PMID:12110170

Citation	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 and Curtis, D (2002) aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev. Cell 3:85-97
Abstract	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.
Links	PubMed
Keywords	Alzheimer Disease/genetics; Alzheimer Disease/metabolism; Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor/genetics; Amyloid beta-Protein Precursor/metabolism; Animals; Aspartic Acid Endopeptidases; Caenorhabditis elegans; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/isolation & purification; Caenorhabditis elegans Proteins/metabolism; Cell Membrane/metabolism; Cell Membrane/ultrastructure; Cells, Cultured; Cloning, Molecular; Drosophila Proteins; Drosophila melanogaster; Endopeptidases/metabolism; Enhancer Elements, Genetic/genetics; Glucagon/metabolism; Glucagon-Like Peptide 1; Helminth Proteins/metabolism; Homeodomain Proteins/genetics; Homeodomain Proteins/isolation & purification; Homeodomain Proteins/metabolism; Humans; Intracellular Membranes/metabolism; Membrane Proteins/genetics; Membrane Proteins/isolation & purification; Membrane Proteins/metabolism; Molecular Sequence Data; Mutation/genetics; Peptide Fragments/metabolism; Presenilin-1; Protein Precursors/metabolism; Receptors, Notch; Sequence Homology, Amino Acid; Sequence Homology, Nucleic Acid; Signal Transduction/genetics
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