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Elsevier, Journal of Biological Chemistry, 17(284), p. 11738-11747, 2009

DOI: 10.1074/jbc.m805894200

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ADAM10, the Rate-limiting Protease of Regulated Intramembrane Proteolysis of Notch and Other Proteins, Is Processed by ADAMS-9, ADAMS-15, and the γ-Secretase

Journal article published in 2009 by Thomas Tousseyn ORCID, Amantha Thathiah, Ellen Jorissen, Tim Raemaekers, Uwe Konietzko, Karina Reiss, Elke Maes, An Snellinx, Lutgarde Serneels, Omar Nyabi, Wim Annaert, Paul Saftig, Dieter Hartmann, Bart De Strooper
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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.