Open AccessInhibitory effect of a presenilin 1 mutation on the Wnt signalling pathway by enhancement of β‐catenin phosphorylation
Author(s) -
Kawamura Yuuki,
Kikuchi Akira,
Takada Ritsuko,
Takada Shinji,
Sudoh Shinji,
Shibamoto Sayumi,
Yanagisawa Katsuhiko,
Komano Hiroto
Publication year - 2001
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1327.2001.02197.x
Subject(s) - wnt signaling pathway , presenilin , phosphorylation , catenin , mutation , beta catenin , microbiology and biotechnology , biology , beta (programming language) , signal transduction , chemistry , genetics , gene , disease , alzheimer's disease , medicine , computer science , programming language
Mutations in the presenilin 1 ( PS1 ) gene are the most common genetic factor underlying the development of early onset familial Alzheimer's disease (FAD). Accumulating evidence has shown that FAD‐linked mutations of PS1 enhance the generation of amyloid‐β (1–42) protein. Recently, β‐catenin has been shown to interact with PS1. β‐catenin is essential for the Wnt signalling pathway. However, the biological significance of the interaction between β‐catenin and PS1 in this signalling pathway remains to be clarified. In this study, we investigated the effect of FAD‐linked PS1 (M146L) mutation in the Wnt signalling pathway using the conditioned medium containing Wnt‐3A. The expression of mutated PS1 inhibited the Wnt‐3A‐induced accumulation of β‐catenin. Chase analysis of β‐catenin in Wnt‐3A‐stimulated cells following cycloheximide treatment revealed that PS1 mutation enhanced the generation of the higher molecular mass form of β‐catenin, most likely, ubiquitinated β‐catenin. In addition, the expression of mutated PS1 elevated the level of phosphorylated β‐catenin, which is targeted to the ubiquitin/proteasome pathway. Thus, it appears that PS1 (M146L) mutation down‐regulates the Wnt‐3A‐induced accumulation of β‐catenin due to an increase in the level of phosphorylated β‐catenin.