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Molecular and Cellular Biology, May 2000, p. 3655-3666, Vol. 20, No. 10
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Ikappa B Kinase alpha  (IKKalpha ) Regulation of IKKbeta Kinase Activity

Yumi Yamamoto, Min-Jean Yin, and Richard B. Gaynor*

Division of Hematology-Oncology, Department of Medicine, Harold Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas

Received 4 October 1999/Returned for modification 12 November 1999/Accepted 23 February 2000

Two related kinases, Ikappa B kinase alpha  (IKKalpha ) and IKKbeta , phosphorylate the Ikappa B proteins, leading to their degradation and the subsequent activation of gene expression by NF-kappa B. IKKbeta has a much higher level of kinase activity for the Ikappa B proteins than does IKKalpha and is more critical than IKKalpha in modulating tumor necrosis factor alpha activation of the NF-kappa B pathway. These results indicate an important role for IKKbeta in activating the NF-kappa B pathway but leave open the question of the role of IKKalpha in regulating this pathway. In the current study, we demonstrate that IKKalpha directly phosphorylates IKKbeta . Moreover, IKKalpha either directly or indirectly enhances IKKbeta kinase activity for Ikappa Balpha . Finally, transfection studies to analyze NF-kappa B-directed gene expression suggest that IKKalpha is upstream of IKKbeta in activating the NF-kappa B pathway. These results indicate that IKKalpha , in addition to its previously described ability to phosphorylate Ikappa Balpha , can increase the ability of IKKbeta to phosphorylate Ikappa Balpha .

* Corresponding author. Mailing address: Division of Hematology-Oncology, Department of Medicine, U.T. Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-8594. Phone: (214) 648-7570. Fax: (214) 648-8862. E-mail: gaynor{at}utsw.swmed.edu.

Molecular and Cellular Biology, May 2000, p. 3655-3666, Vol. 20, No. 10
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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