The shedding activity of ADAM17 is sequestered in lipid rafts

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis

“…Microparticles contain high amounts of lipid rafts, and these cholesterol-rich membrane microdomains are known to harbor a huge variety of signaling molecules, receptors, and proteases, including the mature form of ADAM17. [39][40][41] Lee and coworkers demonstrated that ADAM17, on its activation by paxillin, the HIV Nef protein, and the polycomb protein Eed, is recruited to extracellular particles. After fusion of these microparticles with blood mononuclear cells, ADAM17-induced TNF-a release from the target cells.…”

Overexpression of sigma-1 receptor inhibits ADAM10 and ADAM17 mediated shedding in vitro

“…Cholesterol modification and sigma-1 receptor agonist DHEAS could reduce ionomycin-induced ADAM10-dependent BTC shedding but not ADAM17-dependent HB-EGF shedding Cholesterol is a ligand for sigma-1 receptor (Palmer et al, 2007) and its depletion can affect lipid raft formation and both ADAM10-dependent shedding (Murai et al, 2011) and ADAM17-dependent shedding (von Tresckow et al, 2004;Zimina et al, 2005;Tellier et al, 2006Tellier et al, , 2008. Therefore, we tested the effect of cholesterol in our system.…”

“…Those two transmembrane proteases are also involved in the shedding process of many other substrates, such as ligands of the epidermal growth factor receptor (EGFR), Notch1, L1 cell adhesion molecule (L1CAM), which are involved in pathological processes and human diseases such as cancer and stroke (Pruessmeyer and Ludwig, 2009). It is now known that lipid rafts can affect both ADAM17 and ADAM10 function as cholesterol depletion can trigger both ADAM10-mediated CD44 shedding (Murai et al, 2011) and ADAM17-mediated CD30 shedding (von Tresckow et al, 2004), collagen XVII shedding (Zimina et al, 2005), and TNF shedding (Tellier et al, 2006(Tellier et al, , 2008. It has been reported that ADAM10 is located in the nonraft region of the membrane of neuroblastoma SH-SY5Y cells when functioning as α-secretase of APP (Harris et al, 2009) and it cannot cleave APP in a cholesterolrich environment (Kojro et al, 2010).…”

Identification of Novel Interaction between ADAM17 (a Disintegrin and Metalloprotease 17) and Thioredoxin-1

“…thiol isomerases are involved in the regulation of ADAM proteolytic activity (7)(8)(9)(10)(47)(48)(49)(50). Therefore, we investigated whether ADAM17 activity could be modulated by Trx-1 using a standard approach in a cell model of HB-EGF shedding coupled with an AP reporter assay (7,25).…”

“…The presence of ROS scavengers or the inhibition of cell surface oxidoreductases has previously been shown to prevent HB-EGF cleavage and LPS-induced ADAM17 activity (7,10). Furthermore, we may also consider that ADAM17 cytoplasmic domain can solely function as an anchor domain to recruit Trx-1, which can regulate the redox state of cysteine residues in target proteins near or in the membrane, for instance in lipid rafts (41,50). In summary, the present study has demonstrated that Trx-1 is a novel interaction partner of the ADAM17 cytoplasmic domain and suggests that Trx-1 is a candidate that could be involved in the regulation of ADAM17 activity.…”