ADAM17

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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.

Recently, ADAM17 was discovered as a crucial mediator of resistance to radiotherapy. Radiotherapy can induce a dose-dependent increase of furin-mediated cleavage of the ADAM17 proform to active ADAM17, which results in enhanced ADAM17 activity in vitro and in vivo. It was also shown that radiotherapy activates ADAM17 in non-small cell lung cancer, which results in shedding of multiple survival factors, growth factor pathway activation, and radiotherapy-induced treatment resistance. [3]

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] ADAM17 also has a role in the shedding of L-selectin, a cellular adhesion molecule.[5]

Interactions

ADAM17 has been shown to interact with:

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.[10]

Model organisms

Model organisms have been used in the study of ADAM17 function. A conditional knockout mouse line, called Adam17tm1a(EUCOMM)Wtsi[16][17] 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.[18][19][20]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[14][21] Twenty eight tests were carried out on mutant mice and two significant abnormalities were observed.[14] 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.[14]

References

  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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  3. Sharma A, Bender S, Zimmermann M, Riesterer O, Broggini-Tenzer A, Pruschy MN (September 2016). "Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non-Small Cell Lung Cancer". Clinical Cancer Research. 22 (17): 4428–39. doi:10.1158/1078-0432.CCR-15-2449. PMID 27076628.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  4. Sternlicht MD, Sunnarborg SW, Kouros-Mehr H, Yu Y, Lee DC, Werb Z (September 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  5. Li Y, Brazzell J, Herrera A, Walcheck B (October 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  6. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  7. 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". The Biochemical Journal. 343 Pt 3 (3): 673–80. doi:10.1042/0264-6021:3430673. PMC 1220601. PMID 10527948.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  8. 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". The Journal of Biological Chemistry. 277 (7): 4999–5007. doi:10.1074/jbc.M107430200. PMID 11741929.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  9. 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". Molecular Biology of the Cell. 13 (6): 2031–44. doi:10.1091/mbc.01-11-0561. PMC 117622. PMID 12058067.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  10. 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". Journal of Leukocyte Biology. 72 (6): 1142–7. PMID 12488495.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  11. "Dysmorphology data for Adam17". Wellcome Trust Sanger Institute.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  12. "Salmonella infection data for Adam17". Wellcome Trust Sanger Institute.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  13. "Citrobacter infection data for Adam17". Wellcome Trust Sanger Institute.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  14. 14.0 14.1 14.2 14.3 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  15. Mouse Resources Portal, Wellcome Trust Sanger Institute.
  16. "International Knockout Mouse Consortium".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  17. "Mouse Genome Informatics".<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  18. 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 (June 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  19. Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  20. Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  21. 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>

Further reading

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  • Black RA (January 2002). "Tumor necrosis factor-alpha converting enzyme". The International Journal of Biochemistry & Cell Biology. 34 (1): 1–5. doi:10.1016/S1357-2725(01)00097-8. PMID 11733179.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Maskos K, Fernandez-Catalan C, Huber R, Bourenkov GP, Bartunik H, Ellestad GA, Reddy P, Wolfson MF, Rauch CT, Castner BJ, Davis R, Clarke HR, Petersen M, Fitzner JN, Cerretti DP, March CJ, Paxton RJ, Black RA, Bode W (March 1998). "Crystal structure of the catalytic domain of human tumor necrosis factor-alpha-converting enzyme". Proceedings of the National Academy of Sciences of the United States of America. 95 (7): 3408–12. doi:10.1073/pnas.95.7.3408. PMC 19849. PMID 9520379.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Patel IR, Attur MG, Patel RN, Stuchin SA, Abagyan RA, Abramson SB, Amin AR (May 1998). "TNF-alpha convertase enzyme from human arthritis-affected cartilage: isolation of cDNA by differential display, expression of the active enzyme, and regulation of TNF-alpha". Journal of Immunology. 160 (9): 4570–9. PMID 9574564.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Schroeter EH, Kisslinger JA, Kopan R (May 1998). "Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain". Nature. 393 (6683): 382–6. doi:10.1038/30756. PMID 9620803.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Hirohata S, Seldin MF, Apte SS (November 1998). "Chromosomal assignment of two ADAM genes, TACE (ADAM17) and MLTNB (ADAM19), to human chromosomes 2 and 5, respectively, and of Mltnb to mouse chromosome 11". Genomics. 54 (1): 178–9. doi:10.1006/geno.1998.5544. PMID 9806848.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Lum L, Wong BR, Josien R, Becherer JD, Erdjument-Bromage H, Schlöndorff J, Tempst P, Choi Y, Blobel CP (May 1999). "Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival". The Journal of Biological Chemistry. 274 (19): 13613–8. doi:10.1074/jbc.274.19.13613. PMID 10224132.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Cerretti DP, Poindexter K, Castner BJ, Means G, Copeland NG, Gilbert DJ, Jenkins NA, Black RA, Nelson N (August 1999). "Characterization of the cDNA and gene for mouse tumour necrosis factor alpha converting enzyme (TACE/ADAM17) and its location to mouse chromosome 12 and human chromosome 2p25". Cytokine. 11 (8): 541–51. doi:10.1006/cyto.1998.0466. PMID 10433800.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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". The Biochemical Journal. 343 Pt 3 (Pt 3): 673–80. doi:10.1042/0264-6021:3430673. PMC 1220601. PMID 10527948.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Kärkkäinen I, Rybnikova E, Pelto-Huikko M, Huovila AP (June 2000). "Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS". Molecular and Cellular Neurosciences. 15 (6): 547–60. doi:10.1006/mcne.2000.0848. PMID 10860581.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israël A (February 2000). "A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE". Molecular Cell. 5 (2): 207–16. doi:10.1016/S1097-2765(00)80417-7. PMID 10882063.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Lee MH, Verma V, Maskos K, Nath D, Knäuper V, Dodds P, Amour A, Murphy G (May 2002). "Engineering N-terminal domain of tissue inhibitor of metalloproteinase (TIMP)-3 to be a better inhibitor against tumour necrosis factor-alpha-converting enzyme". The Biochemical Journal. 364 (Pt 1): 227–34. PMC 1222565. PMID 11988096.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Lee MH, Verma V, Maskos K, Becherer JD, Knäuper V, Dodds P, Amour A, Murphy G (June 2002). "The C-terminal domains of TACE weaken the inhibitory action of N-TIMP-3". FEBS Letters. 520 (1–3): 102–6. doi:10.1016/S0014-5793(02)02776-X. PMID 12044879.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • 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". Molecular Biology of the Cell. 13 (6): 2031–44. doi:10.1091/mbc.01-11-0561. PMC 117622. PMID 12058067.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Mohan MJ, Seaton T, Mitchell J, Howe A, Blackburn K, Burkhart W, Moyer M, Patel I, Waitt GM, Becherer JD, Moss ML, Milla ME (July 2002). "The tumor necrosis factor-alpha converting enzyme (TACE): a unique metalloproteinase with highly defined substrate selectivity". Biochemistry. 41 (30): 9462–9. doi:10.1021/bi0260132. PMID 12135369.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Gómez-Gaviro MV, González-Alvaro I, Domínguez-Jiménez C, Peschon J, Black RA, Sánchez-Madrid F, Díaz-González F (October 2002). "Structure-function relationship and role of tumor necrosis factor-alpha-converting enzyme in the down-regulation of L-selectin by non-steroidal anti-inflammatory drugs". The Journal of Biological Chemistry. 277 (41): 38212–21. doi:10.1074/jbc.M205142200. PMID 12147693.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Zheng Y, Schlondorff J, Blobel CP (November 2002). "Evidence for regulation of the tumor necrosis factor alpha-convertase (TACE) by protein-tyrosine phosphatase PTPH1". The Journal of Biological Chemistry. 277 (45): 42463–70. doi:10.1074/jbc.M207459200. PMID 12207026.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>

External links