ADAM17


ADAM17
ADAM metallopeptidase domain 17

PDB rendering based on 1bkc.
Identifiers
Symbols ADAM17; ADAM18; CD156B; CSVP; MGC71942; TACE
External IDs OMIM603639 MGI1096335 HomoloGene2395 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 Q3UEC0
RefSeq (mRNA) NM_003183.4 NM_009615.5
RefSeq (protein) NP_003174.3 NP_033745.4
Location (UCSC) Chr 2:
9.63 – 9.7 Mb
Chr 12:
21.33 – 21.38 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.

Contents

Chemical characteristics

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

Enzymes in this family are transmembrane glycoproteins that are characterized by their conserved, multi-domain structure.

Functions

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.

Interactions between ADAM17 and pro-TNF-α

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.

Interactions between ADAM17 and L-selectin

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

Cellular localization of ADAM17

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, exists. The localization of mature ADAM17 to a perinulcear compartment, therefore, raises the possibility that ADAM17-mediated ectodomain shedding may also occur in the intracellular environment, in contrast with the conventional model.

ADAM17 as a target for future medicines?

Since TNF-α is a potent and pivotal mediator in the inflammatory process, considerable investment has been made in the research into – and development of – anti-TNF-α agents, for the purpose of reducing the severity of inflammatory responses in disease states (e.g., the medicine etanercept for treatment of rheumatoid arthritis). The inhibition of ADAM17 by a pharmacological agent may represent another means by which the effects of TNF-α can be modulated, although this is yet to be demonstrated clinically in humans.

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. These data will no doubt contribute to growing interest in the inhibition of ADAM17 as a potential therapeutic strategy.

Other points of interest

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. Other experiments have also suggested that expression of ADAM17 may be inhibited by ethanol.[4]

Interactions

ADAM17 has been shown to interact with MAPK1,[5] DLG1[6] and MAD2L1.[7][8]

References

  1. ^ Black R, Rauch C, Kozlosky C, Peschon J, Slack J, Wolfson M, Castner B, Stocking K, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley K, Gerhart M, Davis R, Fitzner J, Johnson R, Paxton R, March C, Cerretti D (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 et al. (1997). "Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha". Nature 385 (6618): 733–36. 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1895557. 
  4. ^ 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. 
  5. ^ Díaz-Rodríguez, Elena; Montero Juan Carlos, Esparís-Ogando Azucena, Yuste Laura, Pandiella Atanasio (Jun. 2002). "Extracellular Signal-regulated Kinase Phosphorylates Tumor Necrosis Factor α-converting Enzyme at Threonine 735: A Potential Role in Regulated Shedding". Mol. Biol. Cell (United States) 13 (6): 2031–44. doi:10.1091/mbc.01-11-0561. ISSN 1059-1524. PMC 117622. PMID 12058067. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=117622. 
  6. ^ Peiretti, Franck; Deprez-Beauclair Paule, Bonardo Bernadette, Aubert Helene, Juhan-Vague Irene, Nalbone Gilles (May. 2003). "Identification of SAP97 as an intracellular binding partner of TACE". J. Cell. Sci. (England) 116 (Pt 10): 1949–57. doi:10.1242/jcs.00415. ISSN 0021-9533. PMID 12668732. 
  7. ^ Nelson, K K; Schlöndorff J, Blobel C P (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". Biochem. J. (ENGLAND) 343 Pt 3 (Pt 3): 673–80. ISSN 0264-6021. PMC 1220601. PMID 10527948. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1220601. 
  8. ^ Poghosyan, Zaruhi; Robbins Stephen M, Houslay Miles D, Webster Ailsa, Murphy Gillian, Edwards Dylan R (Feb. 2002). "Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases". J. Biol. Chem. (United States) 277 (7): 4999–5007. doi:10.1074/jbc.M107430200. ISSN 0021-9258. PMID 11741929. 

Further reading

External links


Wikimedia Foundation. 2010.

Look at other dictionaries:

  • ADAM17 — Обозначения Символы ADAM17; TACE Entrez Gene …   Википедия

  • Alpha secretase — Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer s disease associated peptide… …   Wikipedia

  • GP5 — Glycoprotein V (platelet) (GP5) also known as CD42d (Cluster of Differentiation 42d), is a human gene.cite web | title = Entrez Gene: GP5 glycoprotein V (platelet)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene Cmd=ShowDetailView… …   Wikipedia

  • L-Selectina — Saltar a navegación, búsqueda La L selectina (conocida también como CD62L o SELL) es una molécula de adhesión celular (MAC) que pertenece a la familia de las selectinas. La L selectina es una glicoproteína localizada en la superficie celular de… …   Wikipedia Español

  • ADAM-протеазы — Схема активации и работы металлопротеазы семейства ADAM. ADAM протеазы (сокращение от англ. A Disintegrin And Metallopr …   Википедия

  • ADAM10 — Обозначения Символы ADAM10; kuz, MADM, HsT18717, CD156c Entrez Gene …   Википедия

  • L-selectina — Células endoteliales, sobre las cuales migran los glóbulos blancos sanguíneos por medio de interacciones por la L selectina. La L selectina (conocida también como CD62L o SELL) es una molécula de adhesión celular (MAC) que pertenece a la familia… …   Wikipedia Español

  • Tumor necrosis factor-alpha — Tumor necrosis factor (TNF, cachexin or cachectin and formally known as tumor necrosis factor alpha ) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that all stimulate the acute phase reaction. TNF causes… …   Wikipedia

  • Murder of Adam Walsh — For other people named Adam Walsh, see Adam Walsh (disambiguation). Adam Walsh Born November 14, 1974(1974 11 14) Hollywood, Florida, United States Died July 27, 1981 …   Wikipedia

  • Matrix metalloproteinase — Cell surface associated MT1 MMP (MMP14), Green fluorescent protein (GFP) fused to the C term produces a signal on the surface of the cell[1] Matrix metalloproteinases (MMPs) are zinc dependent endopeptidases; other family members are adamalysins …   Wikipedia


Share the article and excerpts

Direct link
Do a right-click on the link above
and select “Copy Link”

We are using cookies for the best presentation of our site. Continuing to use this site, you agree with this.