PMID:11104755

Citation	Kirschenbaum, F, Hsu, SC, Cordell, B and McCarthy, JV (2001) Substitution of a glycogen synthase kinase-3beta phosphorylation site in presenilin 1 separates presenilin function from beta-catenin signaling. J. Biol. Chem. 276:7366-75
Abstract	The majority of cases with early onset familial Alzheimer's disease have been attributed to mutations in the presenilin 1 (PS1) gene. PS1 protein is a component of a high molecular weight membrane-bound complex that also contains beta-catenin. The physiological relevance of the association between PS1 and beta-catenin remains controversial. In this study, we report the identification and functional characterization of a highly conserved glycogen synthase kinase-3beta consensus phosphorylation site within the hydrophilic loop domain of PS1. Site-directed mutagenesis, together with in vitro and in vivo phosphorylation assays, indicates that PS1 residues Ser(353) and Ser(357) are glycogen synthase kinase-3beta targets. Substitution of one or both of these residues greatly reduces the ability of PS1 to associate with beta-catenin. By disrupting this interaction, we demonstrate that the association between PS1 and beta-catenin has no effect on Abeta peptide production, beta-catenin stability, or cellular susceptibility to apoptosis. Significantly, in the absence of PS1/beta-catenin association, we found no alteration in beta-catenin signaling using induction of this pathway by exogenous expression of Wnt-1 or beta-catenin and a Tcf/Lef transcriptional assay. These results argue against a pathologically relevant role for the association between PS1 and beta-catenin in familial Alzheimer's disease.
Links	PubMed Online version:10.1074/jbc.M004697200
Keywords	Alzheimer Disease/metabolism; Amino Acid Motifs; Amino Acid Sequence; Amyloid beta-Peptides/chemistry; Apoptosis; Binding Sites; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinases/chemistry; Cell Death; Cell Line; Cell Nucleus/metabolism; Cytoskeletal Proteins/chemistry; Cytoskeletal Proteins/metabolism; Cytoskeletal Proteins/physiology; Cytosol/metabolism; DNA, Complementary/metabolism; Genetic Vectors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Humans; Luciferases/metabolism; Membrane Proteins/chemistry; Membrane Proteins/genetics; Membrane Proteins/physiology; Microscopy, Fluorescence; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Peptide Fragments/chemistry; Phosphorylation; Precipitin Tests; Presenilin-1; Protein Binding; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Serine/chemistry; Signal Transduction; Trans-Activators; Transfection; beta Catenin
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