Activation of glycogen synthase kinase-3 inhibits protein phosphatase-2A and the underlying mechanisms.
The activity of protein phosphatase-2A (PP-2A) is significantly suppressed in the brain of Alzheimer's disease (AD) patients, but the mechanism is not understood. Here, we found an in vivo association of glycogen synthase kinase 3beta (GSK-3beta) with inhibitor-2 of PP-2A (I(2)(PP-2A)). The activation of GSK-3 resulted in accumulation of I(2)(PP-2A) with concomitant suppression of PP-2A activity and increases of tau phosphorylation in HEK293, N2a and PC12 cells, while inhibition of GSK-3 caused decreases of I(2)(PP-2A) with increased PP-2A activity and decreased tau phosphorylation. A positive correlation between GSK-3beta and I(2)(PP-2A) (R=0.9158) and a negative correlation between GSK-3beta and PP-2A (R=-0.9166) were detected. GSK-3 activation did not affect I(2)(PP-2A) mRNA level, while it increased the mRNA level of a heterogeneous ribonucleoprotein A18 (hnRNP A18). The activation of GSK-3 increased the expression and the activity of proteasome system. It suggests that activation of GSK-3 inhibits PP-2A through up-regulation of I(2)(PP-2A) with hnRNP A18-involved mechanism.
Liu
Gong-Ping
GP
Pathophysiology Department, Key Laboratory of Neurological Disease of Hubei Province, Tongji Medical College, Hua-Zhong University of Science and Technology, Wuhan 430030, PR China.
Zhang
Yao
Y
Yao
Xiu-Qing
XQ
Zhang
Chang-E
CE
Fang
Jiang
J
Wang
Qun
Q
Wang
Jian-Zhi
JZ
D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000008:administration & dosage*; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D056488:Histone Chaperones; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000008:administration & dosage*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C513473:SET protein, human; D014157:Transcription Factors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2