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FLASH GENE
Symbol ADAM17 contributors: mct/shn - updated : 27-03-2019
HGNC name ADAM metallopeptidase domain 17
HGNC id 195
Location 2p25.1      Physical location : 9.629.412 - 9.695.917
Synonym name
  • ADAM metallopeptidase domain 18
  • snake venom-like protease
  • tumor necrosis factor-alpha converting enzyme
  • tumor necrosis factor, alpha, converting enzyme
  • CD156b antigen
  • TNF-alpha converting enzyme
  • TNF-alpha convertase
  • disintegrin and metalloproteinase domain 17
  • disintegrin and metalloproteinase domain-containing protein 17
  • CD156b antigen
  • Synonym symbol(s) TACE, cSVP, CD156B, MGC71942, ADAM18, NISBD
    EC.number 3.4.24.86
    DNA
    TYPE functioning gene
    STRUCTURE 66.51 kb     19 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked Y status confirmed
    Map pter - D2S287 - D2S2207 - ADAM17 - D2S2169 - D2S423 - cen
    Authors Hirohata (98)
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    19 - 3572 70 824 - - 9034191
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly Homo sapiens
    Digestiveintestinesmall intestine  moderately Homo sapiens
     liver   lowly Homo sapiens
    Endocrinepancreas   specific Homo sapiens
    Lymphoid/Immunespleen   moderately Homo sapiens
     thymus   moderately Homo sapiens
    Nervousbrain   lowly Homo sapiens
    Reproductivefemale systemovary  highly Homo sapiens
     female systemplacenta  highly Homo sapiens
     male systemprostate  moderately Homo sapiens
     male systemtestis  highly Homo sapiens
    Respiratorylung   lowly Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal moderately Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal, growth/childhood
    Text brain, lung, liver, kidney (
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • an unknown prodomain, a cysteine switch, a catalytic domain, a zinc binding region, a disintegrin region, an EGF-like domain, a transmembrane domain, and a unique cytoplasmic region (
  • conjugated GlycoP , MetalloP
    isoforms Precursor TNFalpha induces the conversion from the proform of ADAM-17 to its mature form
    HOMOLOGY
    interspecies ortholog to Adam17, Mus musculus
    ortholog to Adam17, Rattus norvegicus
    ortholog to ADAM17, Pan troglodytes
    Homologene
    FAMILY
  • ADAM (a disintegrin and metalloprotease domain) family
  • CATEGORY adhesion , enzyme
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic
    text membrane bound processed to a secreted form, (membrane type 1 protein)
    basic FUNCTION
  • a functional paracrine/autocrine role in osteoarthritis -affected cartilage (
  • role in the processing of cell surface proteins TNF receptor, the L-selectin adhesion molecule, and transforming growth factor-alpha (
  • an essential role mammalian development (
  • role in the regulated shedding of EGFR ligands (
  • acts as alpha-secretases in A172 cells (
  • functions as an effector of GPCR-mediated signalling and represents a key element of the cellular receptor cross-talk network (
  • mediating the cleavage and shedding of fraktalkine (CX3CL1)
  • releasing TNFA from its membrane bound precursor, also reported to cleave APP
  • contributing to heart development
  • growth hormone binding protein sheddase (see GHR)
  • metalloprotease disintegrin cleaving a variety of membrane proteins, releasing ("shedding") their extracellular domains from cells
  • playing a role in the regulation of platelet glycoprotein V
  • may be having a role in both the induction and down-regulation of neutrophil activity
  • involved in invasion of oral squamous cell carcinoma, probably through CD44 cleavage
  • being responsible with ADAM10 for the cytokine-induced shedding of CXCL16
  • involved in the tumor-associated proteolytic release of soluble MICA facilitating tumor immune escape (
  • important regulator of several key steps during angiogenesis
  • involved in the conversion of MMP2 from the latent form to the intermediate-sized form and plays a particularly key role in the conversion of the intermediate-sized form to the fully activated form
  • may regulate angiogenesis via its effects on endothelial cells proliferation, network formation, invasion and MMP2 activation
  • involved in the cleavage of NOTCH1
  • is required for NOTCH1 signaling independent of ligands
  • mediates inflammation-induced shedding of SDC1 and SDC4 by lung epithelial cells
  • responsible for cleaving the membrane-proximal extracellular domain of L-selectin, which reduces the efficiency of leucocyte recruitment to sites of inflammation
  • shedding JAG1 in a lipid-raft-independent manner, and the cytosolic domain of the former protein is not a pre-requisite for either constitutive or regulated shedding
  • through the cleavage of VASN, the metalloprotease controls TGFB-mediated epithelial-to-mesenchymal transition
  • cleaves neuregulin-1 type III in the epidermal growth factor domain and negatively regulates peripheral nervous system myelination (
  • a modulator of NRG1 type III activity and is a negative regulator of myelination in the peripheral nervous system (
  • its induction during apoptosis may rapidly diminish neutrophil sensitivity to the inflammatory environment, complementing other anti-inflammatory activities by these cells during inflammation resolution
  • may play a broad role in the homeostatic maintenance of various substrates in the blood
  • is a novel UPR-regulated gene in response to severe hypoxia and ER stress, which is actively involved in the release of TNFRSF1A under these conditions
  • potential functional link between ADAM17 and ICOSLG in controlling adaptive immune responses
  • 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
  • both ADAM10 and ADAM17 are associated with FASLG-containing secretory lysosomes
  • ADAM17 has a prominent role in ANCA-associated vasculitis (AAV) and might account for the vascular complications associated with this disease
  • ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function
  • is regarded as a first line of defense against injury and infection, by releasing tumor necrosis factor alpha (TNF) to promote inflammation and epidermal growth factor (EGF) receptor ligands to maintain epidermal barrier function
  • PDIA6 regulation of ADAM17 shedding activity and EGFR-mediated migration and invasion of glioblastoma cells
  • ADAM17 central role in signalling implies that ADAM17 activity has to be tightly regulated, including at the level of localisation
  • regulation of the shedding activity of ADAM17 is multilayered and different regions of the protease are involved
  • inhibition of ADAM17 in cortical lesions favors neuronal formation by promoting the differentiation of progenitors and by facilitating migration of neuroblasts from the subventricular zone (SVZ) towards the injured area
  • implicated in many shedding processes
  • importance of ADAM17 on podosome disassembly and thus cell motility and normal cell function of macrophages
  • CELLULAR PROCESS protein, post translation
    protein, degradation
    PHYSIOLOGICAL PROCESS development
    text
  • major sheddase for ectodomain shedding of TNF-alpha (
  • PATHWAY
    metabolism
    signaling
  • part of a novel pro-angiogenic pathway leading to MMP2 activation and vessel formation
  • critical role of the ADAM17-EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier
  • a component
    INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • Zn2+
  • protein
  • mitotic arrest deficient 2, MAD2 and metalloprotease-disintegrin MDC9 (
  • protein-tyrosine phosphatase PTPH1 (
  • SAP97 (
  • Integrin alpha5beta1 (
  • Four and Half LIM domain 2 protein, FHL2 (
  • ALCAM
  • ADAM17 mediates ectodomain shedding of the scavenger receptor CD163
  • VASN
  • participates at least in part in the shedding of LMAN2
  • SIGMAR1 overexpression diminished ADAM17- and ADAM10-dependent shedding
  • ANXA2, ANXA8, ANXA9, play an essential role in the ADAM17-mediated ectodomain shedding of EGFR ligands
  • ADAM17 is likely the PTK7 sheddase
  • ALCAM directly associates with the tetraspanin CD9 on the leukocyte surface in protein complexes that also include the metalloproteinase ADAM17/TACE
  • major sheddase for the EGF receptor ligands and is considered to be one of the main proteases responsible for the ectodomain shedding of surface proteins
  • TXN is a partner of the ADAM17 cytoplasmic domain that could be involved in the regulation of ADAM17 activity
  • role of ADAM17 during embryonic eyelid closure is to transactivate EGFR signaling
  • over-activation of ADAM17 in NK cells may be detrimental to their effector functions by down-regulating surface expression of FCGR3A and SELL
  • ADAM17 regulates likely terminal differentiation of chondrocytes during endochondral ossification by activating the TGFA/EGFR signaling axis
  • PROCR can be shed from the cell surface, and this is mediated by tumor necrosis factor-alpha-converting enzyme (ADAM17)
  • TMPRSS2 was found to compete with the metalloprotease ADAM17 for ACE2 processing, but only cleavage by TMPRSS2 resulted in augmented SARS-S-driven entry
  • in hepatocytes, CAV1 is required for TGFB1-mediated activation of the metalloprotease ADAM17 that is responsible for shedding of EGFR ligands and activation of the EGFR pathway, which counteracts the TGFB1 pro-apoptotic effects
  • ANPEP is required for ADAM17 downregulation
  • FCGR3A cleavage by ADAM17, but non-cleavable version of FCGR3A can be expressed in engineered NK cells (
  • PACS2 is a regulator of ADAM17 trafficking and ErbB signalling
  • ADAM17-mediated degradation of IFNG may block the anti-tumorigenic and anti-osteoclastogenic effects of IFNG
  • hepatic TIMP3 can slow progression of Non-alcoholic fatty liver disease (NAFLD), and tumorigenesis, at least in part, through the regulation of ADAM17 activity
  • HSPA5 protects ADAM17 against PDIAA6 catalyzed inactivation
  • RHBDF2 controls multiple aspects of ADAM17 biology, including stimulated shedding on the cell surface
  • STING1 activates ADAM17 and this activation produces soluble proinflammatory SEMA4D independently of the TBK1/IRF3-mediated transcriptional pathway
  • FRMD8 binds to RHBDF1, RHBDF2, enhancing the cell surface stability of RHBDF1, RHBDF2 and ADAM17, preventing their degradation in lysosome (
  • FRMD8 binds to the cytoplasmic N-terminus of RHBDF1, RHBDF2 and is necessary to stabilise RHBDF1, RHBDF2 and ADAM17 at the cell surface
  • ADAM17 is involved in the protective effect of CALCA against AGT-induced inflammation via the EGFR-ERK1/2 pathway in Vascular Smooth Muscle Cells
  • cell & other
    REGULATION
    activated by in response to cellular stimulation
    HDLs (
    induced by and redistributed in AGT-damaged kidneys
    inhibited by TIMP3
    Phosphorylated by Erk at threonine 735 (
    Other regulated by IL10 (regulates ADAM17, involving a TIMP3 dependent and independent mechanism)
    negatively regulated by protein-tyrosine phosphatase PTPH1 (
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in arthritis affected cartilage
    tumoral     --over  
    promoted the progression of gastric cancer, potentially via NOTCH and/or WNT signaling pathway activation
    constitutional     --over  
    in inflammatory myopathy with interstitial lung diseases (ILD)
    Susceptibility
    Variant & Polymorphism
    Candidate gene
  • participating in signaling intrinsic to NOTCH1 mutations associated with leukemia
  • Marker
  • may serve as a useful prognostic marker in gastric cancer
  • Therapy target
  • a principal target for the treatment of TNF-dependent pathologies (
  • SystemTypeDisorderPubmed
    miscelleaneousurinarychronic kidney disease
    therapeutic strategy for preventing progression of chronic renal diseases (inhibitor of ADAM17)
    cancerangiogenesis 
    may serve as a novel therapeutic target for diseases in which the inhibition or stimulation of angiogenesis could be beneficial
    ANIMAL & CELL MODELS
  • inactivation of Adam17 gene in mouse cells caused a marked decrease in soluble TNF-alpha production (
  • TACE inactivation in mouse myeloid cells or temporal inactivation at 6 wk offers strong protection from endotoxin shock lethality in mice by preventing increased TNF serum levels (
  • perinatal and postnatal defects in mice lacking TACE were associated with numerous epithelial anomalies (
  • Lentivirus-mediated knockdown of ADAM17 in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination (
  • motor neurons of conditional knockout mice lacking ADAM17 are significantly hypermyelinated, and small-caliber fibers are aberrantly myelinated (
  • mice lacking ADAM17 in chondrocytes (A17&
  • 916;Ch) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones