Identification and Characterization of an IkappaB Kinase

Cell. 1997 Jul 25;90(2):373-83. doi: 10.1016/s0092-8674(00)80344-x.

Abstract

Activation of the transcription factor NF-kappaB by tumor necrosis factor (TNF) and interleukin-1 (IL-1) requires the NF-kappaB-inducing kinase (NIK). In a yeast two-hybrid screen for NIK-interacting proteins, we have identified a protein kinase previously known as CHUK. Overexpression of CHUK activates a NF-kappaB-dependent reporter gene. A catalytically inactive mutant of CHUK is a dominant-negative inhibitor of TNF-, IL-1-, TRAF-, and NIK-induced NF-kappaB activation. CHUK associates with the NF-kappaB inhibitory protein, IkappaB-alpha, in mammalian cells. CHUK specifically phosphorylates IkappaB-alpha on both serine 32 and serine 36, modifications that are required for targeted degradation of IkappaB-alpha via the ubiquitin-proteasome pathway. This phosphorylation of IkappaB-alpha is greatly enhanced by NIK costimulation. Thus, CHUK is a NIK-activated IkappaB-alpha kinase that links TNF- and IL-1-induced kinase cascades to NF-kappaB activation.

MeSH terms

  • Cloning, Molecular
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Molecular Sequence Data
  • Mutagenesis / physiology
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Sequence Homology, Amino Acid
  • Signal Transduction / physiology
  • Transcription Factor RelB
  • Transcription Factors*
  • Yeasts / genetics

Substances

  • NF-kappa B
  • Proto-Oncogene Proteins
  • RELB protein, human
  • Transcription Factors
  • Transcription Factor RelB
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • NF-kappa B kinase

Associated data

  • GENBANK/AF012890