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

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.

Pubmed ID: 10993067


  • 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 LS
  • Sorbi S
  • Bruni A
  • Fraser P
  • St George-Hyslop P



Publication Data

September 7, 2000

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor
  • Animals
  • Aspartic Acid Endopeptidases
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • DNA, Complementary
  • Endopeptidases
  • Humans
  • Membrane Glycoproteins
  • Membrane Proteins
  • Molecular Sequence Data
  • Presenilin-1
  • Presenilin-2
  • Receptors, Notch
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Transfection