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Molecular and Cellular Biology, February 2000, p. 1170-1178, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Activation of the Heterodimeric Ikappa B Kinase alpha  (IKKalpha )-IKKbeta Complex Is Directional: IKKalpha Regulates IKKbeta under Both Basal and Stimulated Conditions

Alison O'Mahony,1 Xin Lin,1 Romas Geleziunas,1 and Warner C. Greene1,2,*

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-kappa B transcription factor involves the stimulatory action of select mitogen-activated protein kinase kinase kinases on the Ikappa B kinases (IKKalpha and IKKbeta ) which reside in a macromolecular signaling complex termed the signalsome. While genetic studies indicate that IKKbeta is the principal kinase involved in proinflammatory cytokine-induced Ikappa B phosphorylation, the function of the equivalently expressed IKKalpha is less clear. Here we demonstrate that assembly of IKKalpha with IKKbeta in the heterodimeric signalsome serves two important functions: (i) in unstimulated cells, IKKalpha inhibits the constitutive Ikappa B kinase activity of IKKbeta ; (ii) in activated cells, IKKalpha kinase activity is required for the induction of IKKbeta . The introduction of kinase-inactive IKKalpha , activation loop mutants of IKKalpha , or IKKalpha antisense RNA into 293 or HeLa cells blocks NIK (NF-kappa B-inducing kinase)-induced phosphorylation of the IKKbeta activation loop occurring in functional signalsomes. In contrast, catalytically inactive mutants of IKKbeta do not block NIK-mediated phosphorylation of IKKalpha in these macromolecular signaling complexes. This requirement for kinase-proficient IKKalpha to activate IKKbeta in heterodimeric IKK signalsomes is also observed with other NF-kappa B inducers, including tumor necrosis factor alpha, human T-cell leukemia virus type 1 Tax, Cot, and MEKK1. Conversely, the theta  isoform of protein kinase C, which also induces NF-kappa B/Rel, directly targets IKKbeta for phosphorylation and activation, possibly acting through homodimeric IKKbeta 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 IKKalpha to activate IKKbeta .

* 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.

Molecular and Cellular Biology, February 2000, p. 1170-1178, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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