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 Mel Zhang; Dong Hong Xu; Christine Sato; Evgeny Rogaev; Marsha Smith; Christopher Janus; Yanni Zhang; Ruedl Aebersold; Lindsay Farrer; Sandro Sorbl; Amalia Bruni; Paul Fraser; Peter St George-Hyslop

doi:10.1038/35024009

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 Mel Zhang, Dong Hong Xu, Christine SatoEvgeny Rogaev, Marsha Smith, Christopher Janus, Yanni Zhang, Ruedl Aebersold, Lindsay Farrer, Sandro Sorbl, Amalia Bruni, Paul Fraser, Peter St George-Hyslop

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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.

Original language	English (US)
Pages (from-to)	48-54
Number of pages	7
Journal	Nature
Volume	407
Issue number	6800
DOIs	https://doi.org/10.1038/35024009
State	Published - Sep 2000

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Yu, G., Nishimura, M., Arawaka, S., Levitan, D., Zhang, L., Tandon, A., Song, Y. Q., Rogaeva, E., Chen, F., Kawarai, T., Supala, A., Levesque, L., Yu, H., Yang, D. S., Holmes, E., Milman, P., Liang, Y., Zhang, D. M., Xu, D. H., ... George-Hyslop, P. S. (2000). Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature, 407(6800), 48-54. https://doi.org/10.1038/35024009

Yu, G, Nishimura, M, Arawaka, S, Levitan, D, Zhang, L, Tandon, A, Song, YQ, Rogaeva, E, Chen, F, Kawarai, T, Supala, A, Levesque, L, Yu, H, Yang, DS, Holmes, E, Milman, P, Liang, Y, Zhang, DM, Xu, DH, Sato, C, Rogaev, E, Smith, M, Janus, C, Zhang, Y, Aebersold, R, Farrer, L, Sorbl, S, Bruni, A, Fraser, P & George-Hyslop, PS 2000, 'Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing', Nature, vol. 407, no. 6800, pp. 48-54. https://doi.org/10.1038/35024009

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title = "Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing",

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.",

author = "Gang Yu and Masaki Nishimura and Shigeki Arawaka and Diane Levitan and Lili Zhang and Anurag Tandon and Song, {You Qiang} and Ekaterina Rogaeva and Fusheng Chen and Toshitaka Kawarai and Agnes Supala and Lyne Levesque and Haung Yu and Yang, {Dun Sheng} and Erin Holmes and Paul Milman and Yan Liang and Zhang, {Dong Mel} and Xu, {Dong Hong} and Christine Sato and Evgeny Rogaev and Marsha Smith and Christopher Janus and Yanni Zhang and Ruedl Aebersold and Lindsay Farrer and Sandro Sorbl and Amalia Bruni and Paul Fraser and George-Hyslop, {Peter St}",

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AU - Zhang, Lili

AU - Tandon, Anurag

AU - Song, You Qiang

AU - Rogaeva, Ekaterina

AU - Chen, Fusheng

AU - Kawarai, Toshitaka

AU - Supala, Agnes

AU - Levesque, Lyne

AU - Yu, Haung

AU - Yang, Dun Sheng

AU - Holmes, Erin

AU - Milman, Paul

AU - Liang, Yan

AU - Zhang, Dong Mel

AU - Xu, Dong Hong

AU - Sato, Christine

AU - Rogaev, Evgeny

AU - Smith, Marsha

AU - Janus, Christopher

AU - Zhang, Yanni

AU - Aebersold, Ruedl

AU - Farrer, Lindsay

AU - Sorbl, Sandro

AU - Bruni, Amalia

AU - Fraser, Paul

AU - George-Hyslop, Peter St

PY - 2000/9

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N2 - 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.

AB - 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.

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

Abstract

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