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.
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.
Tousseyn
Thomas
T
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.
Thathiah
Amantha
A
Jorissen
Ellen
E
Raemaekers
Tim
T
Konietzko
Uwe
U
Reiss
Karina
K
Maes
Elke
E
Snellinx
An
A
Serneels
Lutgarde
L
Nyabi
Omar
O
Annaert
Wim
W
Saftig
Paul
P
Hartmann
Dieter
D
De Strooper
Bart
B
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
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