A structural switch of presenilin 1 by glycogen synthase kinase 3β-mediated phosphorylation regulates the interaction with β-catenin and its nuclear signaling

Abstract

Presenilins (PS) are critical components of the γ-secretase complex that mediates cleavage of type I membrane proteins including the β-amyloid precursor protein to generate the amyloid β-peptide. In addition, PS1 interacts with β-catenin and facilitates its metabolism. We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3β (GSK3β) induces a structural change of the hydrophilic loop of PS1 that can also be mimicked by substitution of the phosphorylation sites by negatively charged amino acids in vitro and in cultured cells. The structural change of PS1 reduces the interaction with β-catenin leading to decreased phosphorylation and ubiquitination of β-catenin. The decreased interaction of PS1 with β-catenin leads to stabilization of β-catenin thereby increasing its nuclear signaling and the transcription of target genes, including c-MYC. Consistent with increased expression of c-myc, a PS1 mutant that mimics phosphorylated PS1 increased cell proliferation as compared with wild-type PS1. These results indicate a regulatory mechanism in which GSK3β-mediated phosphorylation induces a structural change of the hydrophilic loop of PS1 thereby negatively modulating the formation of a ternary complex between β-catenin, PS1, and GSK3β, which leads to stabilization of β-catenin. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.