title: Cross talk between PI3K-AKT-GSK-3β and PP2A pathways determines tau hyperphosphorylation.
abstract: Glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) are the important enzymes controlling tau hyperphosphorylation. The relationship between these two enzymes and its impact on tau hyperphosphorylation are not well understood. In the present study, we determined the cross talk between PI3K-AKT-GSK-3β and PP2A pathways and found that the former regulated the methylation of PP2Ac via GSK-3β. Upregulation of GSK-3β led to an increase in the methylation and activity of PP2Ac through suppression of protein phosphatase methylesterase-1 expression and phosphorylation of leucine carboxyl methyltransferase 1. PP2A also regulated GSK-3β phosphorylation. Downregulation of PP2A enhanced Ser9 phosphorylation of GSK-3β and inhibited its kinase activity. Thus, GSK-3β and PP2A regulate each other and control tau phosphorylation both directly and indirectly through each other. Reduction of tau phosphorylation by inhibition of GSK-3β may be more than offset by inhibition of PP2A through a shift in phosphatase methylesterase-1/leucine carboxyl methyltransferase 1 balance; PP2A regulates phosphorylation of tau at Ser262/356, a required site for tau pathology. These findings suggest targeting PP2A rather than GSK-3β to inhibit tau pathology.
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China; Department of Immunology, Medical School, Nantong University, Nantong, Jiangsu, P. R. China.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China.
authors.forename: Riyun
authors.initials: R
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China; Department of Biochemistry and Molecular Biology, Medical School, Nantong University, Nantong, Jiangsu, P. R. China.
authors.forename: Jianlan
authors.initials: J
authors.lastname: Gu
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China; Department of Biochemistry and Molecular Biology, Medical School, Nantong University, Nantong, Jiangsu, P. R. China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Yin
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China; Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: Nana
authors.initials: N
authors.lastname: Jin
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China; Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: Shutao
authors.initials: S
authors.lastname: Xie
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China; Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Chang
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China; Department of Biochemistry and Molecular Biology, Medical School, Nantong University, Nantong, Jiangsu, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China; Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China; Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
authors.affiliation: Department of Immunology, Medical School, Nantong University, Nantong, Jiangsu, P. R. China. Electronic address: ccheng@ntu.edu.cn.
authors.forename: Chun
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, P. R. China; Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA. Electronic address: feiliu63@hotmail.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008745:Methylation; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation / Q000235:genetics; D011497:Protein O-Methyltransferase / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D002265:Carboxylic Ester Hydrolases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D019869:Phosphatidylinositol 3-Kinases; D011497:Protein O-Methyltransferase; D054648:Protein Phosphatase 2; D016875:tau Proteins; C524761:LCMT1 protein, human; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C119357:protein phosphatase methylesterase-1
keywords: Alzheimer's disease; GSK-3β; LCMT-1; PME-1; PP2A; Tau phosphorylation