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 RIS Download
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