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]
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]
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