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aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation.

Presenilins are components of the gamma-secretase protein complex that mediates intramembranous cleavage of betaAPP and Notch proteins. A C. elegans genetic screen revealed two genes, aph-1 and pen-2, encoding multipass transmembrane proteins, that interact strongly with sel-12/presenilin and aph-2/nicastrin. Human aph-1 and pen-2 partially rescue the C. elegans mutant phenotypes, demonstrating conserved functions. The human genes must be provided together to rescue the mutant phenotypes, and the inclusion of presenilin-1 improves rescue, suggesting that they interact closely with each other and with presenilin. RNAi-mediated inactivation of aph-1, pen-2, or nicastrin in cultured Drosophila cells reduces gamma-secretase cleavage of betaAPP and Notch substrates and reduces the levels of processed presenilin. aph-1 and pen-2, like nicastrin, are required for the activity and accumulation of gamma-secretase.

Pubmed ID: 12110170


  • Francis R
  • McGrath G
  • Zhang J
  • Ruddy DA
  • Sym M
  • Apfeld J
  • Nicoll M
  • Maxwell M
  • Hai B
  • Ellis MC
  • Parks AL
  • Xu W
  • Li J
  • Gurney M
  • Myers RL
  • Himes CS
  • Hiebsch R
  • Ruble C
  • Nye JS
  • Curtis D


Developmental cell

Publication Data

July 11, 2002

Associated Grants


Mesh Terms

  • Alzheimer Disease
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor
  • Animals
  • Aspartic Acid Endopeptidases
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Cell Membrane
  • Cells, Cultured
  • Cloning, Molecular
  • Drosophila Proteins
  • Drosophila melanogaster
  • Endopeptidases
  • Enhancer Elements, Genetic
  • Glucagon
  • Glucagon-Like Peptide 1
  • Helminth Proteins
  • Homeodomain Proteins
  • Humans
  • Intracellular Membranes
  • Membrane Proteins
  • Molecular Sequence Data
  • Mutation
  • Peptide Fragments
  • Presenilin-1
  • Protein Precursors
  • Receptors, Notch
  • Sequence Homology, Amino Acid
  • Sequence Homology, Nucleic Acid
  • Signal Transduction