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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

Authors

  • Kirschenbaum F
  • Hsu SC
  • Cordell B
  • McCarthy JV

Journal

The Journal of biological chemistry

Publication Data

March 9, 2001

Associated Grants

None

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