ADAM17

ADAM metallopeptidase domain 17
PDB rendering based on 1bkc.
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
Symbols	ADAM17 ; ADAM18; CD156B; CSVP; NISBD; NISBD1; TACE
External IDs	OMIM: 603639 MGI: 1096335 HomoloGene: 2395 ChEMBL: 3706 GeneCards: ADAM17 Gene
EC number	3.4.24.86
Gene ontology Molecular function • metalloendopeptidase activity • Notch binding • interleukin-6 receptor binding • integrin binding • protein binding • metallopeptidase activity • zinc ion binding • SH3 domain binding • PDZ domain binding Cellular component • cytoplasm • plasma membrane • integral component of plasma membrane • cell-cell junction • focal adhesion • cell surface • actin cytoskeleton • membrane • apical plasma membrane • ruffle membrane • membrane raft Biological process • response to hypoxia • positive regulation of protein phosphorylation • neutrophil mediated immunity • germinal center formation • positive regulation of leukocyte chemotaxis • proteolysis • membrane protein ectodomain proteolysis • cell adhesion • cell surface receptor signaling pathway • epidermal growth factor receptor signaling pathway • Notch signaling pathway • Notch receptor processing • positive regulation of cell proliferation • positive regulation of T cell chemotaxis • extracellular matrix disassembly • B cell differentiation • extracellular matrix organization • positive regulation of cell growth • positive regulation of cell migration • positive regulation of transforming growth factor beta receptor signaling pathway • negative regulation of transforming growth factor beta receptor signaling pathway • collagen catabolic process • membrane protein intracellular domain proteolysis • positive regulation of cyclin-dependent protein serine/threonine kinase activity involved in G1/S transition of mitotic cell cycle • response to lipopolysaccharide • positive regulation of chemokine production • regulation of mast cell apoptotic process • T cell differentiation in thymus • tumor necrosis factor-mediated signaling pathway • cell adhesion mediated by integrin • wound healing, spreading of epidermal cells • epidermal growth factor-activated receptor transactivation by G-protein coupled receptor signaling pathway • response to drug • positive regulation of epidermal growth factor-activated receptor activity • neurotrophin TRK receptor signaling pathway • spleen development • cell motility • defense response to Gram-positive bacterium • PMA-inducible membrane protein ectodomain proteolysis • positive regulation of cellular component movement • response to high density lipoprotein particle • JAK-STAT cascade involved in growth hormone signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
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: 9.49 – 9.56 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

ADAM17 is an 824-amino acid polypeptide.

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.

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

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.

Interactions

ADAM17 has been shown to interact with:

• DLG1
• MAD2L1, and
• MAPK1.

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.

Model organisms

Adam17 knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Abnormal
Recessive lethal study	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Plasma immunoglobulins	Normal
Haematology	Normal
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Tail epidermis wholemount	Normal
Skin Histopathology	Normal
Brain histopathology	Normal
Eye Histopathology	Normal
Micro-CT & Quantitative Faxitron	Abnormal
Salmonella infection	Normal
Citrobacter infection	Normal
All tests and analysis from

Model organisms have been used in the study of ADAM17 function. A conditional knockout mouse line, called Adam17^{tm1a(EUCOMM)Wtsi} 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.

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

External links

• CD156b Antigen at the US National Library of Medicine Medical Subject Headings (MeSH)