Research Paper Volume 11, Issue 21 pp 9672—9688
Glycogen synthase kinase-3β suppresses the expression of protein phosphatase methylesterase-1 through β-catenin
- 1 Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China
- 2 Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA
Received: May 15, 2019 Accepted: October 28, 2019 Published: November 12, 2019
https://doi.org/10.18632/aging.102413How to Cite
Copyright © 2019 Jin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Protein phosphatase 2A (PP2A) is the major tau phosphatase. Its activity toward tau is regulated by the methylation of PP2A catalytic subunit (PP2Ac) at Leu309. Protein phosphatase methylesterase-1 (PME-1) demethylates PP2Ac and suppresses its activity. We previously found that glycogen synthase kinase-3β (GSK-3β) suppresses PME-1 expression. However, the underlying molecular mechanism is unknown. In the present study, we analyzed the promoter of PME-1 gene and found that human PME-1 promoter contains two lymphoid enhancer binding factor-1/T-cell factor (LEF1/TCF) cis-elements in which β-catenin serves as a co-activator. β-catenin acted on these two cis-elements and promoted PME-1 expression. GSK-3β phosphorylated β-catenin and suppressed its function in promoting PME-1 expression. Inhibition and activation of GSK-3β by PI3K-AKT pathway promoted and suppressed, respectively, PME-1 expression in primary cultured neurons, SH-SY5Y cells and in the mouse brain. These findings suggest that GSK-3β phosphorylates β-catenin and suppresses its function on PME-1 expression, resulting in an increase of PP2Ac methylation.