A structural switch of presenilin 1 by glycogen synthase kinase 3beta-mediated phosphorylation regulates the interaction with beta-catenin and its nuclear signaling.
Presenilins (PS) are critical components of the gamma-secretase complex that mediates cleavage of type I membrane proteins including the beta-amyloid precursor protein to generate the amyloid beta-peptide. In addition, PS1 interacts with beta-catenin and facilitates its metabolism. We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (GSK3beta) 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 beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin. The decreased interaction of PS1 with beta-catenin leads to stabilization of beta-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 GSK3beta-mediated phosphorylation induces a structural change of the hydrophilic loop of PS1 thereby negatively modulating the formation of a ternary complex between beta-catenin, PS1, and GSK3beta, which leads to stabilization of beta-catenin.
Prager
Kai
K
Department of Neurology, University of Bonn, Bonn, Germany.
Wang-Eckhardt
Lihua
L
Fluhrer
Regina
R
Killick
Richard
R
Barth
Esther
E
Hampel
Heike
H
Haass
Christian
C
Walter
Jochen
J
D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D010766:Phosphorylation; D053764:Presenilin-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013347:Subcellular Fractions; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D053764:Presenilin-1; D025801:Ubiquitin; D051176:beta Catenin; D008156:Luciferases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3