The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Regulatory B Subunits of Protein Phosphatase 2A Are Involved in Site-specific Regulation of Tau Protein Phosphorylation

  • Yu, Un Young (Department of Biochemistry, Ewha Womans University College of Medicine) ;
  • Yoo, Byong Chul (Colorectal Cancer Branch, Research Institute, National Cancer Center) ;
  • Ahn, Jung-Hyuck (Department of Biochemistry, Ewha Womans University College of Medicine)
  • Received : 2014.01.14
  • Accepted : 2014.02.28
  • Published : 2014.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Overexpression of amyloid precursor protein with the Swedish mutation causes abnormal hyperphosphorylation of the microtubule-associated protein tau. Hyperphosphorylated isoforms of tau are major components of neurofibrillary tangles, which are histopathological hallmarks of Alzheimer's disease. Protein phosphatase 2A (PP2A), a major tau protein phosphatase, consists of a structural A subunit, catalytic C subunit, and a variety of regulatory B subunits. The B subunits have been reported to modulate function of the PP2A holoenzyme by regulating substrate binding, enzyme activity, and subcellular localization. In the current study, we characterized regulatory B subunit-specific regulation of tau protein phosphorylation. We showed that the PP2A B subunit PPP2R2A mediated dephosphorylation of tau protein at Ser-199, Ser-202/Thr-205, Thr-231, Ser-262, and Ser-422. Down-regulation of PPP2R5D expression decreased tau phosphorylation at Ser-202/Thr-205, Thr-231, and Ser-422, which indicates activation of the tau kinase glycogen synthase kinase 3 beta ($GSK3{\beta}$) by PP2A with PPP2R5D subunit. The level of activating phosphorylation of the $GSK3{\beta}$ kinase Akt at Thr-308 and Ser-473 were both increased by PPP2R5D knockdown. We also characterized B subunit-specific phosphorylation sites in tau using mass spectrometric analysis. Liquid chromatography-mass spectrometry revealed that the phosphorylation status of the tau protein may be affected by PP2A, depending on the specific B subunits. These studies further our understanding of the function of various B subunits in mediating site-specific regulation of tau protein phosphorylation.

Keywords

References

  1. Alonso AC, Grundke-Iqbal I, Iqbal K. Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med. 1996;2: 783-787. https://doi.org/10.1038/nm0796-783
  2. Mairet-Coello G, Courchet J, Pieraut S, Courchet V, Maximov A, Polleux F. The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of A$\beta$ oligomers through Tau phosphorylation. Neuron. 2013;78:94-108. https://doi.org/10.1016/j.neuron.2013.02.003
  3. Louis JV, Martens E, Borghgraef P, Lambrecht C, Sents W, Longin S, Zwaenepoel K, Pijnenborg R, Landrieu I, Lippens G, Ledermann B, Götz J, Van Leuven F, Goris J, Janssens V. Mice lacking phosphatase PP2A subunit PR61/B'delta (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3beta. Proc Natl Acad Sci U S A. 2011;108:6957-6962. https://doi.org/10.1073/pnas.1018777108
  4. Liu Y, Su Y, Sun S, Wang T, Qiao X, Run X, Liang Z. Tau phosphorylation and $\mu$-calpain activation mediate the dexamethasone- induced inhibition on the insulin-stimulated Akt phosphorylation. PLoS One. 2012;7:e35783. https://doi.org/10.1371/journal.pone.0035783
  5. Choe MA, Koo BS, An GJ, Jeon S. Effects of treadmill exercise on the recovery of dopaminergic neuron loss and muscle atrophy in the 6-ohda lesioned parkinson's disease rat model. Korean J Physiol Pharmacol. 2012;16:305-312. https://doi.org/10.4196/kjpp.2012.16.5.305
  6. Mercado-Gómez O, Hernández-Fonseca K, Villavicencio-Queijeiro A, Massieu L, Chimal-Monroy J, Arias C. Inhibition of Wnt and PI3K signaling modulates GSK-3beta activity and induces morphological changes in cortical neurons: role of tau phosphorylation. Neurochem Res. 2008;33:1599-1609. https://doi.org/10.1007/s11064-008-9714-9
  7. Kuo YC, Huang KY, Yang CH, Yang YS, Lee WY, Chiang CW. Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt. J Biol Chem. 2008;283:1882-1892. https://doi.org/10.1074/jbc.M709585200
  8. Qian W, Shi J, Yin X, Iqbal K, Grundke-Iqbal I, Gong CX, Liu F. PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta. J Alzheimers Dis. 2010; 19:1221-1229. https://doi.org/10.3233/JAD-2010-1317
  9. Zhang H, Sun S, Herreman A, De Strooper B, Bezprozvanny I. Role of presenilins in neuronal calcium homeostasis. J Neurosci. 2010;30:8566-8580. https://doi.org/10.1523/JNEUROSCI.1554-10.2010
  10. Ahn JH, Sung JY, McAvoy T, Nishi A, Janssens V, Goris J, Greengard P, Nairn AC. The B"/PR72 subunit mediates Ca2+- dependent dephosphorylation of DARPP-32 by protein phosphatase 2A. Proc Natl Acad Sci U S A. 2007;104:9876-9881. https://doi.org/10.1073/pnas.0703589104
  11. Ahn JH, McAvoy T, Rakhilin SV, Nishi A, Greengard P, Nairn AC. Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56delta subunit. Proc Natl Acad Sci U S A. 2007;104:2979-2984. https://doi.org/10.1073/pnas.0611532104
  12. Margolis SS, Perry JA, Forester CM, Nutt LK, Guo Y, Jardim MJ, Thomenius MJ, Freel CD, Darbandi R, Ahn JH, Arroyo JD, Wang XF, Shenolikar S, Nairn AC, Dunphy WG, Hahn WC, Virshup DM, Kornbluth S. Role for the PP2A/B56delta phosphatase in regulating 14-3-3 release from Cdc25 to control mitosis. Cell. 2006;127:759-773. https://doi.org/10.1016/j.cell.2006.10.035
  13. Yu UY, Ahn JH. Phosphorylation on the PPP2R5D B regulatory subunit modulates the biochemical properties of protein phosphatase 2A. BMB Rep. 2010;43:263-267. https://doi.org/10.5483/BMBRep.2010.43.4.263
  14. Sontag JM, Nunbhakdi-Craig V, White CL 3rd, Halpain S, Sontag E. The protein phosphatase PP2A/B${alpha}$ binds to the microtubule-associated proteins Tau and MAP2 at a motif also recognized by the kinase Fyn: implications for tauopathies. J Biol Chem. 2012;287:14984-14993. https://doi.org/10.1074/jbc.M111.338681
  15. Salcedo-Tello P, Hernández-Ortega K, Arias C. Susceptibility to GSK3$\beta$-induced tau phosphorylation differs between the young and aged hippocampus after wnt signaling inhibition. J Alzheimers Dis. 2014;39:775-785.
  16. Shin J, Yu SB, Yu UY, Jo SA, Ahn JH. Swedish mutation within amyloid precursor protein modulates global gene expression towards the pathogenesis of Alzheimer's disease. BMB Rep. 2010;43:704-709. https://doi.org/10.5483/BMBRep.2010.43.10.704
  17. Park JH, Sung HY, Lee JY, Kim HJ, Ahn JH, Jo I. B56$\alpha$ subunit of protein phosphatase 2A mediates retinoic acid-induced decreases in phosphorylation of endothelial nitric oxide synthase at serine 1179 and nitric oxide production in bovine aortic endothelial cells. Biochem Biophys Res Commun. 2013; 430:476-481. https://doi.org/10.1016/j.bbrc.2012.12.011
  18. Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K. Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimers Dis. 2013;33 Suppl 1:S123-139.
  19. Kamat PK, Rai S, Swarnkar S, Shukla R, Ali S, Najmi AK, Nath C. Okadaic acid-induced Tau phosphorylation in rat brain: role of NMDA receptor. Neuroscience. 2013;238:97-113. https://doi.org/10.1016/j.neuroscience.2013.01.075
  20. Janssens V, Longin S, Goris J. PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem Sci. 2008;33:113-121. https://doi.org/10.1016/j.tibs.2007.12.004
  21. Li X, Virshup DM. Two conserved domains in regulatory B subunits mediate binding to the A subunit of protein phosphatase 2A. Eur J Biochem. 2002;269:546-552. https://doi.org/10.1046/j.0014-2956.2001.02680.x
  22. Ahn JH, Kim Y, Kim HS, Greengard P, Nairn AC. Protein kinase C-dependent dephosphorylation of tyrosine hydroxylase requires the B56$\delta$ heterotrimeric form of protein phosphatase 2A. PLoS One. 2011;6:e26292. https://doi.org/10.1371/journal.pone.0026292
  23. Creyghton MP, Roël G, Eichhorn PJ, Hijmans EM, Maurer I, Destrée O, Bernards R. PR72, a novel regulator of Wnt signaling required for Naked cuticle function. Genes Dev. 2005;19: 376-386. https://doi.org/10.1101/gad.328905
  24. Cho US, Xu W. Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature. 2007;445:53-57. https://doi.org/10.1038/nature05351
  25. Longin S, Zwaenepoel K, Louis JV, Dilworth S, Goris J, Janssens V. Selection of protein phosphatase 2A regulatory subunits is mediated by the C terminus of the catalytic Subunit. J Biol Chem. 2007;282:26971-26980. https://doi.org/10.1074/jbc.M704059200
  26. Arif M, Kazim SF, Grundke-Iqbal I, Garruto RM, Iqbal K. Tau pathology involves protein phosphatase 2A in Parkinsonism- dementia of Guam. Proc Natl Acad Sci U S A. 2014;111: 1144-1149. https://doi.org/10.1073/pnas.1322614111
  27. Sontag JM, Nunbhakdi-Craig V, Montgomery L, Arning E, Bottiglieri T, Sontag E. Folate deficiency induces in vitro and mouse brain region-specific downregulation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A B(alpha) subunit expression that correlate with enhanced tau phosphorylation. J Neurosci. 2008;28:11477-11487. https://doi.org/10.1523/JNEUROSCI.2816-08.2008
  28. Landrieu I, Smet-Nocca C, Amniai L, Louis JV, Wieruszeski JM, Goris J, Janssens V, Lippens G. Molecular implication of PP2A and Pin1 in the Alzheimer's disease specific hyperphosphorylation of Tau. PLoS One. 2011;6:e21521. https://doi.org/10.1371/journal.pone.0021521

Cited by

  1. Pathway Analysis Based on a Genome-Wide Association Study of Polycystic Ovary Syndrome vol.10, pp.8, 2014, https://doi.org/10.1371/journal.pone.0136609
  2. De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism vol.17, pp.1, 2014, https://doi.org/10.1007/s10048-015-0466-9
  3. Amyloid Beta-Mediated Hypomethylation of Heme Oxygenase 1 Correlates with Cognitive Impairment in Alzheimer’s Disease vol.11, pp.4, 2016, https://doi.org/10.1371/journal.pone.0153156
  4. Toward Neuroproteomics in Biological Psychiatry: A Systems Approach Unravels Okadaic Acid-Induced Alterations in the Neuronal Phosphoproteome vol.21, pp.9, 2014, https://doi.org/10.1089/omi.2017.0108
  5. Protein phosphatase 2A and tau: an orchestrated ‘Pas de Deux’ vol.592, pp.7, 2014, https://doi.org/10.1002/1873-3468.12907
  6. ERα36 gene silencing promotes tau protein phosphorylation, inhibits cell proliferation, and induces apoptosis in human neuroblastoma SH‐SY5Y cells vol.32, pp.12, 2014, https://doi.org/10.1096/fj.201701386
  7. To be or not to be: PP2A as a dual player in CNS functions, its role in neurodegeneration, and its interaction with brain insulin signaling vol.76, pp.12, 2014, https://doi.org/10.1007/s00018-019-03063-y
  8. UBE3A-mediated PTPA ubiquitination and degradation regulate PP2A activity and dendritic spine morphology vol.116, pp.25, 2014, https://doi.org/10.1073/pnas.1820131116
  9. Dysregulation of PP2A-Akt interaction contributes to Sucrose non-fermenting related kinase (SNRK) deficiency induced insulin resistance in adipose tissue vol.28, pp.None, 2019, https://doi.org/10.1016/j.molmet.2019.07.009
  10. Early‐Onset Parkinsonism Is a Manifestation of the PPP2R5D p.E200K Mutation vol.88, pp.5, 2014, https://doi.org/10.1002/ana.25863
  11. Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice vol.79, pp.1, 2021, https://doi.org/10.3233/jad-201015
  12. Altered Cerebrospinal Fluid Exosomal microRNA Levels in Young-Onset Alzheimer’s Disease and Frontotemporal Dementia vol.5, pp.1, 2021, https://doi.org/10.3233/adr-210311