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-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.
Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Co-innovation Center of Neuroregeneration, Nantong, PR China.
Dandan
D
Chu
Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Co-innovation Center of Neuroregeneration, Nantong, PR China.
Jianxin
J
Tan
Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Co-innovation Center of Neuroregeneration, Nantong, PR China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Shutao
S
Xie
Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Co-innovation Center of Neuroregeneration, Nantong, PR China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Nana
N
Jin
Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Co-innovation Center of Neuroregeneration, Nantong, PR China.
Xiaomin
X
Yin
Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Cheng-Xin
CX
Gong
Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Khalid
K
Iqbal
Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Co-innovation Center of Neuroregeneration, Nantong, PR China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Fei
F
Liu
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D007930:Leucine / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011497:Protein O-Methyltransferase / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D008164:Luminescent Proteins; D034741:RNA, Small Interfering; C413663:fluorescent protein 583; D016875:tau Proteins; D012694:Serine; C586068:Lcmt1 protein, mouse; D011497:Protein O-Methyltransferase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1; D054648:Protein Phosphatase 2; D007930:Leucine; D007608:Kainic Acid
GSK-3β; PP2A; methylation; phosphorylation