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J. Biol. Chem., Vol. 275, Issue 44, 34021-34024, November 3, 2000

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ACCELERATED PUBLICATION
The NF-B-inducing Kinase Induces PC12 Cell Differentiation and Prevents Apoptosis^*

Erik D. Foehr^§, Jan Bohuslav, Lin-Feng Chen, Carlos DeNoronha, Romas Geleziunas, Xin Lin, Alison O'Mahony, and Warner C. Greene^¶

From the  Gladstone Institute of Virology and Immunology and the Departments of ^¶ Medicine and  Microbiology and Immunology, University of California, San Francisco, California 94141

NF-B has been implicated in the survival and differentiation of PC12 cells. In this study, we examined the effect of the NF-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 IB kinase activation and induced nuclear translocation of NF-B. However, NIK-induced neurite outgrowth was only partially blocked by concomitant expression of a nondegradable form of IB that completely blocks NF-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 IB kinase and MAPK signaling cascades in NIK-induced differentiation of PC12 cells.

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