The NF-kappa B-inducing kinase induces PC12 cell differentiation and prevents apoptosis.
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.
Foehr
E D
ED
Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94141, USA. efoehr@gladstone.ucsf.edu
Bohuslav
J
J
Chen
L F
LF
DeNoronha
C
C
Geleziunas
R
R
Lin
X
X
O'Mahony
A
A
Greene
W C
WC
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D009841:Oligonucleotides; D016716:PC12 Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction; D000097782:NF-kappaB-Inducing Kinase
D009841:Oligonucleotides; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase