Tousseyn Thomas, Thathiah Amantha, Jorissen Ellen, Raemaekers Tim, Konietzko Uwe, Reiss Karina, Maes Elke, Snellinx An, Serneels Lutgarde, Nyabi Omar, Annaert Wim, Saftig Paul, Hartmann Dieter, De Strooper Bart
Center for Human Genetics, Katholieke Universiteit Leuven (K. U. Leuven), Department for Developmental and Molecular Genetics, and Laboratory of Membrane Trafficking, Vlaams Instituut voor Biotechnologie (VIB), K. U. Leuven, B-3000 Leuven, Belgium.
J Biol Chem. 2009 Apr 24;284(17):11738-47. doi: 10.1074/jbc.M805894200. Epub 2009 Feb 11.
ADAM10 is involved in the proteolytic processing and shedding of proteins such as the amyloid precursor protein (APP), cadherins, and the Notch receptors, thereby initiating the regulated intramembrane proteolysis (RIP) of these proteins. Here, we demonstrate that the sheddase ADAM10 is also subject to RIP. We identify ADAM9 and -15 as the proteases responsible for releasing the ADAM10 ectodomain, and Presenilin/gamma-Secretase as the protease responsible for the release of the ADAM10 intracellular domain (ICD). This domain then translocates to the nucleus and localizes to nuclear speckles, thought to be involved in gene regulation. Thus, ADAM10 performs a dual role in cells, as a metalloprotease when it is membrane-bound, and as a potential signaling protein once cleaved by ADAM9/15 and the gamma-Secretase.
ADAM10参与蛋白质的蛋白水解加工和脱落，如淀粉样前体蛋白（APP）、钙黏蛋白和Notch受体，从而启动这些蛋白质的调节性膜内蛋白水解（RIP）。在此，我们证明了脱落酶ADAM10也会经历RIP。我们确定ADAM9和-15为负责释放ADAM10胞外域的蛋白酶，早老素/γ-分泌酶为负责释放ADAM10细胞内结构域（ICD）的蛋白酶。该结构域随后转移至细胞核并定位于核斑，核斑被认为参与基因调控。因此，ADAM10在细胞中发挥双重作用，膜结合时作为金属蛋白酶，一旦被ADAM9/15和γ-分泌酶切割则作为潜在的信号蛋白。
