However, little is known about the physiological function of the PP2A heterotrimeric holoenzyme in regulating tau hyperphosphorylation in AD pathogenesis such as tauopathy. The activity of PP2A is regulated by protein kinases such as protein kinase A (PKA), protein kinase C (PKC), and also regulate the activity of several important kinases directly or indirectly. Four protein families of the B subunit exist, and the expression of several B subunits is abnormally altered in an AD model cell line. Another B subunit PPP2R5D involved in dopamine signaling pathway or cell cycle regulation with the phosphorylation on its Ser residues. PPP2R3A subunit contains two calcium ion-binding motif (EF-hand), and upon Ca 2+ binding, the activity of PP2A with PPP2R3A regulatory subunit is increased up to three times. PP2A is composed of a 36-kDa catalytic subunit, a 64-kDa structural subunit, and a variety of B subunits that regulate subcellular localization and enzyme specificity. PP2A regulates tau phosphorylation via direct or indirect mechanisms. Akt also forms a signaling protein complex with protein phosphatase 2A (PP2A), which is a known negative regulator of Akt through Thr-308 and/or Ser-473 dephosphorylation. The role of PP2A in the regulation of Akt activity has been shown in the pathways controlling cell growth and survival. Phosphorylation by phosphoinositide 3-kinase at Thr-308 and Ser-473 activates Akt, which in turn, phosphorylates GSK3β at inhibitory Ser-9, resulting in hypophosphorylated tau protein. The serine/threonine kinase Akt is a known regulator of GSK3β activity via phosphorylation. The most common tau protein kinases are cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 beta (GSK3β), and both have multiple phosphorylation sites in tau protein. Abnormally hyperphosphorylated tau causes misfolding and disruption of microtubules. Hyperphosphorylated tau protein is the major component of paired helical filaments and neurofibrillary tangles, which are diagnostic hallmarks of AD. These studies further our understanding of the function of various B subunits in mediating site-specific regulation of tau protein phosphorylation.Īlzheimer's disease (AD) is an age-dependent neurodegenerative disorder characterized by progressive memory decline and deterioration of cognitive function. Liquid chromatography-mass spectrometry revealed that the phosphorylation status of the tau protein may be affected by PP2A, depending on the specific B subunits. We also characterized B subunit-specific phosphorylation sites in tau using mass spectrometric analysis.
The level of activating phosphorylation of the GSK3β kinase Akt at Thr-308 and Ser-473 were both increased by PPP2R5D knockdown. 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 (GSK3β) by PP2A with PPP2R5D subunit. 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. In the current study, we characterized regulatory B subunit-specific regulation of tau protein phosphorylation. The B subunits have been reported to modulate function of the PP2A holoenzyme by regulating substrate binding, enzyme activity, and subcellular localization. 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. Hyperphosphorylated isoforms of tau are major components of neurofibrillary tangles, which are histopathological hallmarks of Alzheimer's disease. Overexpression of amyloid precursor protein with the Swedish mutation causes abnormal hyperphosphorylation of the microtubule-associated protein tau.
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