The γ-Secretase-Generated Intracellular Domain of β-Amyloid Precursor Protein Binds Numb and Inhibits Notch Signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-05, Vol.99 (10), p.7102-7107
• Main Authors: Roncarati, Roberta, Šestan, Nenad, Scheinfeld, Meir H., Berechid, Bridget E., Lopez, Peter A., Meucci, Olimpia, McGlade, Jane C., Rakic, Pasko, D'Adamio, Luciano
• Format: Article
• Language: English
• Subjects: AIDS; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases; Animals; Antibodies; Aspartic Acid Endopeptidases; Binding Sites; Biological Sciences; Biology; Brain; Cell Line, Transformed; Cells; Cells, Cultured; Endopeptidases - metabolism; HEK293 cells; HeLa Cells; Humans; Intracellular Fluid - metabolism; Intracellular Signaling Peptides and Proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Neurons; Protein isoforms; Protein precursors; Protein Processing, Post-Translational; Proteins; Receptors, Notch; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Signal Transduction; Studies; Transactivation; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.102192599

The β-amyloid precursor protein (APP) and the Notch receptor undergo intramembranous proteolysis by the Presenilin-dependent γ-secretase. The cleavage of APP by γ-secretase releases amyloid-β 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 γ-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, γ-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.