NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase

Osman Nidai Ozes, Lindsey D. Mayo, Jason A. Gustin, Susan R. Pfeffer, Lawrence M. Pfeffer and David B. Donner ()
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Osman Nidai Ozes: Indiana University School of Medicine and the Walther Oncology Center
Lindsey D. Mayo: Indiana University School of Medicine and the Walther Oncology Center
Jason A. Gustin: Indiana University School of Medicine and the Walther Oncology Center
Susan R. Pfeffer: University of Tennessee Health Science Center
Lawrence M. Pfeffer: University of Tennessee Health Science Center
David B. Donner: Indiana University School of Medicine and the Walther Oncology Center

Nature, 1999, vol. 401, issue 6748, 82-85

Abstract: Abstract Activation of the nuclear transcription factor NF-κB by inflammatory cytokines requires the successive action of NF-κB-inducing kinase (NIK) and an IκB-kinase (IKK) complex composed of IKKα and IKKβ1,2,3,4,5. Here we show that the Akt serine–threonine kinase6 is involved in the activation of NF-κB 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-κB activation. Constitutively active Akt induces NF-κB activity and this effect is blocked by dominant-negative NIK. Conversely, NIK activates NF-κB and this is blocked by kinase-dead Akt. Thus, both Akt and NIK are necessary for TNF activation of NF-κB. Akt mediates IKKα phosphorylation at threonine 23. Mutation of this amino acid blocks phosphorylation by Akt or TNF and activation of NF-κB. These findings indicate that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses.

Date: 1999
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DOI: 10.1038/43466

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