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*

By Nywana Sizemore, N. Lerner, Nicole Dombrowski, H. Sakurai, G. Stark. Journal of Biological Chemistry, 2001

372 citations recorded by the source corpus.

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 IκB 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 Iκβα 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 PI3K/AKT pathway.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/e270f407bf3320afaef870a96fd7a20b0dd732bf

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Citations in the corpus

• To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis (2003, background): “…kinase II and AKT are among the kinases that can phosphorylate the transactivation domains of RelA or c-Rel in response to NF-kB-inducing stimuli (Wang and Baldwin, 1998; Sakurai et al., 1999; Martin and Fresno, 2000; Wang et al., 2000; Mayo et al., 2002; Sizemore et al., 2002; Yang et al., 2003).”
• IKKβ phosphorylates p65 at S468 in transactivaton domain 2 (2005, background): “Although it has been shown that IKKβ mediates the majority of NF-κB activation through the classical pathway, it has been controversial whether IKKα or IKKβ mediate p65 phosphorylation at S536 (24, 25 ).”
• Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. (2008, background): “We and others reported (Madrid et al. 2001; Sizemore et al. 2002) that Akt functions through IKK to promote the transactivation potential and phosphorylation (RelA) of NF- B. Akt is proposed to promote metastasis and angiogenesis through IKK in a manner that depends on NFB and -catenin activation…”
• MAPK pathways in radiation responses (2003, background): “Several manuscripts have suggested that NFkB signaling is regulated by the PI3K pathway (Sizemore et al., 2002), whereas others have suggested that ERK signaling can regulate this transcription factor through autocrine mechanisms, for example, enhanced TNF-a expression (Troppmair et al., 1998; Tuyt…”
• Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway (2006, background): “These include IKKa (see also below), IKKe (also known as IKKi) and NF-kB activating kinase (NAK, also known as TBK1, TANK-binding kinase 1) (Sakurai et al., 1999; Sizemore et al., 2002; Jiang et al., 2003; Buss et al., 2004b; Lawrence et al., 2005).”