ADAM17

ADAM17
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
Aliases	ADAM17, ADAM18, CD156B, CSVP, NISBD, NISBD1, TACE, ADAM metallopeptidase domain 17
External IDs	OMIM: 603639 MGI: 1096335 HomoloGene: 2395 GeneCards: ADAM17
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p25.1 Start 9,488,486 bp[1] End 9,556,732 bp[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)[2] Band 12 A1.3|12 8.3 cM Start 21,373,510 bp[2] End 21,423,633 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in oocyte Achilles tendon pericardium monocyte sural nerve lower lobe of lung right lung gallbladder upper lobe of lung upper lobe of left lung Top expressed in saccule otic placode secondary oocyte cumulus cell left lung lobe ciliary body conjunctival fornix spleen body of femur ascending aorta More reference expression data BioGPS More reference expression data
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
Orthologs Species Human Mouse Entrez 6868 11491 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 enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases, activated by substrate presentation.

Chemical characteristics

ADAM17 is an 824-amino acid polypeptide.^[5][6]

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.^[7]

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.^[8] ADAM17 also has a role in the shedding of L-selectin, a cellular adhesion molecule.^[9]

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. ^[14] The overall process is called substrate presentation and regulated by cholesterol. Research also 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.^[15]

Clinical significance

Adam17 may facilitate entry of the SARS‑CoV‑2 virus, possibly by enabling fusion of virus particles with the cytoplasmic membrane.^[16] Adam17 has similar ACE2 cleavage activity as TMPRSS2, but by forming soluble ACE2, Adam17 may actually have the protective effect of blocking circulating SARS‑CoV‑2 virus particles.^[16]

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

References

Further reading

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.