ADAM17

ADAM metallopeptidase domain 17 (ADAM17), also called TACE (tumor necrosis factor-α-converting enzyme), is a 70-kDa is_associated_with::enzyme that belongs to the is_associated_with::ADAM protein family of is_associated_with::disintegrins and is_associated_with::metalloproteases.

Chemical characteristics
ADAM17 is an 824-is_associated_with::amino acid is_associated_with::polypeptide.

Function
ADAM17 is understood to be involved in the processing of tumor necrosis factor alpha (is_associated_with::TNF-α) at the surface of the cell, and from within the is_associated_with::intracellular membranes of the is_associated_with::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 'is_associated_with::sheddase' to be identified, and is also understood to play a role in the release of a diverse variety of membrane-anchored is_associated_with::cytokines, is_associated_with::cell adhesion molecules, receptors, is_associated_with::ligands, and enzymes.

Cloning of the TNF-α is_associated_with::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 is_associated_with::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 (is_associated_with::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 is_associated_with::L-selectin, a cellular adhesion molecule.

Recent is_associated_with::in vitro experiments have provided evidence that suggests that ADAM17 may play a prominent role in the is_associated_with::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:
 * is_associated_with::DLG1
 * is_associated_with::MAD2L1, and
 * is_associated_with::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, is_associated_with::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 is_associated_with::ulcerative colitis, a main form of is_associated_with::inflammatory bowel disease. Other experiments have also suggested that expression of ADAM17 may be inhibited by is_associated_with::ethanol.

Model organisms
is_associated_with::Model organisms have been used in the study of ADAM17 function. A conditional is_associated_with::knockout mouse line, called Adam17tm1a(EUCOMM)Wtsi was generated as part of the is_associated_with::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 is_associated_with::phenotypic screen to determine the effects of deletion. Twenty eight tests were carried out on is_associated_with::mutant mice and two significant abnormalities were observed. Few is_associated_with::homozygous is_associated_with::mutant embryos were identified during gestation. The remaining tests were carried out on is_associated_with::heterozygous mutant adult mice; an increased is_associated_with::bone mineral content was observed in these animals using is_associated_with::Micro-CT.