Journal article
The [gamma]-secretase-generated intracellular domain of [beta]-amyloid precursor protein binds Numb and inhibits Notch signaling
Proceedings of the National Academy of Sciences - PNAS, Vol.99(10), p7102
14 May 2002
Abstract
The [beta]-amyloid precursor protein (APP) and the Notch receptor undergo intramembranous proteolysis by the Presenilin-dependent [gamma]-secretase. The cleavage of APP by [gamma]-secretase releases amyloid-[beta] peptides, which have been implicated in the pathogenesis of Alzheimer's disease, and the APP intracellular domain (AID), for which the function is not yet well understood. A similar [gamma]-secretase-mediated cleavage of the Notch receptor liberates the Notch intracellular domain (NICD). NICD translocates to the nucleus and activates the transcription of genes that regulate the generation, differentiation, and survival of neuronal cells. Hence, some of the effects of APP signaling and Alzheimer's disease pathology may be mediated by the interaction of APP and Notch. Here, we show that membrane-tethered APP binds to the cytosolic Notch inhibitors Numb and Numb-like in mouse brain lysates. AID also binds Numb and Numb-like, and represses Notch activity when released by APP. Thus, [gamma]-secretase may have opposing effects on Notch signaling; positive by cleaving Notch and generating NICD, and negative by processing APP and generating AID, which inhibits the function of NICD.
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Details
- Title
- The [gamma]-secretase-generated intracellular domain of [beta]-amyloid precursor protein binds Numb and inhibits Notch signaling
- Creators
- Roberta RoncaratiNenad SestanMeir H ScheinfeldBridget E BerechidPeter A LopezOlimpia MeucciJane C McGladePasko RakicLuciano D'Adamio
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.99(10), p7102
- Publisher
- National Academy of Sciences
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Identifiers
- 991020111175804721