The concerted signaling of ERK1/2 and JNKs is essential for PC12 cell neuritogenesis and converges at the level of target proteins.

Mitogen-activated protein kinase (MAPK) pathways are central signaling elements, which translate and integrate stimuli from cell surface receptors into cytoplasmic and transcriptional responses. Here, we systematically compare the role of MAPKs in the nerve growth factor-induced long-term differentiation of PC12 cells and show the persistent nuclear and dose-dependent cytoplasmic activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the increasing nuclear and cytoplasmic activation of c-Jun N-terminal kinases (JNKs). Inhibition of ERK1/2 and JNKs significantly reduced neurite outgrowth. Both synergistically controlled the expression of c-Jun, the induction and/or phosphorylation of neurofilament, and the phosphorylation of Elk-1. JNKs alone were responsible for the phosphorylation of c-Jun and activating transcription factor 2 as well as for the expression of MAPK phosphatase 1. In contrast, p38alpha was only transiently activated and marginally involved in these processes. Thus, JNKs and ERK1/2 accomplish differentiation by signaling in parallel cascades that converge only at the target level.