIN_2 (PS50214)    EGF_3 (PS50026)    ZINC_PROTEASE (PS00142)   
Domains : Interpro (EBI)ADAM_Cys-rich    Disintegrin_CS    Disintegrin_dom    Disintegrin_dom_sf    EGF-like_dom    MetalloPept_cat_dom_sf    Peptidase_M12B    Peptidase_M12B_N    Reprolysin_adamalysin   
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)  
Conserved Domain (NCBI)ADAM12
AlphaFold pdb e-kbO43184   
Human Protein Atlas [tissue]ENSG00000148848-ADAM12 [tissue]
Protein Interaction databases
IntAct (EBI)O43184
Ontologies - Pathways
Ontology : AmiGOmetalloendopeptidase activity  protein binding  extracellular region  nucleoplasm  plasma membrane  plasma membrane  plasma membrane  proteolysis  cell adhesion  myoblast fusion  metallopeptidase activity  integral component of membrane  SH3 domain binding  extracellular matrix organization  positive regulation of angiogenesis  metal ion binding  
Ontology : EGO-EBImetalloendopeptidase activity  protein binding  extracellular region  nucleoplasm  plasma membrane  plasma membrane  plasma membrane  proteolysis  cell adhesion  myoblast fusion  metallopeptidase activity  integral component of membrane  SH3 domain binding  extracellular matrix organization  positive regulation of angiogenesis  metal ion binding  
Pathways : BIOCARTARole of EGF Receptor Transactivation by GPCRs in Cardiac Hypertrophy [Genes]   
REACTOMEO43184 [protein]
REACTOME PathwaysR-HSA-8941237 [pathway]   
NDEx NetworkADAM12
Atlas of Cancer Signalling NetworkADAM12
Wikipedia pathwaysADAM12
Orthology - Evolution
GeneTree (enSembl)ENSG00000148848
Phylogenetic Trees/Animal Genes : TreeFamADAM12
Homologs : HomoloGeneADAM12
Homology/Alignments : Family Browser (UCSC)ADAM12
Gene fusions - Rearrangements
Fusion : MitelmanCTBP2::ADAM12 [10q26.13/10q26.2]  
Fusion : QuiverADAM12
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerADAM12 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ADAM12
Exome Variant ServerADAM12
GNOMAD BrowserENSG00000148848
Varsome BrowserADAM12
ACMGADAM12 variants
Genomic Variants (DGV)ADAM12 [DGVbeta]
DECIPHERADAM12 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisADAM12 
ICGC Data PortalADAM12 
TCGA Data PortalADAM12 
Broad Tumor PortalADAM12
OASIS PortalADAM12 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICADAM12  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DADAM12
Mutations and Diseases : HGMDADAM12
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)ADAM12
DoCM (Curated mutations)ADAM12
CIViC (Clinical Interpretations of Variants in Cancer)ADAM12
NCG (London)ADAM12
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry ADAM12
NextProtO43184 [Medical]
Target ValidationADAM12
Huge Navigator ADAM12 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDADAM12
Pharm GKB GenePA24507
Clinical trialADAM12
DataMed IndexADAM12
PubMed206 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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