title: 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.
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.
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tousseyn
authors.forename: Amantha
authors.initials: A
authors.lastname: Thathiah
authors.forename: Ellen
authors.initials: E
authors.lastname: Jorissen
authors.forename: Tim
authors.initials: T
authors.lastname: Raemaekers
authors.forename: Uwe
authors.initials: U
authors.lastname: Konietzko
authors.forename: Karina
authors.initials: K
authors.lastname: Reiss
authors.forename: Elke
authors.initials: E
authors.lastname: Maes
authors.forename: An
authors.initials: A
authors.lastname: Snellinx
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Serneels
authors.forename: Omar
authors.initials: O
authors.lastname: Nyabi
authors.forename: Wim
authors.initials: W
authors.lastname: Annaert
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Dieter
authors.initials: D
authors.lastname: Hartmann
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism* / Q000502:physiology*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D053763:Presenilins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D008565:Membrane Proteins; D053763:Presenilins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; C490902:Adam15 protein, mouse; C498316:Adam9 protein, mouse; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse