GSK-3β is Dephosphorylated by PP2A in a Leu309 Methylation-Independent Manner

Hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase-3 beta (GSK-3 beta) and protein phosphate 2A (PP2A) are crucial enzymes to regulate tau phosphorylation. GSK-3 beta activity is regulated by its inhibitory phosphorylation at Ser9. We previously reported the cross-talk between GSK-3 beta and PP2A signaling and showed that PP2A could dephosphorylate GSK-3 beta at Ser9. Here, we investigated the dephosphorylation of GSK-3 beta in brain extracts in the presence of phosphatase inhibitors and found that a PP2A-like phosphatase activity was required for dephosphorylation of GSK-3 beta at Ser9. PP2A interacted with GSK-3 beta and suppressed its Ser9 phosphorylation in vitro and in HEK-293FT cells. Activity of PP2A negatively correlated to the level of phosphorylated GSK-3 beta in kainic acid-induced excitotoxic mouse brain. Alteration of methylation of the catalytic subunit of PP2A (PP2Ac) at Leu309 did not affect GSK-3 beta phosphorylation. These findings suggest that Leu309 methylation is not required for PP2A to dephosphorylate GSK-3 beta at Ser9.