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J. Biol. Chem., Vol. 279, Issue 36, 37452-37460, September 3, 2004

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Detection of IKK-IKK Subcomplexes in Monocytic Cells and Characterization of Associated Signaling^*

Martina Quirling, Sharon Page, Nikolaus Jilg, Katharina Plenagl, Dominik Peus¶, Christine Grubmüller¶, Monika Weingärtner, Claudia Fischer, Dieter Neumeier, and Korbinian Brand||

From the Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany and the ^¶Department of Dermatology and Allergology, Biederstein, Technische Universität München, 80802 München, Germany

The IB kinase (IKK) complex is one major step in the regulation of the NF-B/Rel system that is involved in inflammatory and immune responses as well as in proliferation and apoptosis. At present it is not clear whether besides the "classical" IKK-IKK-IKK configuration additional complexes exist in vivo that solely contain IKK and IKK (without IKK). In the current study we were able to demonstrate in monocytic cells that endogenous complexes, which only include IKK as the kinase-active molecule do indeed exist in vivo and that these complexes contain IKK as an additional component. Furthermore, we showed that these IKK-IKK complexes are involved in mainstream NF-B activation cascades because they can be activated by tumor necrosis factor. In contrast, these subcomplexes appear not to participate in NIK-dependent pathways. As a next step we showed that exogenous IKK-IKK complexes can be formed in an intact cell by overexpression and that these artificial complexes fulfill the requirement for participation in regular signaling. Finally, in the absence of IKK we found a retarded proteolysis of IB, but not of IB, which is associated with a reduced IKK activity. Differential pathways represented by various IKK subcomplexes may open attractive possibilities in treatment of inflammation or cancer allowing specific therapeutic intervention.

Received for publication, November 5, 2003 , and in revised form, June 25, 2004.

^* This work was supported by the Deutsche Forschungsgemeinschaft (Br 1026/3-3 and Pe 635/1-2) and the Deutsche Gesellschaft für Klinische Chemie. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Institute of Clinical Chemistry and Pathobiochemistry, Technische Universität München, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 München, Germany. Tel.: 49-89-4140-4084; Fax: 49-89-4140-4080; E-mail: brand{at}klinchem.med.tum.de.

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