Title | GSK-3β is Dephosphorylated by PP2A in a Leu309 Methylation-Independent Manner. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Chu, D, Tan, J, Xie, S, Jin, N, Yin, X, Gong, C-X, Iqbal, K, Liu, F |
Journal | J Alzheimers Dis |
Volume | 49 |
Issue | 2 |
Pagination | 365-75 |
Date Published | 2016 |
ISSN | 1875-8908 |
Keywords | Animals, Brain, Carboxylic Ester Hydrolases, Cell Line, Transformed, Dose-Response Relationship, Drug, Enzyme Inhibitors, Excitatory Amino Acid Agonists, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Kainic Acid, Leucine, Luminescent Proteins, Male, Methylation, Mice, Phosphorylation, Protein O-Methyltransferase, Protein Phosphatase 2, RNA, Small Interfering, Serine, tau Proteins |
Abstract | 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. |
DOI | 10.3233/JAD-150497 |
Alternate Journal | J. Alzheimers Dis. |
PubMed ID | 26484916 |