同: a Disintegrin and metalloprotease- 17, Tumor necrosis factor-α- converting enzyme

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/04/18 06:27:23」(JST)

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ADAM metallopeptidase domain 17 (ADAM17), also called TACE (tumor necrosis factor-α-converting enzyme), is a 70-kDa enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases.

Chemical characteristics

ADAM17 is an 824-amino acid polypeptide.^[1]^[2]

Function

ADAM17 is understood to be involved in the processing of tumor necrosis factor alpha (TNF-α) at the surface of the cell, and from within the intracellular membranes of the trans-Golgi network. This process, which is also known as 'shedding', involves the cleavage and release of a soluble ectodomain from membrane-bound pro-proteins (such as pro-TNF-α), and is of known physiological importance. ADAM17 was the first 'sheddase' to be identified, and is also understood to play a role in the release of a diverse variety of membrane-anchored cytokines, cell adhesion molecules, receptors, ligands, and enzymes.

Cloning of the TNF-α gene revealed it to encode a 26 kDa type II transmembrane pro-polypeptide that becomes inserted into the cell membrane during its maturation. At the cell surface, pro-TNF-α is biologically active, and is able to induce immune responses via juxtacrine intercellular signaling. However, pro-TNF-α can undergo a proteolytic cleavage at its Ala76-Val77 amide bond, which releases a soluble 17kDa extracellular domain (ectodomain) from the pro-TNF-α molecule. This soluble ectodomain is the cytokine commonly known as TNF-α, which is of pivotal importance in paracrine signaling. This proteolytic liberation of soluble TNF-α is catalyzed by ADAM17.

ADAM17 also has a role in the shedding of L-selectin, a cellular adhesion molecule.^[3]

Recent in vitro experiments have provided evidence that suggests that ADAM17 may play a prominent role in the Notch signaling pathway, during the proteolytic release of the Notch intracellular domain (from the Notch1 receptor) that occurs following ligand binding. ADAM17 also regulates the MAP kinase signaling pathway by regulating shedding of the EGFR ligand amphiregulin in the mammary gland.^[4]

Interactions

ADAM17 has been shown to interact with:

DLG1^[5]
MAD2L1,^[6]^[7] and
MAPK1.^[8]

Cellular localization

The localization of ADAM17 is speculated to be an important determinant of shedding activity. TNF-α processing has classically been understood to occur in the trans-Golgi network, and be closely connected to transport of soluble TNF-α to the cell surface. However, research that suggests that the majority of mature, endogenous ADAM17 may be localized to a perinuclear compartment, with only a small amount of TACE being present on the cell surface. The localization of mature ADAM17 to a perinuclear compartment, therefore, raises the possibility that ADAM17-mediated ectodomain shedding may also occur in the intracellular environment, in contrast with the conventional model.

Functional ADAM17 has been documented to be ubiquitously expressed in the human colon, with increased activity in the colonic mucosa of patients with ulcerative colitis, a main form of inflammatory bowel disease. Other experiments have also suggested that expression of ADAM17 may be inhibited by ethanol.^[9]

Model organisms

*Adam17* knockout mouse phenotype
Characteristic	Phenotype
Homozygote viability	Abnormal
Recessive lethal study	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal^[10]
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Plasma immunoglobulins	Normal
Haematology	Normal
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Tail epidermis wholemount	Normal
Skin Histopathology	Normal
Brain histopathology	Normal
Eye Histopathology	Normal
Micro-CT & Quantitative Faxitron	Abnormal
Salmonella infection	Normal^[11]
Citrobacter infection	Normal^[12]
All tests and analysis from^[13]^[14]

Model organisms have been used in the study of ADAM17 function. A conditional knockout mouse line, called Adam17^{tm1a(EUCOMM)Wtsi}^[15]^[16] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.^[17]^[18]^[19]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.^[13]^[20] Twenty eight tests were carried out on mutant mice and two significant abnormalities were observed.^[13] Few homozygous mutant embryos were identified during gestation. The remaining tests were carried out on heterozygous mutant adult mice; an increased bone mineral content was observed in these animals using Micro-CT.^[13]

References

^ Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP (Feb 1997). "A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells". Nature 385 (6618): 729–33. doi:10.1038/385729a0. PMID 9034190.
^ Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, Chen WJ, Clay WC, Didsbury JR, Hassler D, Hoffman CR, Kost TA, Lambert MH, Leesnitzer MA, McCauley P, McGeehan G, Mitchell J, Moyer M, Pahel G, Rocque W, Overton LK, Schoenen F, Seaton T, Su JL, Becherer JD (Feb 1997). "Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha". Nature 385 (6618): 733–6. doi:10.1038/385733a0. PMID 9034191.
^ Li Y, Brazzell J, Herrera A, Walcheck B (Oct 2006). "ADAM17 deficiency by mature neutrophils has differential effects on L-selectin shedding". Blood 108 (7): 2275–9. doi:10.1182/blood-2006-02-005827. PMC: 1895557. PMID 16735599.
^ Sternlicht MD, Sunnarborg SW, Kouros-Mehr H, Yu Y, Lee DC, Werb Z (Sep 2005). "Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin". Development 132 (17): 3923–33. doi:10.1242/dev.01966. PMC: 2771180. PMID 16079154.
^ Peiretti F, Deprez-Beauclair P, Bonardo B, Aubert H, Juhan-Vague I, Nalbone G (May 2003). "Identification of SAP97 as an intracellular binding partner of TACE". Journal of Cell Science 116 (Pt 10): 1949–57. doi:10.1242/jcs.00415. PMID 12668732.
^ Nelson KK, Schlöndorff J, Blobel CP (Nov 1999). "Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2beta". The Biochemical Journal 343 (3): 673–80. doi:10.1042/0264-6021:3430673. PMC: 1220601. PMID 10527948.
^ Poghosyan Z, Robbins SM, Houslay MD, Webster A, Murphy G, Edwards DR (Feb 2002). "Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases". The Journal of Biological Chemistry 277 (7): 4999–5007. doi:10.1074/jbc.M107430200. PMID 11741929.
^ Díaz-Rodríguez E, Montero JC, Esparís-Ogando A, Yuste L, Pandiella A (Jun 2002). "Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding". Molecular Biology of the Cell 13 (6): 2031–44. doi:10.1091/mbc.01-11-0561. PMC: 117622. PMID 12058067.
^ Taïeb J, Delarche C, Ethuin F, Selloum S, Poynard T, Gougerot-Pocidalo MA, Chollet-Martin S (Dec 2002). "Ethanol-induced inhibition of cytokine release and protein degranulation in human neutrophils". Journal of Leukocyte Biology 72 (6): 1142–7. PMID 12488495.
^ "Dysmorphology data for Adam17". Wellcome Trust Sanger Institute.
^ "Salmonella infection data for Adam17". Wellcome Trust Sanger Institute.
^ "Citrobacter infection data for Adam17". Wellcome Trust Sanger Institute.
^ ^a ^b ^c ^d Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88: 0. doi:10.1111/j.1755-3768.2010.4142.x.
^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
^ "International Knockout Mouse Consortium".
^ "Mouse Genome Informatics".
^ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC: 3572410. PMID 21677750.
^ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
^ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC: 3218837. PMID 21722353.

External links

CD156b Antigen at the US National Library of Medicine Medical Subject Headings (MeSH)

Molecular and Cellular Biology portal

English Journal

Co-ordinated regulation of plasmacytoid dendritic cell surface receptors upon stimulation with herpes simplex virus type 1.

Schuster P, Donhauser N, Pritschet K, Ries M, Haupt S, Kittan NA, Korn K, Schmidt B.SourceInstitute of Clinical and Molecular Virology, German National Reference Centre for Retroviruses, University of Erlangen-Nürnberg, Erlangen, Germany.
Immunology.Immunology.2010 Feb;129(2):234-47. doi: 10.1111/j.1365-2567.2009.03176.x. Epub 2009 Sep 9.
Human plasmacytoid dendritic cells (PDC) are crucial for innate and adaptive immune responses against viral infections, mainly through production of type I interferons. Evidence is accumulating that PDC surface receptors play an important role in this process. To investigate the PDC phenotype in mor
PMID 19824924

Reactivity of new adhesion molecules on lymphocytes from patients with chronic graft versus host disease.

Regéczy N, Kormos L, Szigetvári CM, Torbágyi E, Hajdu M, Gopcsa L, Bányai A, Pálóczi K.SourceNational Medical Centre, Institute of Haematology and Immunology, Research Group of Hungarian Academy of Sciences, Budapest, Hungary.
Acta microbiologica et immunologica Hungarica.Acta Microbiol Immunol Hung.2003;50(1):55-65.
Reaction patterns of the 7th Human Leukocyte Differentiation Antigen Workshop blind panel adhesion molecules were studied on CD3/CD4, CD3/CD8, CD3/TCR gamma delta double positive T cells from peripheral blood of patients with chronic graft versus host disease (n = 8) and healthy controls (n = 4). Re
PMID 12793201

Related Pictures

cd156b polyclonal antibody unconjugated bs factor alpha converting enzyme anti cd156b AP ADAM17 Antibody ADAM 17, ADAM17, CD156b ada17 adam 17 cd156b antigen csvp tace sds 100ug ADAM17 Antibody 1 mg/ml from Thermo （Thr735）抗体|磷酸化CD156b抗体 CD156b / ADAM17 antibody | acris CD156B Churchill VI (75mm) - Skytrex (2013

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関連記事	「CD15」「CD156」

「CD15」

ADAM metallopeptidase domain 17
	PDB rendering based on 1bkc.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1BKC, 1ZXC, 2A8H, 2DDF, 2FV5, 2FV9, 2I47, 2M2F, 2OI0, 3B92, 3CKI, 3E8R, 3EDZ, 3EWJ, 3G42, 3KMC, 3KME, 3L0T, 3L0V, 3LE9, 3LEA, 3LGP, 3O64
Identifiers
Symbols	ADAM17 ; ADAM18; CD156B; CSVP; NISBD; NISBD1; TACE
External IDs	OMIM: 603639 MGI: 1096335 HomoloGene: 2395 ChEMBL: 3706 GeneCards: ADAM17 Gene
EC number	3.4.24.86
Gene ontology
Molecular function	• metalloendopeptidase activity; • Notch binding; • interleukin-6 receptor binding; • integrin binding; • protein binding; • metallopeptidase activity; • zinc ion binding; • SH3 domain binding; • PDZ domain binding;
Cellular component	• cytoplasm; • plasma membrane; • integral component of plasma membrane; • cell-cell junction; • focal adhesion; • cell surface; • actin cytoskeleton; • membrane; • apical plasma membrane; • ruffle membrane; • membrane raft;
Biological process	• response to hypoxia; • positive regulation of protein phosphorylation; • neutrophil mediated immunity; • germinal center formation; • positive regulation of leukocyte chemotaxis; • proteolysis; • membrane protein ectodomain proteolysis; • cell adhesion; • cell surface receptor signaling pathway; • epidermal growth factor receptor signaling pathway; • Notch signaling pathway; • Notch receptor processing; • positive regulation of cell proliferation; • positive regulation of T cell chemotaxis; • extracellular matrix disassembly; • 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; • positive regulation of chemokine production; • regulation of mast cell apoptotic process; • T cell differentiation in thymus; • tumor necrosis factor-mediated signaling pathway; • 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; • positive regulation of epidermal growth factor-activated receptor activity; • neurotrophin TRK receptor signaling pathway; • spleen development; • cell motility; • defense response to Gram-positive bacterium; • 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;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

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発現細胞

好中球、好酸球、単球

機能

糖脂質や多くの細胞表面糖タンパクに発現している末端の3糖

別名

Lewis^x, Le^x

「CD156」

　　[★]

同: a Disintegrin and metalloprotease-8, MS2 human

[pmid9034190-1] Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP (Feb 1997). "A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells". Nature 385 (6618): 729–33. doi:10.1038/385729a0. PMID 9034190.

[pmid9034191-2] Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, Chen WJ, Clay WC, Didsbury JR, Hassler D, Hoffman CR, Kost TA, Lambert MH, Leesnitzer MA, McCauley P, McGeehan G, Mitchell J, Moyer M, Pahel G, Rocque W, Overton LK, Schoenen F, Seaton T, Su JL, Becherer JD (Feb 1997). "Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha". Nature 385 (6618): 733–6. doi:10.1038/385733a0. PMID 9034191.

[pmid16735599-3] Li Y, Brazzell J, Herrera A, Walcheck B (Oct 2006). "ADAM17 deficiency by mature neutrophils has differential effects on L-selectin shedding". Blood 108 (7): 2275–9. doi:10.1182/blood-2006-02-005827. PMC: 1895557. PMID 16735599.

[pmid16079154-4] Sternlicht MD, Sunnarborg SW, Kouros-Mehr H, Yu Y, Lee DC, Werb Z (Sep 2005). "Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin". Development 132 (17): 3923–33. doi:10.1242/dev.01966. PMC: 2771180. PMID 16079154.

[pmid12668732-5] Peiretti F, Deprez-Beauclair P, Bonardo B, Aubert H, Juhan-Vague I, Nalbone G (May 2003). "Identification of SAP97 as an intracellular binding partner of TACE". Journal of Cell Science 116 (Pt 10): 1949–57. doi:10.1242/jcs.00415. PMID 12668732.

[pmid10527948-6] Nelson KK, Schlöndorff J, Blobel CP (Nov 1999). "Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2beta". The Biochemical Journal 343 (3): 673–80. doi:10.1042/0264-6021:3430673. PMC: 1220601. PMID 10527948.

[pmid11741929-7] Poghosyan Z, Robbins SM, Houslay MD, Webster A, Murphy G, Edwards DR (Feb 2002). "Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases". The Journal of Biological Chemistry 277 (7): 4999–5007. doi:10.1074/jbc.M107430200. PMID 11741929.

[pmid12058067-8] Díaz-Rodríguez E, Montero JC, Esparís-Ogando A, Yuste L, Pandiella A (Jun 2002). "Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding". Molecular Biology of the Cell 13 (6): 2031–44. doi:10.1091/mbc.01-11-0561. PMC: 117622. PMID 12058067.

[pmid12488495-9] Taïeb J, Delarche C, Ethuin F, Selloum S, Poynard T, Gougerot-Pocidalo MA, Chollet-Martin S (Dec 2002). "Ethanol-induced inhibition of cytokine release and protein degranulation in human neutrophils". Journal of Leukocyte Biology 72 (6): 1142–7. PMID 12488495.

[Dysmorphology-10] "Dysmorphology data for Adam17". Wellcome Trust Sanger Institute.

[.27.27Salmonella.27.27_infection-11] "Salmonella infection data for Adam17". Wellcome Trust Sanger Institute.

[.27.27Citrobacter.27.27_infection-12] "Citrobacter infection data for Adam17". Wellcome Trust Sanger Institute.

[mgp_reference-13] Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88: 0. doi:10.1111/j.1755-3768.2010.4142.x.

[14] Mouse Resources Portal, Wellcome Trust Sanger Institute.

[allele_ref-15] "International Knockout Mouse Consortium".

[mgi_allele_ref-16] "Mouse Genome Informatics".

[pmid21677750-17] Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC: 3572410. PMID 21677750.

[mouse_library-18] Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.

[mouse_for_all_reasons-19] Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.

[pmid21722353-20] van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC: 3218837. PMID 21722353.

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案内

CD156b