NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176

Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3792-7. doi: 10.1073/pnas.95.7.3792.


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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites / genetics
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Molecular Sequence Data
  • Mutation
  • NF-kappaB-Inducing Kinase
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Sequence Alignment
  • Serine / genetics
  • Serine / metabolism
  • Signal Transduction*


  • Serine
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human