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

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.

journal_name

Nature

journal_title

Nature

authors

Ozes ON,Mayo LD,Gustin JA,Pfeffer SR,Pfeffer LM,Donner DB

doi

10.1038/43466

keywords:

subject

Has Abstract

pub_date

1999-09-02 00:00:00

pages

82-5

issue

6748

eissn

0028-0836

issn

1476-4687

journal_volume

401

pub_type

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