NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176.
Activation of the transcription factor NF-kappaB by inflammatory cytokines involves the successive action of NF-kappaB-inducing kinase (NIK) and two IkappaB kinases, IKK-alpha and IKK-beta. Here we show that NIK preferentially phosphorylates IKK-alpha over IKK-beta, leading to the activation of IKK-alpha kinase activity. This phosphorylation of IKK-alpha occurs specifically on Ser-176 in the activation loop between kinase subdomains VII and VIII. A mutant form of IKK-alpha containing alanine at residue 176 cannot be phosphorylated or activated by NIK and acts as a dominant negative inhibitor of interleukin 1- and tumor necrosis factor-induced NF-kappaB activation. Conversely, a mutant form of IKK-alpha containing glutamic acid at residue 176 is constitutively active. Thus, the phosphorylation of IKK-alpha on Ser-176 by NIK may be required for cytokine-mediated NF-kappaB activation.[1]References
- NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176. Ling, L., Cao, Z., Goeddel, D.V. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
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