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J. Biol. Chem., Vol. 275, Issue 48, 37966-37977, December 1, 2000
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From the To understand the mechanism of activation of the
I
Activation of the I
B Kinases by RIP via IKK
/NEMO-mediated
Oligomerization*
,
,,,, and¶
Center for Apoptosis Research and the
Department of Microbiology and Immunology, Kimmel Cancer Institute,
Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and the
§ Department of Microbiology, Tokyo Medical and Dental
University, School of Medicine, Yushima 1-5-45, Bunkyo-ku,
Tokyo 113-8519, Japan
B kinase (IKK) complex in the tumor necrosis factor (TNF)
receptor 1 pathway, we examined the possibility that
oligomerization of the IKK complex triggered by ligand-induced
trimerization of the TNF receptor 1 complex is responsible for
activation of the IKKs. Gel filtration analysis of the IKK complex
revealed that TNF
stimulation induces a large increase in the size
of this complex, suggesting oligomerization. Substitution of the
C-terminal region of IKK
, which interacts with RIP, with a truncated
DR4 lacking its cytoplasmic death domain, produced a molecule that
could induce IKK and NF-B activation in cells in response to TRAIL.
Enforced oligomerization of the N terminus of IKK or truncated
IKK or IKK
lacking their serine-cluster domains can also induce
IKK and NF-B activation. These data suggest that IKK functions as
a signaling adaptor between the upstream regulators such as RIP and the
IKKs and that oligomerization of the IKK complex by upstream regulators
is a critical step in activation of this complex.
*
This work was supported by National Institutes of Health
Grants CA78890 and CA85421 (to E. S. A) and CA38047 (to
P. N. T.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Special Fellow of the Leukemia and Lymphoma Society.
¶
To whom correspondence should be addressed. Tel.:
215-503-4632; Fax: 215-923-1098; Email:
E_Alnemri@lac.jci.tju.edu.
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