Inhibition of glycogen synthase kinase-3β (GSK3β) is one of the mechanisms by which phosphatidylinositol 3-kinase (PI3K) activation protects neurons from apoptosis. Here, we report that inhibition of ERK1/2 increased the basal activity of GSK3β in cortical neurons and that both ERK1/2 and PI3K were required for brain-derived neurotrophic factor (BDNF) suppression of GSK3β activity. Moreover, cortical neuron apoptosis induced by expression of recombinant GSK3β was inhibited by coexpression of constitutively active MKK1 or PI3K. Activation of both endogenous ERK1/2 and PI3K signaling pathways was required for BDNF to block apoptosis induced by expression of recombinant GSK3β. Furthermore, cortical neuron apoptosis induced by LY294002-mediated activation of endogenous GSK3β was blocked by expression of constitutively active MKK1 or by BDNF via stimulation of the endogenous ERK1/2 pathway. Although both PI3K and ERK1/2 inhibited GSK3β activity, neither had an effect on GSK3β phosphorylation at Tyr-216. Interestingly, PI3K (but not ERK1/2) induced the inhibitory phosphorylation of GSK3β at Ser-9. Significantly, coexpression of constitutively active MKK1 (but not PI3K) still suppressed neuronal apoptosis induced by expression of the GSK3β(S9A) mutant. These data suggest that activation of the ERK1/2 signaling pathway protects neurons from GSK3β-induced apoptosis and that inhibition of GSK3β may be a common target by which ERK1/2 and PI3K protect neurons from apoptosis. Furthermore, ERK1/2 inhibits GSK3β activity via a novel mechanism that is independent of Ser-9 phosphorylation and likely does not involve Tyr-216 phosphorylation.
Tau phosphorylation by glycogen synthase kinase 3β modulates enzyme acetylcholinesterase expression
