| First Author | Kirschenbaum F | Year | 2001 |
| Journal | J Biol Chem | Volume | 276 |
| Issue | 10 | Pages | 7366-75 |
| PubMed ID | 11104755 | Mgi Jnum | J:67950 |
| Mgi Id | MGI:1931728 | Doi | 10.1074/jbc.M004697200 |
| Citation | Kirschenbaum F, et al. (2001) Substitution of a Glycogen Synthase Kinase-3beta Phosphorylation Site in Presenilin 1 Separates Presenilin Function from beta -Catenin Signaling. J Biol Chem 276(10):7366-75 |
| abstractText | 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. |
