We have updated our privacy policy. If you have any question, contact us at privacy@scicrunch.org. Dismiss and don't show again

Searching across hundreds of databases

Our searching services are busy right now. Your search will reload in five seconds.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Substitution of a glycogen synthase kinase-3beta phosphorylation site in presenilin 1 separates presenilin function from beta-catenin signaling.

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.

Pubmed ID: 11104755 RIS Download

Mesh terms: Alzheimer Disease | Amino Acid Motifs | Amino Acid Sequence | Amyloid beta-Peptides | Apoptosis | Binding Sites | Blotting, Western | Calcium-Calmodulin-Dependent Protein Kinases | Cell Death | Cell Line | Cell Nucleus | Cytoskeletal Proteins | Cytosol | DNA, Complementary | Genetic Vectors | Glycogen Synthase Kinase 3 | Glycogen Synthase Kinases | Humans | Luciferases | Membrane Proteins | Microscopy, Fluorescence | Models, Molecular | Molecular Sequence Data | Mutagenesis, Site-Directed | Mutation | Peptide Fragments | Phosphorylation | Precipitin Tests | Presenilin-1 | Protein Binding | Protein Structure, Tertiary | Sequence Homology, Amino Acid | Serine | Signal Transduction | Trans-Activators | Transfection | beta Catenin

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

We have not found any resources mentioned in this publication.