Abstract
NF-kappa B has been implicated in the survival and differentiation of PC12 cells. In this study, we examined the effect of the NF-kappa B-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 I kappa B kinase activation and induced nuclear translocation of NF-kappa B. However, NIK-induced neurite outgrowth was only partially blocked by concomitant expression of a nondegradable form of I kappa B alpha that completely blocks NF-kappa B 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 I kappa B kinase and MAPK signaling cascades in NIK-induced differentiation of PC12 cells.
Highlights
From the ‡Gladstone Institute of Virology and Immunology and the Departments of ¶Medicine and ʈMicrobiology and Immunology, University of California, San Francisco, California 94141
In search of additional signaling pathways activated by NF-B-inducing kinase (NIK), we 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; a dominantly interfering mutant of the upstream Shc adapter failed to alter this response. These findings reveal a new function for NIK as a MEK1dependent activator of the MAPK pathway and implicate both the IB kinase and MAPK signaling cascades in NIK-induced differentiation of PC12 cells
Summary
When inducibly expressed in PC12 cells, a kinase-proficient but not -deficient form of NIK promoted neurite process formation and mediated anti-apoptotic signaling. These findings reveal a new function for NIK as a MEK1dependent activator of the MAPK pathway and implicate both the IB kinase and MAPK signaling cascades in NIK-induced differentiation of PC12 cells.
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