ADAM17

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ADAM metallopeptidase domain 17
Protein ADAM17 PDB 1bkc.png
PDB rendering based on 1bkc.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ADAM17 ; ADAM18; CD156B; CSVP; NISBD; TACE
External IDs OMIM603639 MGI1096335 HomoloGene2395 ChEMBL: 3706 GeneCards: ADAM17 Gene
EC number 3.4.24.86
RNA expression pattern
PBB GE ADAM17 205746 s at tn.png
PBB GE ADAM17 205745 x at tn.png
PBB GE ADAM17 213532 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6868 11491
Ensembl ENSG00000151694 ENSMUSG00000052593
UniProt P78536 Q9Z0F8
RefSeq (mRNA) NM_003183 NM_001277266
RefSeq (protein) NP_003174 NP_001264195
Location (UCSC) Chr 2:
9.63 – 9.7 Mb
Chr 12:
21.32 – 21.37 Mb
PubMed search [1] [2]

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[edit]

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

Function[edit]

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[edit]

ADAM17 has been shown to interact with:

Cellular localization[edit]

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[edit]

Model organisms have been used in the study of ADAM17 function. A conditional knockout mouse line, called Adam17tm1a(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[edit]

  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 (February 1997). "A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells". Nature 385 (6618): 729–33. doi:10.1038/385729a0. PMID 9034190. 
  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 (February 1997). "Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha". Nature 385 (6618): 733–6. doi:10.1038/385733a0. PMID 9034191. 
  3. ^ Li Y, Brazzell J, Herrera A, Walcheck B (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. 
  4. ^ Sternlicht MD, Sunnarborg SW, Kouros-Mehr H, Yu Y, Lee DC, Werb Z (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. 
  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". J. Cell. Sci. 116 (Pt 10): 1949–57. doi:10.1242/jcs.00415. PMID 12668732. 
  6. ^ Nelson KK, Schlöndorff J, Blobel CP (November 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". Biochem. J. 343 Pt 3: 673–80. doi:10.1042/0264-6021:3430673. PMC 1220601. PMID 10527948. 
  7. ^ Poghosyan Z, Robbins SM, Houslay MD, Webster A, Murphy G, Edwards DR (February 2002). "Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases". J. Biol. Chem. 277 (7): 4999–5007. doi:10.1074/jbc.M107430200. PMID 11741929. 
  8. ^ Díaz-Rodríguez E, Montero JC, Esparís-Ogando A, Yuste L, Pandiella A (June 2002). "Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding". Mol. Biol. Cell 13 (6): 2031–44. doi:10.1091/mbc.01-11-0561. PMC 117622. PMID 12058067. 
  9. ^ Taïeb J, Delarche C, Ethuin F, Selloum S, Poynard T, Gougerot-Pocidalo MA, Chollet-Martin S (December 2002). "Ethanol-induced inhibition of cytokine release and protein degranulation in human neutrophils". J. Leukoc. Biol. 72 (6): 1142–7. PMID 12488495. 
  10. ^ "Dysmorphology data for Adam17". Wellcome Trust Sanger Institute. 
  11. ^ "Salmonella infection data for Adam17". Wellcome Trust Sanger Institute. 
  12. ^ "Citrobacter infection data for Adam17". Wellcome Trust Sanger Institute. 
  13. ^ 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. 
  14. ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  15. ^ "International Knockout Mouse Consortium". 
  16. ^ "Mouse Genome Informatics". 
  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 (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. 
  18. ^ Dolgin E (2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718. 
  19. ^ Collins FS, Rossant J, Wurst W (2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  20. ^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism.". Genome Biol 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353. 

Further reading[edit]

External links[edit]