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Rac1 changes the substrate specificity of gamma-secretase between amyloid precursor protein and Notch1

Cited 19 time in Web of Science Cited 19 time in Scopus
Authors
Boo, Jung Hyun; Sohn, Ji Hoon; Kim, Ji Eun; Song, Hyundong; Mook-Jung, Inhee
Issue Date
2008-06-10
Publisher
Elsevier
Citation
Biochemical and Biophysical Research Communications 372(4):913-917
Keywords
Alzheimer Disease/drug therapy/metabolismAminoquinolines/pharmacologyAmyloid Precursor Protein Secretases/*metabolismAmyloid beta-Protein/metabolismAmyloid beta-Protein Precursor/*metabolismAnimalsCOS CellsCell LineCercopithecus aethiopsDrug DesignEnzyme ActivationHumansPresenilin-1/metabolismProtein Structure, TertiaryPyrimidines/pharmacologyReceptor, Notch1/genetics/*metabolismSequence DeletionSubstrate Specificityrac1 GTP-Binding Protein/antagonists & inhibitors/genetics/*metabolism
Abstract
Beta amyloid peptide is generated from amyloid precursor protein (APP) by proteolytic cleavage of beta- and gamma-secretases, and plays a critical role in the pathogenesis of Alzheimer's disease. Since gamma-secretase cleaves several proteins including APP and Notch in a number of cell types, it is important to understand the conditions determining gamma-secretase substrate specificity. In the present study, inhibition of Rac1 attenuated gamma-secretase activity for APP, resulting in decreased production of the APP intracellular domain but accumulated C-terminal fragments (APP-CTF). In contrast, Rac1 inhibitor, NSC23766 increased production of the Notch1 intracellular domain but slightly decreased the ectodomain-shed form of Notch1 (NotchDeltaE). To elucidate the mechanism underlying these observations, we performed co-immunoprecipitation experiments to analyze the interaction between Rac1 and presenilin1 (PS1), a component of the gamma-secretase complex. Inhibition of Rac1 enhanced its interaction with PS1. Under the same condition, PS1 interacted more strongly with NotchDeltaE than with APP-CTF. Our results suggested that PS1 determines the preferred substrate for gamma-secretase between APP and Notch1, depending on the activation status of Rac1.
ISSN
1090-2104 (Electronic)
Language
English
URI
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WBK-4SNY56P-1-9&_cdi=6713&_user=168665&_orig=search&_coverDate=08%2F08%2F2008&_sk=996279995&view=c&wchp=dGLbVlb-zSkzk&md5=88b81f70dc1aa61118fd67c88c4e960e&ie=/sdarticle.pdf

http://hdl.handle.net/10371/67439
DOI
https://doi.org/10.1016/j.bbrc.2008.05.153
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Biochemistry & Molecular Biology (생화학교실)Journal Papers (저널논문_생화학교실)
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