Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation

Science. 1999 Apr 9;284(5412):309-13. doi: 10.1126/science.284.5412.309.

Abstract

IkappaB [inhibitor of nuclear factor kappaB (NF-kappaB)] kinase (IKK) phosphorylates IkappaB inhibitory proteins, causing their degradation and activation of transcription factor NF-kappaB, a master activator of inflammatory responses. IKK is composed of three subunits-IKKalpha and IKKbeta, which are highly similar protein kinases, and IKKgamma, a regulatory subunit. In mammalian cells, phosphorylation of two sites at the activation loop of IKKbeta was essential for activation of IKK by tumor necrosis factor and interleukin-1. Elimination of equivalent sites in IKKalpha, however, did not interfere with IKK activation. Thus, IKKbeta, not IKKalpha, is the target for proinflammatory stimuli. Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.

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
  • Amino Acid Substitution
  • Cell Line
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • HeLa Cells
  • Helix-Loop-Helix Motifs
  • Humans
  • I-kappa B Kinase
  • I-kappa B Proteins
  • Interleukin-1 / pharmacology
  • Leucine Zippers
  • MAP Kinase Kinase Kinase 1*
  • Molecular Sequence Data
  • Mutation
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Interleukin-1
  • Tumor Necrosis Factor-alpha
  • Phosphoserine
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • NF-kappa B kinase