PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: Effects of FAD mutations. Baki, L., Shioi, J., Wen, P., Shao, Z., Schwarzman, A., Gama-Sosa, M., Neve, R., & Robakis, N. EMBO Journal, 23(13):2586-2596, 2004. cited By 227
PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: Effects of FAD mutations [link]Paper  doi  abstract   bibtex   
Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by activating its downstream effector Akt kinase. Here we show that PS1, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling. This function of PS1 is unaffected by γ-secretase inhibitors. Pharmacological and genetic evidence indicates that PS1 acts upstream of Akt, at or before PI3K kinase. PS1 forms complexes with the p85 subunit of PI3K and promotes cadherin/PBK association. Furthermore, conditions that inhibit this association prevent the PS1-induced PI3K/Akt activation, indicating that PS1 stimulates PI3K/Akt signaling by promoting cadherin/PI3K association. By activating PI3K/Akt signaling, PS1 promotes phosphorylation/inactivation of glycogen synthase kinase-3 (GSK-3), suppresses GSK-3-dependent phosphorylation of tau at residues overphosphorylated in AD and prevents apoptosis of confluent cells. PS1 FAD mutations inhibit the PS1-dependent PI3K/Akt activation, thus promoting GSK-3 activity and tau overphosphorylation at AD-related residues. Our data raise the possibility that PS1 may prevent development of AD pathology by activating the PI3K/Akt signaling pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this pathway.
@ARTICLE{Baki20042586,
author={Baki, L. and Shioi, J. and Wen, P. and Shao, Z. and Schwarzman, A. and Gama-Sosa, M. and Neve, R. and Robakis, N.K.},
title={PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: Effects of FAD mutations},
journal={EMBO Journal},
year={2004},
volume={23},
number={13},
pages={2586-2596},
doi={10.1038/sj.emboj.7600251},
note={cited By 227},
url={https://www.scopus.com/inward/record.uri?eid=2-s2.0-3343005434&doi=10.1038%2fsj.emboj.7600251&partnerID=40&md5=2ddcc14539d32c1990a04bf3a6b5e9ad},
affiliation={Department of Psychiatry, Fishberg Res. Ctr. for Neurobiology, Mount Sinai School of Medicine, New York, NY, United States; Dept. of Psychiat. and Behav. Sci., State Univ. New York at Stony Brook, Stony Brook, NY, United States; Department of Psychiatry, McLean Hospital, Harvard University, Belmont, MA, United States; Mount Sinai School of Medicine, NYU, Annenberg Bldg., One Gustave Levy Pl., New York, NY 10029, United States},
abstract={Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by activating its downstream effector Akt kinase. Here we show that PS1, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling. This function of PS1 is unaffected by γ-secretase inhibitors. Pharmacological and genetic evidence indicates that PS1 acts upstream of Akt, at or before PI3K kinase. PS1 forms complexes with the p85 subunit of PI3K and promotes cadherin/PBK association. Furthermore, conditions that inhibit this association prevent the PS1-induced PI3K/Akt activation, indicating that PS1 stimulates PI3K/Akt signaling by promoting cadherin/PI3K association. By activating PI3K/Akt signaling, PS1 promotes phosphorylation/inactivation of glycogen synthase kinase-3 (GSK-3), suppresses GSK-3-dependent phosphorylation of tau at residues overphosphorylated in AD and prevents apoptosis of confluent cells. PS1 FAD mutations inhibit the PS1-dependent PI3K/Akt activation, thus promoting GSK-3 activity and tau overphosphorylation at AD-related residues. Our data raise the possibility that PS1 may prevent development of AD pathology by activating the PI3K/Akt signaling pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this pathway.},
author_keywords={Alzheimer's disease;  Cadherin;  PBK;  Presenilin;  Tau},
correspondence_address1={Robakis, N.K.; Mount Sinai School of Medicine, NYU, Annenberg Bldg., One Gustave Levy Pl., New York, NY 10029, United States; email: nikos.robakis@mssm.edu},
issn={02614189},
coden={EMJOD},
pubmed_id={15192701},
language={English},
abbrev_source_title={EMBO J.},
document_type={Article},
source={Scopus},
}

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