The NF-κB-inducing kinase induces PC12 cell differentiation and prevents apoptosis

NF-κB has been implicated in the survival and differentiation of PC12 cells. In this study, we examined the effect of the NF-κB-inducing kinase (NIK) on these processes. When inducibly expressed in PC12 cells, a kinase-proficient but not -deficient form of NIK promoted neurite process formation and mediated anti-apoptotic signaling. As expected, NIK expression led to IκB kinase activation and induced nuclear translocation of NF-κB. However, NIK-induced neurite outgrowth was only partially blocked by concomitant expression of a nondegradable form of IκBα that completely blocks NF-κB induction. In search of additional signaling pathways activated by NIK, we now demonstrate that NIK activates MEK1 phosphorylation and induces the Erk1/Erk2 MAPK pathway. Treatment of PC12 cells with PD98059, a MEK1 inhibitor, potently blocked neurite process formation; however, a dominantly interfering mutant of the upstream Shc adapter failed to alter this response. These findings reveal a new function for NIK as a MEK1- dependent activator of the MAPK pathway and implicate both the IκB kinase and MAPK signaling cascades in NIK-induced differentiation of PC12 cells.