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FLASH GENE
Symbol ADAM12 contributors: mct/ - updated : 04-01-2017
HGNC name ADAM metallopeptidase domain 12
HGNC id 190
Location 10q26.2      Physical location : 127.702.901 - 128.077.127
Synonym name
  • a disintegrin and metalloproteinase domain 12 (meltrin alpha)
  • meltrin alpha
  • Synonym symbol(s) MLTN, MCMP, RP11-295J3.5, MLTNA, MCMPMltna, ADAM12-OT1, CAR10
    EC.number 3.4.24.-
    DNA
    TYPE functioning gene
    STRUCTURE 376.17 kb     23 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Map cen - D10S1398E - D10S1602 - ADAM12 - D10S575 - D10S214 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    23 splicing 6093 - 909 membrane protein 2008 18621736
  • also called ADAM12L
  • membrane-anchored long form having a cytoplasmic tail that interacts with several SH3 domain containing proteins including the Src-kinase SRC and YES1
  • contains extracellular prodomain (P), catalytic (C), disintegrin (D), cysteine-rich (CR), and epidermal growth factor-like (EGF) domains; a class I transmembrane region; and a cytoplasmic tail
  • new role for ADAM12L in mediating the functional association of ILK with ITGB1 to regulate cell adhesion/survival through a PI3K/Akt signaling pathway
  • is associated with EMT and contributes to TGFB1-dependent EMT by favoring both SMAD-dependent and SMAD-independent pathways
  • 19 splicing 3433 - 738 secreted form 2008 18621736
  • also called ADAM12S
  • lacking the C-terminal transmembrane and cytoplasmic domains of ADAM12L (PMID: 20533908)
  • the non-catalytic C-terminal domains of ADAM12-S regulate the
  • catalytic activity (PMID: 20533908)
  • active metalloprotease that cleaves IGFBP3 and -5
  • five extracellular domains and a unique stretch of 33 AAs at the C terminus
  • proteolytic activity of trophoblast-derived ADAM12S, and likely ADAM12S exerts its pro-migratory function in trophoblasts by inducing ITGB1-mediated cellular spreading
  • 23 - 8041 - 906 - 2008 18621736
    19 - 3411 - 735 - 2008 18621736
    19 - 3417 - 737 - 2008 18621736
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularvessel     Homo sapiens
    Hearing/Equilibriumear   highly
    Nervousbrain   moderately
    Reproductivefemale systemplacenta  highly Homo sapiens
     male systemprostate  moderately
    Respiratoryrespiratory tractlarynx  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone  highly
    Muscularsmooth   
    Muscularstriatumcardiac  
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial cell Homo sapiens
    Nervousoligodendrocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period pregnancy
    Text term placenta
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a catalytic domain
  • three zinc-binding histidines
  • a catalytic glutamic acid in the conserved HEXXHXXGXXH motif
  • a prodomain/catalytic domain cationic molecular switch, regulated by exogenous heparan sulfate and heparin but also endogenous cell surface proteoglycans and the polyanion, calcium pentosan polysulfate
  • a Zn-binding site metalloproteinase
  • a disintegrin-like domain
  • a cysteine rich domains
  • an EGF-like repeat
  • a transmembrane domain
  • a cytoplasmic tail, proteolytic activity (after cleavage of the prodomain at a site for a furin-like endopeptidase)
  • a c-Src interaction site in the cytoplasmic domain required for the induction of invadopodia clusters
  • conjugated GlycoP , MetalloP
    HOMOLOGY
    interspecies homolog to murine maltrin alpha
    Homologene
    FAMILY
  • ADAM (a disintegrin and metalloprotease domain) family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,nucleus,nucleoplasm
    basic FUNCTION
  • involved in tumor cell adhesion
  • contribution to protease activity in pregnancy serum
  • required for myotube formation and in osteoblast differentiation
  • involved in the development of white adipose tissue, and in obesity induced by high- fat diet
  • membrane-anchored metalloprotease, which has been implicated in activation-inactivation of growth factors that play an important role in wound healing
  • increased expression of ADAM12 in chronic wounds impairs wound healing through the inhibition of keratinocyte migration
  • would be functional in a highly chondroitin sulfate-rich environment
  • multifunctional zinc-dependent enzyme, regulating
  • the availability of bioreactive molecules, such as cell-surface receptors, growth factors and cytokines
  • in normal tissue, may inhibit cell migration by mediating cell adhesion via integrin interactions, whereas, in tumor cells, higher levels of ADAM12-S proteolytic function stimulate cell migration and invasion
  • constitutively internalized primarily via the clathrin-dependent pathway and is subsequently detected in both early and recycling endosomes
  • ADAM12 internalization involves the clathrin-dependent pathway and GRB2
  • can activate membrane-anchored proteins, such as SHH, DLL1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding
  • role for ADAM12 in ectodomain shedding of several membrane-anchored endothelial proteins and likely this process may have importance in tumour neovascularization or/and tumour cell extravasation
  • function for ADAM12 in trophoblast biology, where ADAM12 may play a central role regulating the behavior of invasive trophoblast subsets in early pregnancy
  • BSG and ADAM12 play a major role in cancer invasion and metastasis owing to the fact that they are directly related to the cell microenvironment and extracellular matrix (ECM) degradation
  • function for ADAM12 in regulating trophoblast fusion
  • novel role for ADAM12 in placental development, specifically important role in controlling the differentiation of villous cytotrophoblasts into multinucleated cellular structures
  • ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function
  • CELLULAR PROCESS protein, degradation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • Zn2+
  • protein
  • IGFBP3 and ACTN2, ACTN1 (acting on cell-cell adhesion or cell signaling during myoblast differentiatino and fusion)
  • interacting with ITGB1 and ITGB3 (ADAM12-mediated focal adhesion formation is differently regulated by beta1 and beta3 integrins)
  • may modulate cell adhesion and spreading through interaction with alpha1-integrin
  • SKIL plays likely a role in regulating ADAM12 expression in response to TGFB1
  • positive activation loop between ADAM12 and ERBB2 that may contribute to head and neck squamous cell carcinoma (HNSCC) progression
  • ADAM12 enhanced EPHA1 cleavage in response to TGFB1 in primary tumors
  • CDH1 is a novel ADAM12 substrate
  • cell & other
    REGULATION
    inhibited by TIMP2 (TIMP2 exhibits high inhibitory
    activity against ADAM12)
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --other  
    aberrantly expressed in breast cancer patient urine, and increased urinary levels correlate with breast cancer progression
    tumoral     --over  
    in gastric carcinoma
    constitutional     --over  
    in osteoarthritic cartilage and enhances IGF1-mediated chondrocyte proliferation by degradation of insulin-like growth factor-binding protein IGFBP5
    constitutional     --over  
    fivefold upregulated in the nonhealing edge of chronic ulcers compared to healthy skin
    Susceptibility to late-onset Alzheimer disease
    Variant & Polymorphism other interaction between the ADAM12 and SH3PXD2A genes may confer susceptibility to late-onset Alzheimer disease
    Candidate gene
  • for rapid diagnostic of cancer (detection of urinary ADAM 12 may prove useful in the development of noninvasive diagnostic and prognostic tests for breast and perhaps other cancers)
  • can be detected in the urine of breast and bladder cancer patients, and its levels have been shown to correlate with disease status, stage, and cancer risk
  • Marker
  • urinary MMP9/LCN2 and ADAM12 are potential noninvasive biomarkers for gastric cancer, including early-stage disease
  • serum BSG and ADAM12 values and urine ADAM12 values may be useful markers in prostate cancer
  • is a promising marker for the diagnosis of complete spontaneous abortion and ectopic pregnancy in symptomatic women, and under certain conditions, ADAM12 can diagnose ectopic pregnancy and spontaneous abortion before an ultrasonographic detection of the conditions
  • ADAM12L may serve as a novel marker and/or a novel therapeutic target in breast tumor-initiating cells (BTICs)
  • Therapy target
    SystemTypeDisorderPubmed
    cancerreproductivebreast
    may represent a potential therapeutic target in breast cancer
    immunologyautoimmunearticular
    treatment of patients with the heparin analog CaPPS may promote ADAM12 degradation of IGFBP 3 and stimulate chondrocyte proliferation in osteoarthritic cartilage
    cancerdigestiveoesophagus
    ADAM12L might be potential targets of esophageal carcinoma for anti-metastasis therapy
    miscelleaneousdermatology 
    topical ADAM12 inhibitors may therefore prove useful for the treatment of chronic wounds
    ANIMAL & CELL MODELS