Distinct roles of the IκB kinase α and β subunits in liberating nuclear factor κB (NF-κB) from IκB and in phosphorylating the p65 subunit of NF-κB

Phosphatidylinositol 3′-kinase (PI3K) and the serine/threonine kinase AKT have critical roles in phosphorylating and transactivating the p65 subunit of nuclear factor κB (NF-κB) in response to the pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF). Mouse embryo fibroblasts (MEFs) lacking either the α or β subunit of IKB kinase (IKK) were deficient in NF-κB-dependent transcription following treatment with IL-1 or TNF. However, in contrast to IKKβ-null MEFs, IKKα-null MEFs were not substantially defective in the cytokine-stimulated degradation of IKβα or in the nuclear translocation of NF-κB. The IKK complexes from IKKα- or IKKβ-null MEFs were both deficient in PI3K-mediated phosphorylation of the transactivation domain of the p65 subunit of NF-κB in response to IL-1 and TNF, and constitutively activated forms of PI3K or AKT did not potentiate cytokine-stimulated activation of NF-κB in either IKKα- or IKKβ-null MEFs. Collectively, these data indicate that, in contrast to IKKβ, which is required for both NF-κB liberation and p65 phosphorylation, IKKα is required solely for the cytokine-induced phosphorylation and activation of the p65 subunit of NF-κB that are mediated by the P13K/AKT pathway.