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

Nidai Ozes, Osman, Mayo, Lindsey D., Gustin, Jason A., Pfeffer, Susan R., Pfeffer, Lawrence M., Donner, David B.·1999·Nature
DOI 10.1038/43466
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Abstract

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.

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Research works printed but not linked: 20

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Metadata

Authors
Nidai Ozes, O., Mayo, L. D., Gustin, J. A., Pfeffer, S. R., Pfeffer, L. M., & Donner, D. B.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
1999-09
Volume
401
Issue
6748
Pages
82-85
ISSN
  • 0028-0836
  • 1476-4687
DOI
10.1038/43466
Cited by
1,832
References
0
Language
en
Licence
www.springer.com/tdm (tdm)

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