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FLASH GENE
Symbol ADAM10 contributors: mct - updated : 14-10-2016
HGNC name ADAM metallopeptidase domain 10
HGNC id 188
Corresponding disease
RAK Kitamura reticulate acropigmentation
Location 15q21.3      Physical location : 58.888.509 - 59.042.177
Synonym name
  • kuzbanian protein homolog
  • a disintegrin and metalloproteinase domain 10
  • mammalian disintegrin-metalloprotease
  • CD156c antigen
  • alpha secretase
  • Synonym symbol(s) MADM, KUZ, HsT18717, CD156c, AD10, CDw156
    EC.number 3.4.24.81
    DNA
    TYPE functioning gene
    STRUCTURE 153.67 kb     16 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map cen - D15S209 - D15S121 - ADAM10 - D15S159 - D15S216 - qter
    RNA
    TRANSCRIPTS type messenger
    text with a shorter alternatively spliced form
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    16 - 3927 84 748 - 1998 9618175
    precursor
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivemouthtongue  highly
    Lymphoid/Immunethymus   highly
    Nervousbrain   highly Homo sapiens
    Respiratoryrespiratory tracttrachea  highly
    Skin/Tegumentskin     Homo sapiens
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow  highly Homo sapiens
    Epithelialbarrier liningepidermis highly Homo sapiens
    Muscularstriatumskeletal highly Homo sapiens
    Nervousperipherous  highly Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticprogenitor cell Homo sapiens
    Lymphoid/ImmuneT cell Homo sapiens
    Muscularmyoblast Homo sapiens
    Nervousneuron
    Skin/Tegumentkeratinocyte Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, fetal
    Text somitic dermatome and myotome, fetal liver
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • domains similar to hemorrhagic snake venom proteins (HSVP) with a prodomain
  • a Zn-binding site metalloproteinase
  • a disintegrin-like domain
  • a cysteine rich domain
  • an EGF-like repeat
  • the cytoplasmic domain of ADAM10 negatively regulates its constitutive activity through an ER retention motif but is dispensable for its stimulated activity
  • four potential N-glycosylation sites (N267, N278, N439 and N551), that cleaves several plasma membrane proteins
  • a transmembrane domain
  • a cytoplasmic tail
  • conjugated GlycoP , MetalloP
    isoforms Precursor cleaved by a furin endopeptidase
    HOMOLOGY
    interspecies homolog to Drosophila Kuzbanian
    homolog to rattus Adam10 (96.4pc)
    homolog to murine Adam10 (96.0pc)
    Homologene
    FAMILY
  • ADAM (a disintegrin and metalloprotease domain) family
  • CATEGORY adaptor , enzyme
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,nucleus
    text localized in the plasma membrane but predominantly expressed in the Golgi apparatus and in released membrane vesicles derived likely from the Golgi
    basic FUNCTION
  • may be presenting alpha secretase activity
  • involved in cell-cell and cell-matrix interactions, regulating sympatoadrenal cell fate in development and neoplasia
  • involved in the proteolytic processing of APP and in early vertebrate embryogenesis (through notch signaling pathway)
  • vesicle-based protease, involved in direct cleavage at the cell surface, or release and cleavage in secretory vesicles most likely derived from the Golgi apparatus
  • involved in the constitutive cleavage of CX3CL1 and thereby may regulate the recruitment of monocytic cells to CX3CL1-expressing cell layers
  • playing an essential role during neuronal development
  • cleaving many proteins including TNF-alpha and E-cadherin
  • playing a crucial role on beta-catenin signaling, and constitutes a central switch in the signaling pathway from N-cadherin at the cell surface to beta-catenin/LEF-1-regulated gene expression in the nucleus
  • may contribute to allergic reactions by shedding the low-affinity IgE receptor CD23
  • being responsible with ADAM17 for the cytokine-induced shedding of CXCL16
  • may be critical in muscle fiber differentiation (
  • critically involved in the shedding of FASLG
  • represents an important molecular modulator of FASLG-mediated cell death
  • initiating the regulated intramembrane proteolysis
  • metalloprotease when it is membrane-bound and potential signaling protein once cleaved by ADAM9/15 and the gamma secretase complex
  • is required for NOTCH1 signaling induced by ligands, cleaving NOTCH1
  • contributes to the normal cleavage of the cellular prion protein
  • essential alpha-secretase in neurons, and the control of neuronal ADAM10 activity has crucial importance in the etiology of Alzheimer disease
  • may be involved in the motility of breast cancer cells via its activation by mesenchymal stem cells
  • physiologically relevant, constitutive alpha-secretase of APP
  • ADAM10, but not ADAM9 or 17, is essential for the constitutive alpha-secretase cleavage of APP
  • might not only be important for cleavage of FCER2, but also for sorting FCER into exosomes
  • required for alpha-secretase cleavage in primary neurons
  • key role in the complex sequence of events through which CDH2 affects spine maturation and controls structure and function of glutamatergic synapses
  • involved in the cleavage of PCDH12
  • although ADAM10 is expressed in high abundance in the peripheral nerve, it is not critical for normal myelination
  • involved in the cleavage od CDH1 that mediates epithelial cell sorting downstream of EPHB signalling
  • nonredundant roles of cell-autonomous and non-cell-autonomous ADAM10 activity in the maintenance of hematopoiesis
  • negatively regulates neuronal differentiation, possibly via its proteolytic effect on the NOTCH1 signaling during development of the spinal cord
  • ADAM10 protease is an important factor in mast cell migration and tissue distribution
  • acts in a cell autonomous manner within the intestinal crypt compartment to regulate NOTCH1 signaling
  • ADAM10 and ADAM17 have opposite effects on sprouting angiogenesis that may be unrelated to Notch signalling and involves differentially expressed anti-angiogenic proteins such as TSP1
  • major alpha-secretase that catalyzes the amyloid precursor protein (APP) ectodomain shedding in the brain and prevents amyloid formation
  • both ADAM10 and ADAM17 are associated with FASLG-containing secretory lysosomes
  • is essential for development because it cleaves Notch proteins to induce Notch signaling and regulate cell fate decisions
  • is essential for embryonic development through activation of Notch proteins
  • CELLULAR PROCESS protein, degradation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
  • ADAM10/DLL4 signaling is a major signaling pathway in ECs driving inflammatory events involved in inflammation and immune cell recruitment
  • a component
    INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • Zn2+
  • protein
  • interacting with YWHAZ
  • interacting with CX3CL1 (fractalkine) and regulating CX3CL1-mediated cell-cell adhesion
  • interacting with CDH1 (proteolytic processing of CDH1 for regulating cell-cell adhesion, motility, and proliferation of epithelial cells)
  • interacting with BTC (mediates ectodomain shedding of the betacellulin precursor)
  • cleaving specifically CDH2
  • interaction with FASLG may be of critical importance for the tight regulation of induced cell death in health and disease
  • with RECK (regulates the ectodomain shedding of Notch ligands by directly inhibiting the proteolytic activity of ADAM10)
  • interacting with EFNA2
  • partner for TSPAN12
  • ADAM10 is a sheddase capable of releasing the GPNMB ectodomain from the surface of breast cancer cells, which induces endothelial cell migration
  • binds FCER2 in a protease-independent manner
  • its activity is regulated by inhibition of ADAM9, and this regulation may be used to control shedding of amyloid precursor protein by enhancing &
  • 945;-secretase activity, a key regulatory step in the etiology of Alzheimer disease
  • required for the hypoxia-induced shedding of MICA, a ligand that triggers the cytolytic action of immune effectors, from the surface of tumor cells
  • mediates endogenous CADM1 shedding
  • SIGMAR1 overexpression diminished ADAM17- and ADAM10-dependent shedding
  • TSPAN15 specifically associate with ADAM10 (TSPAN15 accelerates the ER-exit of the ADAM10-TSPAN15 complex and stabilizes the active form of ADAM10 at the cell surface)
  • ADAM10 and/or MMP9 are playing important roles in constitutive and PACAP-induced RAGE shedding
  • TSPAN5 and TSPAN14 positively regulated ligand-induced ADAM10-dependent NOTCH1 signaling
  • P2RX7 activation induces the rapid shedding of CXCL16 and this process involves ADAM10
  • ADAM10-dependent regulation of DLL1 and DLL4 expression in association with changes in HES1 and HEY1 expression
  • in hippocampal neurons, DLG1 an excitatory synapse scaffolding element, governs ADAM10 trafficking from dendritic Golgi outposts to synaptic membranes
  • CDH1/CTNNB1 signaling pathway is regulated by PKD1 and GNA12 via ADAM10
  • TNFRSF13B is released by ADAM10 and reflects B cell activation in autoimmunity
  • is required for shedding of membrane proteins such as EGF, betacellulin, the amyloid precursor protein, and CD23 from cells
  • CTF1 activates NOTCH1 signaling through the up-regulation of ADAM10, a rate-limiting factor of NOTCH1 signaling activation
  • MAZ plays an important role in ADAM10 transcription in response to CTF1 in neural progenitor cells
  • endothelial TSPAN5- and TSPAN17-ADAM10 complexes may regulate inflammation by maintaining normal CDH5 expression and promoting T lymphocyte transmigration
  • TSPANC8s are required for ADAM10 trafficking from the endoplasmic reticulum and its enzymatic maturation
  • ADAM10 associates directly with all members (TSPAN5, TSPAN10, TSPAN14, TSPAN15, TSPAN17 and TSPAN33) of a subgroup of tetraspanins having eight cysteines in the large extracellular domain and referred to as TSPANC8
  • cell & other
    REGULATION
    inhibited by binding of Zn2+
    TIMP1, TIMP3 (but N-terminal domains of TIMPs alone are insufficient for the inhibition of ADAM10)
    SFRP1, SFRP2 (inhibit the ADAM10 metalloprotease, which might have important implications in pathological events, including cancer and Alzheimer disease)
    Other is subject to regulated intramembrane proteolysis by ADAM9/15 and the gamma secretase complex
    induced in osteoarthritis affected-cartilage
    TSPAN12 promotes ADAM10 maturation and thereby facilitates ADAM10-dependent proteolysis of APP
    regulated by N-glycosylation (is crucial for ADAM10 processing and resistance to proteolysis)
    TSPANC8 tetraspanins have a conserved function in the regulation of ADAM10 trafficking and activity, thereby positively regulating NOTCH1 receptor activation
    ASSOCIATED DISORDERS
    corresponding disease(s) RAK
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in atrial fibrillation
    constitutional     --low  
    in platelet of Alzheimer disease
    tumoral       gain of function
    by RAR and acitretin, resulting in an increase of the ratio between alpha- and beta-secretase activity in neuroblastoma cells
    constitutional       gain of function
    constitutive activation of ADAM10 contributes to the growth of mantle cell lymphoma
    constitutional     --other  
    in FRA X fibroblasts, a dual dysregulation of APP and ADAM10 leads to the production of an excess of soluble APPalpha and to synaptic and behavioral deficits
    Susceptibility
    Variant & Polymorphism
    Candidate gene
  • participating in signaling intrinsic to NOTCH1 mutations associated with leukemia
  • candidate gene for Alzeihmer's disease with two potentially pathogenic mutations (Q170H, R181G) with incomplete penetrance
  • Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativealzheimer
    pharmacological activation of alpha-secretase (ADAM10) may be a therapeutic approach to Alzheimer disease
    cancerdigestiveliver
    antidrug cancer can modulate expression of ADAM10, epirubicin therapy may have an effect on antitumor immunity in hepatocellular carcinoma patients
    neurologyneurodegenerativealzheimer
    activation of ADAM10 by epigallocatechin-3-gallate (EGCG), and promotion of non-amyloidogenic APP processing is warranted to support the use of this compound as a safe alternative to estrogen replacement therapy in the prevention and treatment of Alzheime
    cancerhemopathy 
    may be a useful strategy to enhance the response of mantle cell lymphoma to other therapeutic agents
    mental retardationfragile X 
    downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating Fragile X phenotypes
    neurologyneurodegenerativealzheimer
    increasing ADAM10 activity is suggested as a therapy to prevent the production of the neurotoxic APP peptide in Alzheimer disease
    ANIMAL & CELL MODELS
  • ADAM10-null mice display no obvious alteration of myelination