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FLASH GENE
Symbol ADAM17 contributors: mct/shn - updated : 27-03-2019
HGNC name ADAM metallopeptidase domain 17
HGNC id 195
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