TY - JOUR
T1 - A presenilin-1-dependent γ-secretase-like protease mediates release of notch intracellular domain
AU - De Strooper, Bart
AU - Annaert, Wim
AU - Cupers, Philippe
AU - Saftig, Paul
AU - Craessaerts, Katleen
AU - Mumm, Jeffrey S.
AU - Schroeter, Eric H.
AU - Schrijvers, Vincent
AU - Wolfe, Michael S.
AU - Ray, William J.
AU - Goate, Alison
AU - Kopan, Raphael
PY - 1999/4/8
Y1 - 1999/4/8
N2 - 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 pathway. 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.
AB - 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 pathway. 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.
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U2 - 10.1038/19083
DO - 10.1038/19083
M3 - Article
C2 - 10206645
AN - SCOPUS:0033535504
SN - 0028-0836
VL - 398
SP - 518
EP - 522
JO - Nature
JF - Nature
IS - 6727
ER -