Regulatory B Subunits of Protein Phosphatase 2A Are Involved in Site-specific Regulation of Tau Protein Phosphorylation.
10.4196/kjpp.2014.18.2.155
- Author:
Un Young YU
1
;
Byong Chul YOO
;
Jung Hyuck AHN
Author Information
1. Department of Biochemistry, Ewha Womans University College of Medicine, Seoul 158-710, Korea. ahnj@ewha.ac.kr
- Publication Type:Original Article
- Keywords:
Alzheimer's disease;
Phosphorylation;
Protein phosphatase 2A;
Tau protein
- MeSH:
Alzheimer Disease;
Amyloid;
Catalytic Domain;
Down-Regulation;
Glycogen Synthase Kinase 3;
Negotiating;
Neurofibrillary Tangles;
Phosphorylation*;
Phosphotransferases;
Protein Isoforms;
Protein Phosphatase 2*;
Spectrum Analysis;
tau Proteins*
- From:The Korean Journal of Physiology and Pharmacology
2014;18(2):155-161
- CountryRepublic of Korea
- Language:English
-
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 (GSK3beta) by PP2A with PPP2R5D subunit. The level of activating phosphorylation of the GSK3beta 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.
