PMID:15192701

Citation	Baki, L, Shioi, J, Wen, P, Shao, Z, Schwarzman, A, Gama-Sosa, M, Neve, R and Robakis, NK (2004) PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J. 23:2586-96
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 gamma-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/PI3K 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.
Links	PubMed PMC449766 Online version:10.1038/sj.emboj.7600251
Keywords	Alzheimer Disease/genetics; Animals; Apoptosis; Blotting, Western; Cadherins/metabolism; Carbamates/pharmacology; Cell Line, Transformed; Cell Survival; Cell Transformation, Viral; Dipeptides/pharmacology; Enzyme Activation; Enzyme Inhibitors/pharmacology; Fibroblasts/metabolism; Flow Cytometry; Glycogen Synthase Kinase 3/antagonists & inhibitors; Humans; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice/embryology; Mice, Knockout; Mutation; Phosphatidylinositol 3-Kinases/chemistry; Phosphatidylinositol 3-Kinases/metabolism; Phosphorylation; Precipitin Tests; Presenilin-1; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-akt; Simplexvirus/genetics; tau Proteins/antagonists & inhibitors
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