NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase.

Activation of the nuclear transcription factor NF-kappaB by inflammatory cytokines requires the successive action of NF-kappaB-inducing kinase (NIK) and an IKB-kinase (IKK) complex composed of IKKalpha and IKKbeta. Here we show that the Akt serine-threonine kinase is involved in the activation of NF-kappaB by tumour necrosis factor (TNF). TNF activates ...
phosphatidylinositol-3-OH kinase (PI(3)K) and its downstream target Akt (protein kinase B). Wortmannin (a PI(3)K inhibitor), dominant-negative PI(3)K or kinase-dead Akt inhibits TNF-mediated NF-kappaB activation. Constitutively active Akt induces NF-kappaB activity and this effect is blocked by dominant-negative NIK. Conversely, NIK activates NF-kappaB and this is blocked by kinase-dead Akt. Thus, both Akt and NIK are necessary for TNF activation of NF-kappaB. Akt mediates IKKalpha phosphorylation at threonine 23. Mutation of this amino acid blocks phosphorylation by Akt or TNF and activation of NF-kappaB. These findings indicate that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, 3T3 Cells, Amino Acid Sequence, Animals, Antigens, CD, Cell Line, DNA, Enzyme Activation, Hela Cells, Humans, I-kappa B Kinase, Mice, Molecular Sequence Data, NF-kappa B, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Threonine, Tumor Necrosis Factor-alpha
Nature
Date: Sep. 02, 1999
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