Interactions Between Glycogen Synthase Kinase 3β,Protein Kinase B,and Protein Phosphatase 2A in Tau Phosphorylation in Mouse N2a Neuroblastoma Cells

Abstract

In this study, we investigated how tau phosphorylation is regulated by protein kinase glycogen synthase kinase 3β (GSK3β), protein kinase B (PKB), and protein phosphatase 2A (PP2A) in mouse N2a neuroblastoma cells. Results showed that GSK3β overexpression significantly increased PKB phosphorylation at the S473 site but not the T308 site. Neither GSK3β nor PKB overexpression could reduce the PP2A_C phosphorylation at the Y307 site. In contrast, either PKB or GSK3β knockdown could increase PP2A phosphorylation at the Y307 site. PP2A_C knockdown increased GSK3β phosphorylation at the S9 site but not at the Y216 site, and PKB phosphorylation at the T308 site but not at the S473 site. Tau phosphorylation at the S396 site was increased by GSK3β or PKB overexpression. Tau phosphorylation at the S214 site was only induced by PKB overexpression in the study. While GSK3β knockdown decreased tau phosphorylation at the S396 site, PKB knockdown increased tau phosphorylation at both the S396 and S214 sites. PP2A_C knockdown decreased tau phosphorylation at the S396 and S214 sites. These findings suggest that tau phosphorylation at the S396 and S214 sites is differentially regulated by GSK3β, PKB, and PP2A in N2a cells. The final phosphorylation state of tau is possibly caused by the synergic action of the three enzymes.