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

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...

Full description

Saved in:
Bibliographic Details
Published inThe Journal of biological chemistry Vol. 284; no. 17; pp. 11738 - 11747
Main Authors 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
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 24.04.2009
American Society for Biochemistry and Molecular Biology
Subjects
ADAM Proteins - metabolism
ADAM Proteins - physiology
ADAM10 Protein
Amyloid Precursor Protein Secretases - metabolism
Amyloid Precursor Protein Secretases - physiology
Animals
Cell Nucleus - metabolism
Enzyme Catalysis and Regulation
Gene Expression Regulation, Enzymologic
Membrane Proteins - metabolism
Membrane Proteins - physiology
Mice
Microscopy, Fluorescence
Presenilins - metabolism
Protein Structure, Tertiary
Receptors, Notch - metabolism
Signal Transduction
Subcellular Fractions - metabolism
Tissue Distribution
Online AccessGet full text

Cover

More Information
Summary: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/γ-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 γ-Secretase.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
These authors contributed equally to this work.
This work was supported in part by grants from the Alzheimer's Association and the Fonds voor Wetenschappelijik Onderzoek (F.W.O.) (to D. H.), a Stichting Alzheimer Onderzoek-Fondation sur la Recherche sur la Maladie d'Alzheimer-2006 grant (to W. A.), the Deutsche Forschungsgemeinschaft SFB415-TPB9 (to P. S. and K. R.), and a Freedom to Discover grant from Bristol Myers Squib, a Methusalem grant of the Flemish Government (to B. D. S.), and grants from the F.W.O., K.U. Leuven (to G. O. A.), VIB, and Federal Office for Scientific Affairs (IUAP P6/43/), Belgium (to W. A. and B. D. S.).
Fellow of the Fund for Scientific Research, Flanders (F.W.O.) and the Belgian American Educational Foundation.
To whom correspondence may be addressed: Center for Human Genetics, K.U. Leuven and VIB, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel.: 0032-16-346227; Fax: 0032-16-347181; E-mail: Bart.destrooper@med.kuleuven.be.
Both authors contributed equally to this work.
Postdoc fellow of the F.W.O.
Fellow of the Instituut voor de aanmoediging van Innovatie door wetenschap en technologie in Vlaanderen.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.
To whom correspondence may be addressed: Anatomisches Institut der Universität Bonn, Nussallee 10, D 53115 Bonn, Germany. Tel.: 0049-228-73-7684; Fax: 0049-228-73-5905; E-mail: dhartman@uni-bonn.de.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M805894200