title: Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP 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 beta-amyloid precursor protein (betaAPP), and modulates the production of the amyloid beta-peptide (A beta) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase A beta42 and A beta40 peptide secretion. Deletions in this domain inhibit A beta 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 betaAPP.
authors.affiliation: Centre for Research in Neurodegenerative Diseases, Toronto Western Hospital, and Department of Medicine (Neurology), University of Toronto, Ontario, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Yu
authors.forename: M
authors.initials: M
authors.lastname: Nishimura
authors.forename: S
authors.initials: S
authors.lastname: Arawaka
authors.forename: D
authors.initials: D
authors.lastname: Levitan
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Tandon
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Song
authors.forename: E
authors.initials: E
authors.lastname: Rogaeva
authors.forename: F
authors.initials: F
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Kawarai
authors.forename: A
authors.initials: A
authors.lastname: Supala
authors.forename: L
authors.initials: L
authors.lastname: Levesque
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: D S
authors.initials: DS
authors.lastname: Yang
authors.forename: E
authors.initials: E
authors.lastname: Holmes
authors.forename: P
authors.initials: P
authors.lastname: Milman
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.forename: D M
authors.initials: DM
authors.lastname: Zhang
authors.forename: D H
authors.initials: DH
authors.lastname: Xu
authors.forename: C
authors.initials: C
authors.lastname: Sato
authors.forename: E
authors.initials: E
authors.lastname: Rogaev
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: C
authors.initials: C
authors.lastname: Janus
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Aebersold
authors.forename: L S
authors.initials: LS
authors.lastname: Farrer
authors.forename: S
authors.initials: S
authors.lastname: Sorbi
authors.forename: A
authors.initials: A
authors.lastname: Bruni
authors.forename: P
authors.initials: P
authors.lastname: Fraser
authors.forename: P
authors.initials: P
authors.lastname: St George-Hyslop
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins; D018076:DNA, Complementary; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D053764:Presenilin-1; D053766:Presenilin-2; D051880:Receptors, Notch; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D029742:Caenorhabditis elegans Proteins; D018076:DNA, Complementary; C060620:Glp-1 protein, C elegans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D051880:Receptors, Notch; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human