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

Nature | Sep 2, 1999

http://www.ncbi.nlm.nih.gov/pubmed/10485710

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.

Pubmed ID: 10485710 RIS Download

Mesh terms: 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 | Phosphatidylinositol 3-Kinases | 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

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