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J Biol Chem. 2009 Apr 24;284(17):11738-47. doi: 10.1074/jbc.M805894200. Epub 2009 Feb 11.

ADAM10, the rate-limiting protease of regulated intramembrane proteolysis of Notch and other proteins, is processed by ADAMS-9, ADAMS-15, and the gamma-secretase.

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  • 1Center 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.


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.

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