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Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila

Nature Cell Biology volume 3, pages 1129–1132 (2001)Cite this article

Abstract

The transmembrane glycoprotein Nicastrin was identified in a complex with the multipass membrane protein Presenilin1. Presenilin mediates transmembrane cleavage of single-pass transmembrane proteins with short extracellular domains2, including the ligand-activated form of the receptor Notch3,4,5 and β-amyloid precursor protein (β-APP)6,7. Transmembrane cleavage of Notch is essential for signal transduction3,4,5, and transmembrane cleavage of β-APP generates pathogenic amyloid peptides implicated in Alzheimer's disease8. Here, we investigate the requirement for Nicastrin in Presenilin-mediated transmembrane cleavage. We show that, in Drosophila, loss of Nicastrin activity blocks the accumulation of Presenilin associated with the apical plasma membrane, abolishes Presenilin-dependent cleavage of the transmembrane domains of Notch and β-APP, and abrogates Notch signal transduction.

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Figure 1: Nicastrin activity is required for Notch signalling.
Figure 2: Nicastrin is required for the transducing activity of transmembrane forms of Notch.
Figure 3: Nicastrin is required for cleavage of the Notch and β-APP transmembrane domains.
Figure 4: Nicastrin is required for the accumulation of Presenilin associated with the apical plasma membrane.

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Acknowledgements

The nctR46 allele was isolated, mapped and characterized as a neurogenic mutation by J. Jiang in a prior genetic screen; we gratefully acknowledge his contribution to the present work. We also thank A. Adachi for generating transgenic lines, T. Lee, L. Luo, P.M. Macdonald, H. Bellen and Developmental Studies Hybridoma Bank for providing fly stocks and antisera, I. Greenwald for discussion, and I. Greenwald, L. Johnston, R. Mann, and members of the Struhl lab for advice on the manuscript. H.-M. Chung is a research associate and G. Struhl an investigator of the Howard Hughes Medical Institute.

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  1. Department of Genetics and Development,Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, 10032, NY, USA

    Hui-Min Chung & Gary Struhl

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  1. Hui-Min Chung
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Correspondence to Gary Struhl.

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Chung, HM., Struhl, G. Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila. Nat Cell Biol 3, 1129–1132 (2001). https://doi.org/10.1038/ncb1201-1129

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