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 ␥-secretase complex that mediates cleavage of type I membrane proteins including the ␤-amyloid precursor protein to generate the amyloid ␤-peptide. In addition, PS1 interacts with ␤-catenin and facilitates its metabolism. We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3␤ (GSK3␤) 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 ␤-catenin leading to decreased phosphorylation and ubiquitination of ␤-catenin. The decreased interaction of PS1 with ␤-catenin leads to stabilization of ␤-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 GSK3␤-mediated phosphorylation induces a structural change of the hydrophilic loop of PS1 thereby negatively modulating the formation of a ternary complex between ␤-catenin, PS1, and GSK3␤, which leads to stabilization of ␤-catenin.

Dictyostelium possesses highly diverged presenilin/γ-secretase that regulates growth and cell-fate specification and can accurately process human APP: a system for functional studies of the presenilin/γ-secretase complex

“…Still, we recognize that the PS complex might have functions that are not fully dependent upon its proteolytic activity. Mammalian PS can interact with glycogen synthase kinase 3 (GSK3) and potentially function as a scaffold (Kang et al, 2002;Prager et al, 2007;Tesco and Tanzi, 2000). Although in Dictyostelium both PS and GSK3 promote prespore differentiation (Kim et al, 2002;Kim et al, 1999;Plyte et al, 1999), we have been unable to detect a physical interaction of Dictyostelium PS1 with either Dictyostelium or mammalian GSK3 in vivo or in vitro (data not shown).…”

Presenilin 1 Affects Focal Adhesion Site Formation and Cell Force Generation via c-Src Transcriptional and Posttranslational Regulation

“…PS1 can serve also cellular functions independent of ␥-secretase activity (31,32). To assess whether the role of PS1 in cellmatrix adhesion involves the activity of the ␥-secretase complex, we pharmacologically inhibited the protease activity with DAPT (33,34).…”

Zinc-Dependent Interaction between JAB1 and Pre-S 2 Mutant Large Surface Antigen of Hepatitis B Virus and Its Implications for Viral Hepatocarcinogenesis

“…Thus, the finding that its association with ⌬2 LHBS was stimulated by Zn 2ϩ ions has raised the possibility that activation of its protease promotes the assembly of the protein complex. There are many examples of this type of protein interacting with and inducing conformational changes of their substrates (34)(35)(36)(37)(38)(39). Interestingly, two putative ubiquitination sites were identified in ⌬2 LHBS, which suggested the hypothesis that ⌬2 LHBS undergoes deubiquitination processes catalyzed by JAB1.…”