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ADAM17 (ADAM metallopeptidase domain 17)

Identity

Other namesADAM18
CD156B
CSVP
MGC71942
TACE
HGNC (Hugo) ADAM17
LocusID (NCBI) 6868
Location 2p25.1
Location_base_pair Starts at 9629411 and ends at 9695917 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Note There are several recommendable reviews about ADAM17 and related proteases, for example Blobel, 2005; Arribas and Esselens, 2009; Gooz, 2010; and Saftig and Reiss, 2011.

DNA/RNA

Description The genomic DNA of ADAM17 extends 66505 base pairs with 19 exons. There is only one known transcription variant.
Transcription The mRNA of ADAM17 (NM_003183.4) contains 3572 base pairs and the open reading frame spans from bp 184 to bp 2658. Different isoforms due to differential splicing are not known.
Pseudogene No pseudogenes have been reported for ADAM17.

Protein

Note ADAM17 belongs to the ADAM (a disintegrin and metalloprotease) family which is part of the adamalysin proteins.
The activity and function of several membrane proteins is regulated by the proteolytic release of their ectodomains, a process known as shedding. About 2-4% of the proteins on the cell surface are affected by ectodomain shedding (Arribas and Massague, 1995). Since there are several of functionally and structurally diverse substrates, ADAMs are involved in various cellular processes. They take part in the regulation of cell adhesion, migration, development and signalling and are also implicated in pathologic conditions such as inflammation and cancer. The consequences of ectodomain shedding can vary, depending on the function of the substrate protein. Membrane-bound precursor proteins can be released by ADAMs as mature active molecules, for example ligands of the EGF receptor or cytokines like TNFa (Peschon et al., 1998; Blobel, 2005). Receptors, for example ErbB2 and ErbB4, can also be cleaved by ADAMs and thus become inactive or may still function as soluble decoy receptors (Molina et al., 2001; Vecchi et al., 1998). Contrariwise, receptors like Notch require proteolytic cleavage to generate intracellular signalling fragments that act as transcription factors after translocation to the nucleus. In this case ectodomain shedding is the prerequisite for regulated intramembrane proteolysis (RIP) mediated by intramembrane cleaving enzymes (Pan and Rubin, 1997; Brou et al., 2000).
 
  The structure of "a disintegrin and metalloproteases" consists of a N-terminal prodomain (aa 1-214) followed by a metalloprotease domain (aa 223-477), a disintegrin domain (aa 484-560) with a cystein-rich region, an epidermal growth factor-like domain (EGF) (aa 571-602), a transmembrane domain (TM) (aa 672-694) and a cytoplasmic tail (aa 695-824) (Arribas and Esselens, 2009 - modified). Amino acid specifications according to Pubmed graphics for ADAM17 (NP_003174.3).
Description The preproform of ADAM17 contains 824 amino acids (134 kDa). After cleavage of the prodomain by furin or other proprotein convertases, the mature form has a predicted molecular weight of 98 kDa. The prodomain serves as a chaperone and keeps the enzyme in an inactive state during maturation in the trans-Golgi network (Schlöndorff et al., 2000). The catalytic domain contains the characteristic zinc binding motif (HEXXHXXGXXH) and three potential N-glycosylation sites. The disintegrin domain is discussed to be involved in regulation of the catalytic activity of ADAM17 (Li and Fan, 2004; Smith et al., 2002), but might also be involved in interaction with integrins and therefore mediate cell-cell adhesion or cell-matrix interaction. The cytoplasmic tail of ADAM17 was thought to be important in regulation of the enzyme activity because of its potential tyrosine phosphorylation site, but recent studies showed that overexpressed ADAM17 lacking its cytoplasmic domain was able to cleave TNFalpha upon phorbolester stimulation (Reddy et al., 2000; Horiuchi et al., 2007). The transmembrane domain might play a role in regulation of ADAM activity as studies with ADAM-chimera with exchanged transmembrane domains and experiments with plasma membrane modulating stimuli indicate (Le Gall et al., 2010; Reiss et al., 2011).
Expression ADAM17 is ubiquitously expressed in various tissues, for example in the brain, kidney, heart and skeletal muscles. The expression pattern changes during embryonic development and the adult life (Black et al., 1997).
Localisation ADAM17 is a type I transmembrane protein, but only 10% of the total protein can be found in the plasma membrane on the cell surface (Schlöndorff et al., 2000). Most of the protein is localised in the endoplasmic reticulum and trans-Golgi network. It is suggested that ADAM17 accumulates in cholesterol rich departments of the plasma membrane (lipid rafts) (Tellier et al., 2006).
Function ADAM17 knockout mice display a severe phenotype that resembles mice lacking the epidermal growth factor receptor (EGFR) or one of its ligands (TGFalpha, HB-EGF or amphiregulin). Perinatal mortality is probably due to defects in heart development.
Because of their catalytic and their disintegrin domain, ADAMs can have both adhesive and proteolytic functions. ADAM17 is best studied for its proteolytic properties and cleaves its substrates in the juxtamembrane region. The proteins processed by ADAM17 have different functions and therefore proteolytic processing can either activate or abrogate processes. For example both receptors and ligands can be cleaved, thus signalling can be either initiated or stopped by ADAM17.
Homology Homologs of the human ADAM17 are found in various species ranging from other mammalians to primitive chordates like zebrafish. See table 1 for results of NCBI-Blast/blastp with human ADAM17 (NP_003174.3) as query sequence. Its closest relative in the family of human ADAM metalloproteases is ADAM10 (NP_001101.1), but there is only less than 30% amino acid sequence identity according to NCBI-Blast (blastp).

SpeciesAccession #identity to human ADAM17similarity to human ADAM17
Sus scrofa
NP_001093396.1
92%
97%
Mus musculus
NP_033745.4
92%
96%
Rattus norwegicus
NP_064702.1
92%
96%
Gallus gallus
NP_001008682.1
77%
87%
Xenopus laevis
NP_001089130.1
73%
85%
Danio rerio
NP_955967.1
61%
74%
Drosophila melanogaster
NP_733334.1
42%
59%

Mutations

Note So far no common germinal or somatic mutation variants are known.

Implicated in

Entity Cancer
Note Various growth factors necessary for tumor progression and growth are shed by ADAM17 and increased shedding of EGFR ligands was observed in tissues developing a malignant phenotype (Katakowski et al., 2009). ADAM17 is supposed to play a role in different malignancies: increased levels of the enzyme were detected in gastric carcinoma (Yoshimura et al., 2002), primary colon carcinoma (Blanchot-Jossic et al., 2005), skin malignancies (Oh et al., 2009) and ovarian cancer (Tanaka et al., 2005) but its role is best studied in breast cancer (see below).
  
Entity Breast cancer
Disease It was shown that overexpression of ADAM17 in breast cancer correlated with TGFalpha expression (Borrell-Pages et al., 2003), metastasis and tumor progression (McGowan et al., 2007) and shorter survival of patients (McGowan et al., 2008). Recent studies by Kenny and Bissell demonstrated that the malignant phenotype of a breast cancer cell line was reverted to a normal phenotype using siRNA against ADAM17 (Kenny and Bissell, 2007).
  
Entity Inflammation
Note The identification of ADAM17 as TNFalpha converting enzyme suggested an important role of this metalloprotease in inflammatory diseases with elevated levels of soluble TNFalpha, such as rheumatoid arthritis and inflammatory bowel disease. Indeed, increased enzymatic activity of ADAM17 was shown in tissues of patients with osteoarthritis (Amin, 1999) and rheumatoid arthritis (Ohta et al., 2001). Furthermore ADAM17 was shown to process several factors that are involved in leukocyte recruitment to the site of inflammation. Moreover ADAM17 regulates leukocyte transmigration through the vascular endothelium for example by cleaving adhesion molecules between endothelial cells. The vascular cell adhesion molecule (CC: TXT: V-CAM ID: 42784>) is released by ADAM17 and functions as the ligand of the leukocyte very late antigen 4 (VLA-4 or alpha4beta1 integrin), which is implicated in the leukocyte adhesion to the vascular endothelium (Garton et al., 2003). L-Selectin cleavage by ADAM17 promotes leukocyte migration through the basal membrane after adhering to the endothelium (Faveeuw et al., 2001; Peschon et al., 1998). ADAM17 was also identified as the sheddase of the tight junction molecule JAM-1 between endothelial cells (Koenen et al., 2009). Cleavage of JAM-1 contributes to the passage of leukocytes through the endothelial cell layer and the processed molecule serves as a biomarker of inflammation.
Disease - rheumatoid arthritis (see above),
- osteoarthritis (see above),
- inflammatory bowel disease (high levels of ADAM17 expression were reported in epithelial cells during the active phase of Crohn's disease (Cesaro et al., 2009)),
- psoriasis (ADAM17 expression was upregulated in keratinocytes, blood vessels and mast cells from patients (Kawaguchi et al., 2005)),
- pulmonary inflammation (reduced invasion of eosinophils in a model of acute allergic lung inflammation after treatment with ADAM17/MMP inhibitors (Trifilieff et al., 2002)).
  
Entity Alzheimer's disease
Note The majority of the amyloid precursor protein (APP) is physiologically cleaved by alpha-secretase (ADAM10 or ADAM17). This cleavage leads to the generation of a soluble non-amyloidogenic fragment (sAPPalpha), whereas shedding of APP by beta-secretase produces the amyloidogenic Abeta peptide (Allinson et al., 2003). Accordingly, decreased activity of alpha-secretase results in the formation of amyloid plaques. While ADAM10 represents the most important alpha-secretase, ADAM17 could contribute to APP-processing under certain conditions (Buxbaum et al., 1998; Jorissen et al., 2010).
  
Entity Kidney diseases
Note In polycystic kidney disease (PDK) increased activation of the EGF receptor leads to cyst formation and loss of kidney function. These symptoms could be significantly decreased by treatment with ADAM17 inhibitors (Richards et al., 1998; Dell et al., 2001). Which EGFR ligand is responsible in this context remains unclear, but TGFalpha knockout mice were shown to still develop PDK (Nemo et al., 2005). ADAM17 is also involved in chronic kidney disease (CDK) and it is suggested that this is due to the transactivation of EGFR through the GPCR agonist angiotensin-II (Lautrette et al., 2005). In this process ADAM17 is activated by the GPCR and releases TGFalpha, which in turn activates the EGFR.
  

External links

Nomenclature
HGNC (Hugo)ADAM17   195
Cards
AtlasADAM17ID572ch2p25
Entrez_Gene (NCBI)ADAM17  6868  ADAM metallopeptidase domain 17
GeneCards (Weizmann)ADAM17
Ensembl (Hinxton)ENSG00000151694 [Gene_View]  chr2:9629411-9695917 [Contig_View]  ADAM17 [Vega]
ICGC DataPortalENSG00000151694
AceView (NCBI)ADAM17
Genatlas (Paris)ADAM17
WikiGenes6868
SOURCE (Princeton)NM_003183
Genomic and cartography
GoldenPath (UCSC)ADAM17  -  2p25.1   chr2:9629411-9695917 -  2p25   [Description]    (hg19-Feb_2009)
EnsemblADAM17 - 2p25 [CytoView]
Mapping of homologs : NCBIADAM17 [Mapview]
OMIM603639   614328   
Gene and transcription
Genbank (Entrez)AK289829 AY422721 BC062687 BC136783 BC146658
RefSeq transcript (Entrez)NM_003183
RefSeq genomic (Entrez)AC_000134 NC_000002 NC_018913 NG_029873 NT_005334 NW_001838766 NW_004929298
Consensus coding sequences : CCDS (NCBI)ADAM17
Cluster EST : UnigeneHs.404914 [ NCBI ]
CGAP (NCI)Hs.404914
Alternative Splicing : Fast-db (Paris)GSHG0017416
Alternative Splicing GalleryENSG00000151694
Gene ExpressionADAM17 [ NCBI-GEO ]     ADAM17 [ SEEK ]   ADAM17 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP78536 (Uniprot)
NextProtP78536  [Medical]
With graphics : InterProP78536
Splice isoforms : SwissVarP78536 (Swissvar)
Catalytic activity : Enzyme3.4.24.86 [ Enzyme-Expasy ]   3.4.24.863.4.24.86 [ IntEnz-EBI ]   3.4.24.86 [ BRENDA ]   3.4.24.86 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)ADAM_MEPRO (PS50215)    DISINTEGRIN_2 (PS50214)    ZINC_PROTEASE (PS00142)   
Domains : Interpro (EBI)Blood-coag_inhib_Disintegrin    MetalloPept_cat_dom    Peptidase_M12B    Peptidase_M12B_N   
Related proteins : CluSTrP78536
Domain families : Pfam (Sanger)Disintegrin (PF00200)    Pep_M12B_propep (PF01562)   
Domain families : Pfam (NCBI)pfam00200    pfam01562   
Domain families : Smart (EMBL)DISIN (SM00050)  
DMDM Disease mutations6868
Blocks (Seattle)P78536
PDB (SRS)1BKC    1ZXC    2A8H    2DDF    2FV5    2FV9    2I47    2M2F    2OI0    3B92    3CKI    3E8R    3EDZ    3EWJ    3G42    3KMC    3KME    3L0T    3L0V    3LE9    3LEA    3LGP    3O64   
PDB (PDBSum)1BKC    1ZXC    2A8H    2DDF    2FV5    2FV9    2I47    2M2F    2OI0    3B92    3CKI    3E8R    3EDZ    3EWJ    3G42    3KMC    3KME    3L0T    3L0V    3LE9    3LEA    3LGP    3O64   
PDB (IMB)1BKC    1ZXC    2A8H    2DDF    2FV5    2FV9    2I47    2M2F    2OI0    3B92    3CKI    3E8R    3EDZ    3EWJ    3G42    3KMC    3KME    3L0T    3L0V    3LE9    3LEA    3LGP    3O64   
PDB (RSDB)1BKC    1ZXC    2A8H    2DDF    2FV5    2FV9    2I47    2M2F    2OI0    3B92    3CKI    3E8R    3EDZ    3EWJ    3G42    3KMC    3KME    3L0T    3L0V    3LE9    3LEA    3LGP    3O64   
Human Protein AtlasENSG00000151694
Peptide AtlasP78536
HPRD04703
IPIIPI00288894   IPI00029606   IPI00976551   
Protein Interaction databases
DIP (DOE-UCLA)P78536
IntAct (EBI)P78536
FunCoupENSG00000151694
BioGRIDADAM17
IntegromeDBADAM17
STRING (EMBL)ADAM17
Ontologies - Pathways
QuickGOP78536
Ontology : AmiGOresponse to hypoxia  positive regulation of protein phosphorylation  neutrophil mediated immunity  germinal center formation  positive regulation of leukocyte chemotaxis  metalloendopeptidase activity  metalloendopeptidase activity  metalloendopeptidase activity  Notch binding  interleukin-6 receptor binding  integrin binding  protein binding  cytoplasm  plasma membrane  integral component of plasma membrane  cell-cell junction  focal adhesion  proteolysis  membrane protein ectodomain proteolysis  membrane protein ectodomain proteolysis  apoptotic process  cell adhesion  epidermal growth factor receptor signaling pathway  epidermal growth factor receptor signaling pathway  Notch signaling pathway  Notch receptor processing  metallopeptidase activity  metallopeptidase activity  metallopeptidase activity  zinc ion binding  positive regulation of cell proliferation  cell surface  positive regulation of T cell chemotaxis  actin cytoskeleton  membrane  apical plasma membrane  SH3 domain binding  extracellular matrix disassembly  PDZ domain binding  B cell differentiation  extracellular matrix organization  positive regulation of cell growth  positive regulation of cell migration  positive regulation of transforming growth factor beta receptor signaling pathway  negative regulation of transforming growth factor beta receptor signaling pathway  collagen catabolic process  membrane protein intracellular domain proteolysis  positive regulation of cyclin-dependent protein serine/threonine kinase activity involved in G1/S transition of mitotic cell cycle  response to lipopolysaccharide  ruffle membrane  negative regulation of interleukin-8 production  positive regulation of chemokine production  regulation of mast cell apoptotic process  T cell differentiation in thymus  cell adhesion mediated by integrin  wound healing, spreading of epidermal cells  epidermal growth factor-activated receptor transactivation by G-protein coupled receptor signaling pathway  response to drug  membrane raft  positive regulation of epidermal growth factor-activated receptor activity  positive regulation of epidermal growth factor-activated receptor activity  neurotrophin TRK receptor signaling pathway  spleen development  cell motility  PMA-inducible membrane protein ectodomain proteolysis  PMA-inducible membrane protein ectodomain proteolysis  positive regulation of cellular component movement  response to high density lipoprotein particle  JAK-STAT cascade involved in growth hormone signaling pathway  apoptotic signaling pathway  
Ontology : EGO-EBIresponse to hypoxia  positive regulation of protein phosphorylation  neutrophil mediated immunity  germinal center formation  positive regulation of leukocyte chemotaxis  metalloendopeptidase activity  metalloendopeptidase activity  metalloendopeptidase activity  Notch binding  interleukin-6 receptor binding  integrin binding  protein binding  cytoplasm  plasma membrane  integral component of plasma membrane  cell-cell junction  focal adhesion  proteolysis  membrane protein ectodomain proteolysis  membrane protein ectodomain proteolysis  apoptotic process  cell adhesion  epidermal growth factor receptor signaling pathway  epidermal growth factor receptor signaling pathway  Notch signaling pathway  Notch receptor processing  metallopeptidase activity  metallopeptidase activity  metallopeptidase activity  zinc ion binding  positive regulation of cell proliferation  cell surface  positive regulation of T cell chemotaxis  actin cytoskeleton  membrane  apical plasma membrane  SH3 domain binding  extracellular matrix disassembly  PDZ domain binding  B cell differentiation  extracellular matrix organization  positive regulation of cell growth  positive regulation of cell migration  positive regulation of transforming growth factor beta receptor signaling pathway  negative regulation of transforming growth factor beta receptor signaling pathway  collagen catabolic process  membrane protein intracellular domain proteolysis  positive regulation of cyclin-dependent protein serine/threonine kinase activity involved in G1/S transition of mitotic cell cycle  response to lipopolysaccharide  ruffle membrane  negative regulation of interleukin-8 production  positive regulation of chemokine production  regulation of mast cell apoptotic process  T cell differentiation in thymus  cell adhesion mediated by integrin  wound healing, spreading of epidermal cells  epidermal growth factor-activated receptor transactivation by G-protein coupled receptor signaling pathway  response to drug  membrane raft  positive regulation of epidermal growth factor-activated receptor activity  positive regulation of epidermal growth factor-activated receptor activity  neurotrophin TRK receptor signaling pathway  spleen development  cell motility  PMA-inducible membrane protein ectodomain proteolysis  PMA-inducible membrane protein ectodomain proteolysis  positive regulation of cellular component movement  response to high density lipoprotein particle  JAK-STAT cascade involved in growth hormone signaling pathway  apoptotic signaling pathway  
Pathways : BIOCARTAProteolysis and Signaling of Notch [Genes]    Presenilin action in Notch and Wnt signaling [Genes]    g-Secretase mediated ErbB4 Signaling [Genes]   
Pathways : KEGGNotch signaling pathway    Alzheimer's disease    Epithelial cell signaling in Helicobacter pylori infection   
REACTOMEP78536 [protein]
REACTOME PathwaysREACT_578 Apoptosis [pathway]
REACTOME PathwaysREACT_116125 Disease [pathway]
REACTOME PathwaysREACT_118779 Extracellular matrix organization [pathway]
REACTOME PathwaysREACT_6900 Immune System [pathway]
REACTOME PathwaysREACT_2001 Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor [pathway]
REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
Protein Interaction DatabaseADAM17
Wikipedia pathwaysADAM17
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)ADAM17
SNP (GeneSNP Utah)ADAM17
SNP : HGBaseADAM17
Genetic variants : HAPMAPADAM17
1000_GenomesADAM17 
ICGC programENSG00000151694 
CONAN: Copy Number AnalysisADAM17 
Somatic Mutations in Cancer : COSMICADAM17 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
DECIPHER (Syndromes)2:9629411-9695917
Mutations and Diseases : HGMDADAM17
OMIM603639    614328   
MedgenADAM17
GENETestsADAM17
Disease Genetic AssociationADAM17
Huge Navigator ADAM17 [HugePedia]  ADAM17 [HugeCancerGEM]
Genomic VariantsADAM17  ADAM17 [DGVbeta]
Exome VariantADAM17
dbVarADAM17
ClinVarADAM17
snp3D : Map Gene to Disease6868
General knowledge
Homologs : HomoloGeneADAM17
Homology/Alignments : Family Browser (UCSC)ADAM17
Phylogenetic Trees/Animal Genes : TreeFamADAM17
Chemical/Protein Interactions : CTD6868
Chemical/Pharm GKB GenePA24512
Clinical trialADAM17
Cancer Resource (Charite)ENSG00000151694
Other databases
Probes
Litterature
PubMed271 Pubmed reference(s) in Entrez
CoreMineADAM17
GoPubMedADAM17
iHOPADAM17

Bibliography

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Clin Cancer Res. 2005 Jul 1;11(13):4783-92.
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The shedding activity of ADAM17 is sequestered in lipid rafts.
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Exp Cell Res. 2006 Dec 10;312(20):3969-80. Epub 2006 Sep 5.
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Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx.
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ADAM-17 predicts adverse outcome in patients with breast cancer.
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Ann Oncol. 2008 Jun;19(6):1075-81. Epub 2008 Jan 30.
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Differential expression and regulation of ADAM17 and TIMP3 in acute inflamed intestinal epithelia.
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Am J Physiol Gastrointest Liver Physiol. 2009 Jun;296(6):G1332-43. Epub 2009 Mar 19.
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Tumorigenicity of cortical astrocyte cell line induced by the protease ADAM17.
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Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases.
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The disintegrin-metalloproteinases ADAM 10, 12 and 17 are upregulated in invading peripheral tumor cells of basal cell carcinomas.
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ADAM-17: the enzyme that does it all.
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ADAM17 is regulated by a rapid and reversible mechanism that controls access to its catalytic site.
Le Gall SM, Maretzky T, Issuree PD, Niu XD, Reiss K, Saftig P, Khokha R, Lundell D, Blobel CP.
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Unsaturated Fatty Acids Drive Disintegrin and Metalloproteinase (ADAM)-dependent Cell Adhesion, Proliferation, and Migration by Modulating Membrane Fluidity.
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J Biol Chem. 2011 Jul 29;286(30):26931-42. Epub 2011 Jun 3.
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The "A Disintegrin And Metalloproteases" ADAM10 and ADAM17: novel drug targets with therapeutic potential?
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Contributor(s)

Written06-2011Astrid Evers, Karina Reiss
Department of Dermatology and Allergology, University Hospital Schleswig Holstein, Campus Kiel, Schittenhelmstrasse 7, Kiel D-24105, Germany

Citation

This paper should be referenced as such :
Evers, A ; Reiss, K
ADAM17 (ADAM metallopeptidase domain 17)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(12):989-993.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/ADAM17ID572ch2p25.html

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