aph-1 and pen-2 are required for Notch pathway signaling,gamma-secretase cleavage of betaAPP,and presenilin protein accumulation |
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Authors: | Francis Ross McGrath Garth Zhang Jianhuan Ruddy David A Sym Mary Apfeld Javier Nicoll Monique Maxwell Mark Hai Bing Ellis Michael C Parks Annette L Xu Wei Li Jinhe Gurney Mark Myers Richard L Himes Carol S Hiebsch Ronald Ruble Cara Nye Jeffrey S Curtis Daniel |
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Institution: | Exelixis, Inc., South San Francisco, CA 94083, USA. |
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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. |
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