Tumor necrosis factor (TNF)-mediated kinase cascades: Bifurcation of Nuclear Factor-κB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2

Tumor necrosis factor (TNF)-mediated kinase cascades: Bifurcation of Nuclear Factor-κB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2

Tularik, Two Corporate Drive, South San Francisco, CA 94080

Contributed by David V. Goeddel

Abstract

TNF-induced activation of the transcription factor NF-κB and the c-jun N-terminal kinase (JNK/SAPK) requires TNF receptor-associated factor 2 (TRAF2). The NF-κB-inducing kinase (NIK) associates with TRAF2 and mediates TNF activation of NF-κB. Herein we show that NIK interacts with additional members of the TRAF family and that this interaction requires the conserved “WKI” motif within the TRAF domain. We also investigated the role of NIK in JNK activation by TNF. Whereas overexpression of NIK potently induced NF-κB activation, it failed to stimulate JNK activation. A kinase-inactive mutant of NIK was a dominant negative inhibitor of NF-κB activation but did not suppress TNF- or TRAF2-induced JNK activation. Thus, TRAF2 is the bifurcation point of two kinase cascades leading to activation of NF-κB and JNK, respectively.

Footnotes

↵ * Present address: Lilly Corporate Center, Building 98C-4, Indianapolis, IN 46285.
↵ † To whom reprint requests should be addressed. e-mail: rothe{at}tularik.com.
ABBREVIATIONS:

IL-1,

interleukin 1;

JNK (SAPK),

c-jun N-terminal kinase;

MAP kinase,

mitogen-activated protein kinase;

MAP3K,

mitogen-activated protein kinase kinase kinase;

NIK,

NF-κB-inducing kinase;

TNF,

tumor necrosis factor;

TRAF,

TNF receptor-associated factor;

MEKK1,

mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1;

HA,

hemagglutinin;

GST,

glutathione S-transferase