NAK is an IkappaB kinase-activating kinase

Nature. 2000 Apr 13;404(6779):778-82. doi: 10.1038/35008109.


Phosphorylation of IkappaB by the IkappaB kinase (IKK) complex is a critical step leading to IkappaB degradation and activation of transcription factor NF-kappaB. The IKK complex contains two catalytic subunits, IKKalpha and IKKbeta, the latter being indispensable for NF-kappaB activation by pro-inflammatory cytokines. Although IKK is activated by phosphorylation of the IKKbeta activation loop, the physiological IKK kinases that mediate responses to extracellular stimuli remain obscure. Here we describe an IKK-related kinase, named NAK (NF-kappaB-activating kinase), that can activate IKK through direct phosphorylation. NAK induces IkappaB degradation and NF-kappaB activity through IKKbeta. Endogenous NAK is activated by phorbol ester tumour promoters and growth factors, whereas catalytically inactive NAK specifically inhibits activation of NF-kappaB by protein kinase C-epsilon (PKCepsilon). Thus, NAK is an IKK kinase that may mediate IKK and NF-kappaB activation in response to growth factors that stimulate PKCepsilon activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cell Line
  • Cloning, Molecular
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Luciferases / genetics
  • Mice
  • Molecular Sequence Data
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Serine / metabolism
  • Transcription, Genetic
  • Ubiquitins / metabolism


  • NF-kappa B
  • Ubiquitins
  • Serine
  • Luciferases
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse

Associated data

  • GENBANK/AF174536