A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain

Bart De Strooper (), Wim Annaert, Philippe Cupers, Paul Saftig, Katleen Craessaerts, Jeffrey S. Mumm, Eric H. Schroeter, Vincent Schrijvers, Michael S. Wolfe, William J. Ray, Alison Goate and Raphael Kopan ()
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Bart De Strooper: Neuronal Cell Biology and Gene Transfer Laboratory, Flanders Institute for Biotechnology (VIB4), Center for Human Genetics
Wim Annaert: Neuronal Cell Biology and Gene Transfer Laboratory, Flanders Institute for Biotechnology (VIB4), Center for Human Genetics
Philippe Cupers: Neuronal Cell Biology and Gene Transfer Laboratory, Flanders Institute for Biotechnology (VIB4), Center for Human Genetics
Paul Saftig: Zentrum Biochemie und Molekulare Zellbiologie, Universität Göttingen
Katleen Craessaerts: Neuronal Cell Biology and Gene Transfer Laboratory, Flanders Institute for Biotechnology (VIB4), Center for Human Genetics
Jeffrey S. Mumm: Washington University
Eric H. Schroeter: Washington University
Vincent Schrijvers: Neuronal Cell Biology and Gene Transfer Laboratory, Flanders Institute for Biotechnology (VIB4), Center for Human Genetics
Michael S. Wolfe: University of Tennessee
William J. Ray: Washington University School of Medicine
Alison Goate: Washington University School of Medicine
Raphael Kopan: Washington University

Nature, 1999, vol. 398, issue 6727, 518-522

Abstract: Abstract Signalling through the receptor protein Notch, which is involved in crucial cell-fate decisions during development, requires ligand-induced cleavage of Notch. This cleavage occurs within the predicted transmembrane domain, releasing the Notch intracellular domain (NICD), and is reminiscent of γ-secretase-mediated cleavage of β-amyloid precursor protein (APP), a critical event in the pathogenesis of Alzheimer's disease. A deficiency in presenilin-1 (PS1) inhibits processing of APP by γ-secretase in mammalian cells, and genetic interactions between Notch and PS1 homologues in Caenorhabditis elegans indicate that the presenilins may modulate the Notch signalling pathway1,2,3,4. Here we report that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1. Moreover, several γ-secretase inhibitors block this same step in Notch processing, indicating that related protease activities are responsible for cleavage within the predicted transmembrane domains of Notch and APP. Thus the targeting of γ-secretase for the treatment of Alzheimer's disease may risk toxicity caused by reduced Notch signalling.

Date: 1999
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DOI: 10.1038/19083

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