Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing

Gang Yu, Masaki Nishimura, Shigeki Arawaka, Diane Levitan, Lili Zhang, Anurag Tandon, You-Qiang Song, Ekaterina Rogaeva, Fusheng Chen, Toshitaka Kawarai, Agnes Supala, Lyne Levesque, Haung Yu, Dun-Sheng Yang, Erin Holmes, Paul Milman, Yan Liang, Dong Mei Zhang, Dong Hong Xu, Christine Sato, Evgeny Rogaev, Marsha Smith, Christopher Janus, Yanni Zhang, Ruedi Aebersold, Lindsay Farrer, Sandro Sorbi, Amalia Bruni, Paul Fraser and Peter St George-Hyslop ()
Additional contact information
Gang Yu: Centre for Research in Neurodegenerative Diseases
Masaki Nishimura: Centre for Research in Neurodegenerative Diseases
Shigeki Arawaka: Centre for Research in Neurodegenerative Diseases
Diane Levitan: Schering Plough Research Institute
Lili Zhang: Schering Plough Research Institute
Anurag Tandon: Centre for Research in Neurodegenerative Diseases
You-Qiang Song: Centre for Research in Neurodegenerative Diseases
Ekaterina Rogaeva: Centre for Research in Neurodegenerative Diseases
Fusheng Chen: Centre for Research in Neurodegenerative Diseases
Toshitaka Kawarai: Centre for Research in Neurodegenerative Diseases
Agnes Supala: Centre for Research in Neurodegenerative Diseases
Lyne Levesque: Centre for Research in Neurodegenerative Diseases
Haung Yu: Centre for Research in Neurodegenerative Diseases
Dun-Sheng Yang: Centre for Research in Neurodegenerative Diseases
Erin Holmes: Centre for Research in Neurodegenerative Diseases
Paul Milman: Centre for Research in Neurodegenerative Diseases
Yan Liang: Centre for Research in Neurodegenerative Diseases
Dong Mei Zhang: Centre for Research in Neurodegenerative Diseases
Dong Hong Xu: Centre for Research in Neurodegenerative Diseases
Christine Sato: Centre for Research in Neurodegenerative Diseases
Evgeny Rogaev: Centre for Research in Neurodegenerative Diseases
Marsha Smith: Schering Plough Research Institute
Christopher Janus: Centre for Research in Neurodegenerative Diseases
Yanni Zhang: Molecular Biotechnology, University of Washington
Ruedi Aebersold: Molecular Biotechnology, University of Washington
Lindsay Farrer: Genetics Program, Boston University School of Medicine
Sandro Sorbi: University of Florence
Amalia Bruni: Centro Regionale di Neurogenetica, USL 6
Paul Fraser: Centre for Research in Neurodegenerative Diseases
Peter St George-Hyslop: Centre for Research in Neurodegenerative Diseases

Nature, 2000, vol. 407, issue 6800, 48-54

Abstract: Abstract Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of β-amyloid precursor protein (βAPP), and modulates the production of the amyloid β-peptide (Aβ) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase Aβ42 and Aβ40 peptide secretion. Deletions in this domain inhibit Aβ production. Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and βAPP.

Date: 2000
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DOI: 10.1038/35024009

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