Cyclic AMP-induced neuronal differentiation via activation of p38 mitogen-activated protein kinase

The p38 mitogen-activated protein kinase (MAPK) pathway mediates cellular responses to inflammatory cytokines and environmental stress, but recent studies have indicated that p38 MAPK may be involved in a more widespread set of cellular functions. Here we show that activation of the cyclic AMP (cAMP) pathway induces a rapid, dose-dependent phosphorylation and activation of p38 MAPK and that combined stimulation with forskolin and growth factors results in additive stimulation of p38 MAPK. Forskolin-stimulated neurite out-growth in rat pheochromocytoma PC12 cells was inhibited by the p38 MAPK inhibitor SB203580. With the combination of forskolin and nerve growth factor, neurite outgrowth was additively increased, and this effect was also inhibited by SB203580. Finally, transfection of p38AGF, which exhibits a mutated activation loop, inhibited cAMP-mediated neuronal differentiation. The results indicate that p38 MAPK is a downstream target of the cAMP signaling pathway and that p38 MAPK plays a key role in neuronal differentiation induced by cAMP and growth factors by integration of signals from both pathways.