Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila

The transmembrane glycoprotein Nicastrin was identified in a complex with t he multipass membrane protein Presenilin(1). Presenilin mediates transmembr ane cleavage of single-pass transmembrane proteins with short extracellular domains(2), including the ligand-activated form of the receptor Notch(3-5) and beta -amyloid precursor protein (beta -APP)(6,7). Transmembrane cleava ge of Notch is essential for signal transduction(3-5), and transmembrane cl eavage of beta -APP generates pathogenic amyloid peptides implicated in Alz heimer's disease(8). Here, we investigate the requirement for Nicastrin in Presenilin-mediated transmembrane cleavage. We show that, in Drosophila, lo ss of Nicastrin activity blocks the accumulation of Presenilin associated w ith the apical plasma membrane, abolishes Presenilin-dependent cleavage of the transmembrane domains of Notch and beta -APP, and abrogates Notch signa l transduction.