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 3β (GSK-3β) with inhibitor-2 of PP-2A (I2PP-2A). The activation of GSK-3 resulted in accumulation of I2PP-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 I2PP-2A with increased PP-2A activity and decreased tau phosphorylation. A positive correlation between GSK-3β and I2PP-2A (R = 0.9158) and a negative correlation between GSK-3β and PP-2A (R = −0.9166) were detected. GSK-3 activation did not affect I2PP-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 I2PP-2A with hnRNP A18-involved mechanism.