Phosphorylation of Presenilin 1 at the Caspase Recognition Site Regulates Its Proteolytic Processing and the Progression of Apoptosis

Fluhrer, Regina; Friedlein, Arno; Haass, Christian; Walter, Jochen

doi:10.1074/jbc.m306653200

Cited by 57 publications

(47 citation statements)

References 63 publications

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“…2B). The weak phosphorylation of the S353D/S357D mutant is consistent with additional phosphorylation sites in the PS1 CTF besides Ser 353 and Ser 357 (15,31,32). Cell treatment with a GSK3␤ inhibitor decreased the phosphorylation of PS1-wt, but had little effect on that of PS1-S353D/S357D, indicating an involvement of GSK3␤ in the in vivo phosphorylation of PS1 at Ser 353 and Ser 357 (Fig.…”

Section: Gsk3␤ Phosphorylates the Ps1 Hydrophilic Loop At Positions 3supporting

confidence: 67%

A Structural Switch of Presenilin 1 by Glycogen Synthase Kinase 3β-mediated Phosphorylation Regulates the Interaction with β-Catenin and Its Nuclear Signaling

Prager

Wang-Eckhardt

Fluhrer

et al. 2007

Journal of Biological Chemistry

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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.

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Section: Gsk3␤ Phosphorylates the Ps1 Hydrophilic Loop At Positions 3supporting

confidence: 67%

A Structural Switch of Presenilin 1 by Glycogen Synthase Kinase 3β-mediated Phosphorylation Regulates the Interaction with β-Catenin and Its Nuclear Signaling

Prager

Wang-Eckhardt

Fluhrer

et al. 2007

Journal of Biological Chemistry

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“…However, when we performed restoration experiments for the defective PS-1 mutants, it was of great interest to find that their endoproteolyzed forms, NTF and CTF, had different effects on restoring the defective PS-1 mutants with regard to Notch cleavage. To date, NTF is known to interact with Pen-2, whereas CTF interacts with Nicastrin (45) and contains a caspase recognition site (43). The CTF of PS-2 has been shown to affect apoptosis (46), but the different biological functions and regulation of NTF and CTF have not been clearly documented yet.…”

Section: Discussionmentioning

confidence: 99%

Presenilin-1 D257A and D385A Mutants Fail to Cleave Notch in Their Endoproteolyzed Forms, but Only Presenilin-1 D385A Mutant Can Restore Its γ-Secretase Activity with the Compensatory Overexpression of Normal C-terminal Fragment

Kim¹,

Ki²,

Park

et al. 2005

Journal of Biological Chemistry

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The enzyme ␥-secretase is involved in the cleavage of several type I membrane proteins, such as Notch 1 and amyloid precursor protein. Presenilin-1 (PS-1) is one of the critical integral membrane protein components of the ␥-secretase complex and is processed endoproteolytically, generating N-and C-terminal fragments (NTF and CTF, respectively). PS-1 is also known to incorporate into a high molecular weight complex by binding to other ␥-secretase components such as Nicastrin, Aph-1, and Pen-2. Mutations on PS-1 can alter the effects of ␥-secretase on its many substrates to different extents. Here, we showed that PS-1 mutants have a different activity for Notch cleavage, which depended on the PS-1 mutation site. We demonstrated that defective PS-1 mutants located in CTF, i.e. D385A and C410Y, could restore their ␥-secretase activities with the compensatory overexpression of wild type CTF or of minimal deleted CTF (amino acids 349 -467). However, the defective PS-1 D257A mutant could not restore their ␥-secretase activities with the compensatory overexpression of wild type NTF. In comparison, both D257A NTF and D385A CTF could abolish the ␥-secretase activity of wild type and pathogenic PS-1 mutants. We also showed that PS-1 NTF but not CTF forms strong high molecular weight aggregates in SDS-PAGE. Taken together, results have shown that NTF and CTF integrate differently into high molecular weight aggregates and that PS-1 Asp-257 and Asp-385 have different accessibilities in their unendoproteolyzed conformation.

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“…Phosphorylation of PS1 at Ser397 by GSK3β (91) and at Thr354 by P35/ Cdk5 residue (17) regulates C-terminal fragment stability. PKA-mediated phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis, reducing the progression of apoptosis (92). Recent studies have shown that ERK1/2 is an endogenous negative regulator of γ-secretase, potentially through the direct phosphorylation of Nicastrin (93).…”

Section: Phosphorylation Of Presenilin-containing γ-Secretase Complexmentioning

confidence: 99%

Aberrant phosphorylation in the pathogenesis of Alzheimer's disease

Chung

2009

BMB Reports

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Phosphorylation of Presenilin 1 at the Caspase Recognition Site Regulates Its Proteolytic Processing and the Progression of Apoptosis

Cited by 57 publications

References 63 publications

A Structural Switch of Presenilin 1 by Glycogen Synthase Kinase 3β-mediated Phosphorylation Regulates the Interaction with β-Catenin and Its Nuclear Signaling

A Structural Switch of Presenilin 1 by Glycogen Synthase Kinase 3β-mediated Phosphorylation Regulates the Interaction with β-Catenin and Its Nuclear Signaling

Presenilin-1 D257A and D385A Mutants Fail to Cleave Notch in Their Endoproteolyzed Forms, but Only Presenilin-1 D385A Mutant Can Restore Its γ-Secretase Activity with the Compensatory Overexpression of Normal C-terminal Fragment

Aberrant phosphorylation in the pathogenesis of Alzheimer's disease

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