Hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer’s disease (AD) and related tauopathies. Glycogen synthase kinase-3β (GSK-3β) and protein phosphate 2A (PP2A) are crucial enzymes to regulate tau phosphorylation. GSK-3β activity is regulated by its inhibitory phosphorylation at Ser9. We previously reported the cross-talk between GSK-3β and PP2A signaling and showed that PP2A could dephosphorylate GSK-3β at Ser9. Here, we investigated the dephosphorylation of GSK-3β in brain extracts in the presence of phosphatase inhibitors and found that a PP2A-like phosphatase activity was required for dephosphorylation of GSK-3β at Ser9. PP2A interacted with GSK-3β and suppressed its Ser9 phosphorylation in vitro and in HEK-293FT cells. Activity of PP2A negatively correlated to the level of phosphorylated GSK-3β in kainic acid-induced excitotoxic mouse brain. Alteration of methylation of the catalytic subunit of PP2A (PP2Ac) at Leu309 did not affect GSK-3β phosphorylation. These findings suggest that Leu309 methylation is not required for PP2A to dephosphorylate GSK-3β at Ser9.
JopeRSJohnsonGV2004The glamour and gloom of glycogen synthase kinase-3Trends Biochem Sci2995102
2.
LauKFMillerCCAndertonBHShawPC1999Expression analysis of glycogen synthase kinase-3 in human tissuesJ Pept Res548591
3.
LovestoneSReynoldsCHLatimerDDavisDRAndertonBHGalloJMHangerDMulotSMarquardtBStabelS1994Alzheimer’s disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cellsCurr Biol410771086
4.
LiuFLiBTungEJGrundke-IqbalIIqbalKGongCX2007Site-specific effects of tau phosphorylation on its microtubule assembly activity and self-aggregationEur J Neurosci2634293436
5.
WangJZWuQSmithAGrundke-IqbalIIqbalK1998Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinaseFEBS Lett4362834
6.
PeiJJBraakEBraakHGrundke-IqbalIIqbalKWinbladBCowburnRF1999Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changesJ Neuropathol Exp Neurol5810101019
7.
LeroyKYilmazZBrionJP2007Increased level of active GSK-3beta in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degenerationNeuropathol Appl Neurobiol334355
8.
Llorens-MartinMJuradoJHernandezFAvilaJ2014GSK-3beta, a pivotal kinase in Alzheimer diseaseFront Mol Neurosci746
9.
CrossDAAlessiDRCohenPAndjelkovichMHemmingsBA1995Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase BNature378785789
10.
FangXYuSXLuYBastRCJrWoodgettJRMillsGB2000Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase AProc Natl Acad Sci U S A971196011965
11.
Etienne-MannevilleSHallA2003Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarityNature421753756
12.
LeeCWLauKFMillerCCShawPC2003Glycogen synthase kinase-3 beta-mediated tau phosphorylation in cultured cell linesNeuroreport14257260
13.
BakiLShioiJWenPShaoZSchwarzmanAGama-SosaMNeveRRobakisNK2004PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: Effects of FAD mutationsEMBO J2325862596
14.
MartinezACastroADorronsoroIAlonsoM2002Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammationMed Res Rev22373384
15.
MorfiniGSzebenyiGBrownHPantHCPiginoGdeboerSBeffertUBradyST2004A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neuronsEMBO J2322352245
16.
LeeYISeoMKimYKimSYKangUGKimYSJuhnnYS2005Membrane depolarization induces the undulating phosphorylation/dephosphorylation of glycogen synthase kinase 3beta, and this dephosphorylation involves protein phosphatases 2A and 2B in SH-SY5Y human neuroblastoma cellsJ Biol Chem2802204422052
17.
SutherlandCLeightonIACohenP1993Inactivation of glycogen synthase kinase-3 beta by phosphorylation: New kinase connections in insulin and growth-factor signallingBiochem J296Pt 11519
18.
VirshupDMShenolikarS2009From promiscuity to precision: Protein phosphatases get a makeoverMol Cell33537545
19.
LiuFGrundke-IqbalIIqbalKGongCX2005Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylationEur J Neurosci2219421950
20.
GongCXSinghTJGrundke-IqbalIIqbalK1993Phosphoprotein phosphatase activities in Alzheimer disease brainJ Neurochem61921927
21.
ChenJMartinBLBrautiganDL1992Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylationScience25712611264
22.
OgrisEGibsonDMPallasDC1997Protein phosphatase 2A subunit assembly: The catalytic subunit carboxy terminus is important for binding cellular B subunit but not polyomavirus middle tumor antigenOncogene15911917
23.
JanssensVLonginSGorisJ2008PP2A holoenzyme assembly: In cauda venenum (the sting is in the tail)Trends Biochem Sci33113121
24.
LonginSZwaenepoelKLouisJVDilworthSGorisJJanssensV2007Selection of protein phosphatase 2A regulatory subunits is mediated by the C terminus of the catalytic SubunitJ Biol Chem2822697126980
25.
LeeJChenYTolstykhTStockJ1996A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brainProc Natl Acad Sci U S A9360436047
26.
OgrisEDuXNelsonKCMakEKYuXXLaneWSPallasDC1999A protein phosphatase methylesterase (PME-1) is one of several novel proteins stably associating with two inactive mutants of protein phosphatase 2AJ Biol Chem2741438214391
27.
ZhouXWGustafssonJATanilaHBjorkdahlCLiuRWinbladBPeiJJ2008Tau hyperphosphorylation correlates with reduced methylation of protein phosphatase 2ANeurobiol Dis31386394
28.
SontagENunbhakdi-CraigVSontagJMDiaz-ArrastiaROgrisEDayalSLentzSRArningEBottiglieriT2007Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulationJ Neurosci2727512759
29.
WangYYangRGuJYinXJinNXieSChangHQianWShiJIqbalKGongCXChengCLiuF2015Cross talk between PI3K-AKT-GSK-3beta and PP2A pathways determines tau hyperphosphorylationNeurobiol Aging36188200
30.
LiangZLiuFIqbalKGrundke-IqbalIGongCX2009Dysregulation of tau phosphorylation in mouse brain during excitotoxic damageJ Alzheimers Dis17531539
31.
GongCXShaikhSGrundke-IqbalIIqbalK1996Inhibition of protein phosphatase-2B (calcineurin) activity towards Alzheimer abnormally phosphorylated tau by neurolepticsBrain Res74195102
32.
CohenP1991Classification of protein-serine/threonine phosphatases: Identification and quantitation in cell extractsMethods Enzymol201389398
33.
HernandezFLangaECuadrosRAvilaJVillanuevaN2010Regulation of GSK3 isoforms by phosphatases PP1 and PP2AMol Cell Biochem344211215
34.
SontagJMSontagE2014Protein phosphatase 2A dysfunction in Alzheimer’s diseaseFront Mol Neurosci716
35.
SontagELuangpiromAHladikCMudrakIOgrisESpecialeSWhiteCL3rd2004Altered expression levels of the protein phosphatase 2A abalphac enzyme are associated with Alzheimer disease pathologyJ Neuropathol Exp Neurol63287301
36.
SontagEHladikCMontgomeryLLuangpiromAMudrakIOgrisEWhiteCL3rd2004Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesisJ Neuropathol Exp Neurol6310801091
37.
SontagJMNunbhakdi-CraigVWhiteCL3rdHalpainSSontagE2012The protein phosphatase PP2A/Balpha binds to the microtubule-associated proteins tau and MAP2 at a motif also recognized by the kinase Fyn: Implications for tauopathiesJ Biol Chem2871498414993
38.
SontagJMNunbhakdi-CraigVSontagE2013Leucine carboxyl methyltransferase 1 (LCMT1)-dependent methylation regulates the association of protein phosphatase 2A and Tau protein with plasma membrane microdomains in neuroblastoma cellsJ Biol Chem2882739627405
39.
TanimukaiHGrundke-IqbalIIqbalK2005Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer’s diseaseAm J Pathol16617611771
40.
ChenSLiBGrundke-IqbalIIqbalK2008I1PP2A affects tau phosphorylation via association with the catalytic subunit of protein phosphatase 2AJ Biol Chem2831051310521
41.
ArifMWeiJZhangQLiuFBasurto-IslasGGrundke-IqbalIIqbalK2014Cytoplasmic retention of protein phosphatase 2A inhibitor 2 (I2PP2A) induces Alzheimer-like abnormal hyperphosphorylation of TauJ Biol Chem2892767727691
42.
WangXBlanchardJTungYCGrundke-IqbalIIqbalK2015Inhibition of protein phosphatase-2A (PP2A) by I1PP2A leads to hyperphosphorylation of tau, neurodegeneration, and cognitive impairment in ratsJ Alzheimers Dis45423435
43.
SchmidtKKinsSSchildANitschRMHemmingsBAGotzJ2002Diversity, developmental regulation and distribution of murine PR55/B subunits of protein phosphatase 2AEur J Neurosci1620392048
44.
MartensEStevensIJanssensVVermeeschJGotzJGorisJVan HoofC2004Genomic organisation, chromosomal localisation tissue distribution and developmental regulation of the PR61/B’ regulatory subunits of protein phosphatase 2A in miceJ Mol Biol336971986
45.
HendrixPMayer-JackelRECronPGorisJHofsteengeJMerlevedeWHemmingsBA1993Structure and expression of a 72-kda regulatory subunit of protein phosphatase 2A. Evidence for different size forms produced by alternative splicingJ Biol Chem2681526715276
46.
LouisJVMartensEBorghgraefPLambrechtCSentsWLonginSZwaenepoelKPijnenborgRLandrieuILippensGLedermannBGotzJVan LeuvenFGorisJJanssensV2011Mice lacking phosphatase PP2A subunit PR61/b’delta (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3betaProc Natl Acad Sci U S A10869576962
47.
YaoXQZhangXXYinYYLiuBLuoDJLiuDChenNNNiZFWangXWangQWangJZLiuGP2011Glycogen synthase kinase-3beta regulates Tyr307 phosphorylation of protein phosphatase-2A via protein tyrosine phosphatase 1B but not SrcBiochem J437335344
48.
YaoXQLiXCZhangXXYinYYLiuBLuoDJWangQWangJZLiuGP2012Glycogen synthase kinase-3beta regulates leucine-309 demethylation of protein phosphatase-2A via PPMT1 and PME-1FEBS Lett58625222528
