NF-kappaB has been implicated in the survival and differentiation of PC12 c
ells. In this study, we examined the effect of the NF-kappaB-inducing kinas
e (NIK) on these processes. When inducibly expressed in PC12 cells, a kinas
e-proficient but not -deficient form of NIK promoted neurite process format
ion and mediated anti-apoptotic signaling. As expected, NIK expression led
to I kappaB kinase activation and induced nuclear translocation of NF-kappa
B, However, NIK-induced neurite outgrowth was only partially blocked by con
comitant expression of a nondegradable form of I kappaB alpha that complete
ly blocks NF-kappaB induction. In search of additional signaling pathways a
ctivated by NIX, we now demonstrate that NIR. activates MEK1 phosphorylatio
n and induces the Erk1/Erk2 MAPK pathway. Treatment of PC12 cells with PD98
059, a MEK1 inhibitor, potently blocked neurite process formation; however,
a dominantly interfering mutant of the upstream Shc adapter failed to alte
r this response. These findings reveal a new function for MK as a MEK1-depe
ndent activator of the MAPK pathway and implicate both the I kappaB kinase
and MAPK signaling cascades in NIK-induced differentiation of PC12 cells.