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

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... ecule 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.