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Molecular and Cellular Biology, February 2000, p. 1170-1178, Vol. 20, No. 4
Gladstone Institute of Virology and
Immunology1 and Departments of Medicine,
Microbiology and Immunology,2 University of
California, San Francisco, California 94141
Received 16 September 1999/Returned for modification 21 October
1999/Accepted 10 November 1999
Signal-induced nuclear expression of the eukaryotic NF-
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Activation of the Heterodimeric I
B Kinase
(IKK
)-IKK
Complex Is Directional: IKK
Regulates IKK
under Both Basal
and Stimulated Conditions
B
transcription factor involves the stimulatory action of select
mitogen-activated protein kinase kinase kinases on the I
B kinases
(IKK
and IKK
) which reside in a macromolecular signaling complex
termed the signalsome. While genetic studies indicate that IKK
is
the principal kinase involved in proinflammatory cytokine-induced I
B
phosphorylation, the function of the equivalently expressed IKK
is
less clear. Here we demonstrate that assembly of IKK
with IKK
in
the heterodimeric signalsome serves two important functions: (i) in
unstimulated cells, IKK
inhibits the constitutive I
B kinase
activity of IKK
; (ii) in activated cells, IKK
kinase activity is
required for the induction of IKK
. The introduction of
kinase-inactive IKK
, activation loop mutants of IKK
, or IKK
antisense RNA into 293 or HeLa cells blocks NIK (NF-
B-inducing
kinase)-induced phosphorylation of the IKK
activation loop occurring
in functional signalsomes. In contrast, catalytically inactive mutants
of IKK
do not block NIK-mediated phosphorylation of IKK
in these
macromolecular signaling complexes. This requirement for
kinase-proficient IKK
to activate IKK
in heterodimeric IKK
signalsomes is also observed with other NF-
B inducers, including
tumor necrosis factor alpha, human T-cell leukemia virus type 1 Tax,
Cot, and MEKK1. Conversely, the
isoform of protein kinase C, which
also induces NF-
B/Rel, directly targets IKK
for phosphorylation
and activation, possibly acting through homodimeric IKK
complexes.
Together, our findings indicate that activation of the heterodimeric
IKK complex by a variety of different inducers proceeds in a
directional manner and is dependent on the kinase activity of IKK
to
activate IKK
.
*
Corresponding author. Mailing address: Gladstone
Institute of Virology and Immunology, P.O. Box 419100, San Francisco,
CA 94141-9100. Phone: (415) 695-3801. Fax: (415) 826-1817. E-mail: wgreene{at}gladstone.ucsf.edu.
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