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Molecular and Cellular Biology, March 1999, p. 2180-2188, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Activation of Ikappa B Kinase beta  by Protein Kinase C Isoforms

Maria-José Lallena,1 María T. Diaz-Meco,1 Gary Bren,2 Carlos V. Payá,2 and Jorge Moscat1,*

Laboratorio Glaxo Wellcome-CSIC de Biología Molecular y Celular, Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Universidad Autónoma, 28049 Madrid, Spain,1 and Department of Immunology, Mayo Clinic, Rochester, Minnesota 559052

Received 29 June 1998/Returned for modification 26 August 1998/Accepted 12 November 1998

The atypical protein kinase C (PKC) isotypes (lambda /iota PKC and zeta PKC) have been shown to be critically involved in important cell functions such as proliferation and survival. Previous studies have demonstrated that the atypical PKCs are stimulated by tumor necrosis factor alpha (TNF-alpha ) and are required for the activation of NF-kappa B by this cytokine through a mechanism that most probably involves the phosphorylation of Ikappa B. The inability of these PKC isotypes to directly phosphorylate Ikappa B led to the hypothesis that zeta PKC may use a putative Ikappa B kinase to functionally inactivate Ikappa B. Recently several groups have molecularly characterized and cloned two Ikappa B kinases (IKKalpha and IKKbeta ) which phosphorylate the residues in the Ikappa B molecule that serve to target it for ubiquitination and degradation. In this study we have addressed the possibility that different PKCs may control NF-kappa B through the activation of the IKKs. We report here that alpha PKC as well as the atypical PKCs bind to the IKKs in vitro and in vivo. In addition, overexpression of zeta PKC positively modulates IKKbeta activity but not that of IKKalpha , whereas the transfection of a zeta PKC dominant negative mutant severely impairs the activation of IKKbeta but not IKKalpha in TNF-alpha -stimulated cells. We also show that cell stimulation with phorbol 12-myristate 13-acetate activates IKKbeta , which is entirely dependent on the activity of alpha PKC but not that of the atypical isoforms. In contrast, the inhibition of alpha PKC does not affect the activation of IKKbeta by TNF-alpha . Interestingly, recombinant active zeta PKC and alpha PKC are able to stimulate in vitro the activity of IKKbeta but not that of IKKalpha . In addition, evidence is presented here that recombinant zeta PKC directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappa B pathway at the level of IKKbeta activation and Ikappa B degradation.

* Corresponding author. Mailing address: Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma, Canto Blanco, 28049 Madrid, Spain. Phone: 34-913978039. Fax: 34-929690055. E-mail: jmoscat{at}cbm.uam.es.

Molecular and Cellular Biology, March 1999, p. 2180-2188, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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