| pmid | 11104755 | ||||
|---|---|---|---|---|---|
| title | Substitution of a glycogen synthase kinase-3beta phosphorylation site in presenilin 1 separates presenilin function from beta-catenin signaling. | ||||
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| journal | J Biol Chem | ||||
| year | 2001 | ||||
| full_text_available | false | ||||
| doi | 10.1074/jbc.M004697200 |
Substitution of a glycogen synthase kinase-3beta phosphorylation site in presenilin 1 separates presenilin function from beta-catenin signaling.
Authors: Kirschenbaum F, Hsu SC, Cordell B, McCarthy JV Journal: J Biol Chem (2001) DOI: 10.1074/jbc.M004697200
- J Biol Chem. 2001 Mar 9;276(10):7366-75. doi: 10.1074/jbc.M004697200. Epub 2000 Dec 4.
Substitution of a glycogen synthase kinase-3beta phosphorylation site in presenilin 1 separates presenilin function from beta-catenin signaling.
Kirschenbaum F(1), Hsu SC, Cordell B, McCarthy JV.
Author information: (1)Scios Inc., Sunnyvale, California 94086, USA.
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.
DOI: 10.1074/jbc.M004697200 PMID: 11104755 [Indexed for MEDLINE]