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

O Nidai Ozes, LD Mayo, JA Gustin, SR Pfeffer… - Nature, 1999 - nature.com
O Nidai Ozes, LD Mayo, JA Gustin, SR Pfeffer, LM Pfeffer, DB Donner
Nature, 1999nature.com
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 IKKβ,,,,. Here we show that the Akt serine–threonine kinase 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 …
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 IKKβ,,,,. Here we show that the Akt serine–threonine kinase 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.
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