ADAM17

ADAM17
Gene ontology
Molecular function	PDZ domain binding interleukin-6 receptor binding SH3 domain binding metal ion binding Notch binding integrin binding peptidase activity protein binding metalloendopeptidase activity hydrolase activity metallopeptidase activity endopeptidase activity
Cellular component	cytoplasm integral component of membrane membrane cell-cell junction focal adhesion plasma membrane integral component of plasma membrane ruffle membrane cell surface apical plasma membrane actin cytoskeleton membrane raft cytosol
Biological process	Notch signaling pathway positive regulation of transforming growth factor beta receptor signaling pathway positive regulation of epidermal growth factor-activated receptor activity positive regulation of protein phosphorylation response to hypoxia T cell differentiation in thymus cell motility positive regulation of cell migration wound healing, spreading of epidermal cells germinal center formation tumor necrosis factor-mediated signaling pathway negative regulation of transforming growth factor beta receptor signaling pathway spleen development proteolysis positive regulation of leukocyte chemotaxis positive regulation of cell growth response to lipopolysaccharide cell adhesion cell adhesion mediated by integrin membrane protein ectodomain proteolysis membrane protein intracellular domain proteolysis regulation of mast cell apoptotic process positive regulation of T cell chemotaxis positive regulation of cell population proliferation Notch receptor processing positive regulation of chemokine production neutrophil mediated immunity B cell differentiation defense response to Gram-positive bacterium epidermal growth factor receptor signaling pathway receptor transactivation positive regulation of blood vessel endothelial cell migration positive regulation of cyclin-dependent protein serine/threonine kinase activity cellular response to high density lipoprotein particle stimulus negative regulation of cold-induced thermogenesis positive regulation of G1/S transition of mitotic cell cycle positive regulation of tumor necrosis factor-mediated signaling pathway positive regulation of vascular endothelial cell proliferation
Sources:Amigo / QuickGO

Ensembl				ENSG00000151694	ENSMUSG00000052593
UniProt	P78536	Q9Z0F8
RefSeq (mRNA)	NM_003183 NM_001382777 NM_001382778 NM_021832	NM_001277266 NM_009615 NM_001291871
RefSeq (protein)	NP_003174	NP_001264195 NP_001278800 NP_033745
Location (UCSC)	Chr 2: 9.49 – 9.56 Mb	Chr 12: 21.37 – 21.42 Mb
PubMed search	[3]	[4]

Wikidata

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A disintegrin and metalloprotease 17 (ADAM17), also called TACE (tumor necrosis factor-α-converting enzyme), is a 70-kDa

.

Chemical characteristics

ADAM17 is an 824-

Function

ADAM17 is understood to be involved in the processing of tumor necrosis factor alpha (

ligands

, and enzymes.

Cloning of the TNF-α

) 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.[7]

ADAM17 may play a prominent role in the

Interactions

ADAM17 has been shown to

interact

with:

• DLG1^[10]
• MAD2L1,^[11][12] and
• MAPK1.^[13]

Activation

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. Shedding is also associated with clustering of ADAM17 with its substrate, membrane bound TNF, in lipid rafts.

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

Clinical significance

Adam17 may facilitate entry of the

Adam17 sheddase activity may contribute to COVID-19 inflammation by cleavage of TNF-α and Interleukin-6 receptor.^[16]

References

Further reading

• Black RA (January 2002). "Tumor necrosis factor-alpha converting enzyme". The International Journal of Biochemistry & Cell Biology. 34 (1): 1–5.
  PMID 11733179
  .
• Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806.
  PMID 8889548
  .
• 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.
  S2CID 4251053
  .
• 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.
  S2CID 4335616
  .
• 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.
  PMID 9520379
  .
• 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.
  S2CID 54023449
  .
• Schroeter EH, Kisslinger JA, Kopan R (May 1998). "Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain". Nature. 393 (6683): 382–6.
  S2CID 4431882
  .
• 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.
  PMID 9806848
  .
• 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.
  PMID 10224132
  .
• 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.
  PMID 10433800
  .
• 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.
  PMID 10527948
  .
• 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.
  S2CID 36643322
  .
• 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.
  PMID 10882063
  .
• 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.
  PMID 11988096
  .
• 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.
  S2CID 1433047
  .
• 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.
  PMID 12058067
  .
• 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.
  PMID 12135369
  .
• 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.
  PMID 12147693
  .
• 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.
  PMID 12207026
  .

External links

• CD156b+Antigen at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human ADAM17 genome location and ADAM17 gene details page in the UCSC Genome Browser.
• Human ADAM18 genome location and ADAM18 gene details page in the UCSC Genome Browser.