The essential role of MEKK3 in TNF-induced NF-kappaB activation

Nat Immunol. 2001 Jul;2(7):620-4. doi: 10.1038/89769.

Abstract

Activation of IkappaB kinase (IKK) is the key step in stimulation of the transcription factor NF-kappaB, which regulates many genes in the inflammatory response pathway. The molecular mechanism that underlies IKK activation in response to tumor necrosis factor (TNF) is still unknown. Using mitogen-activated protein kinase kinase kinase 3 (MEKK3)-deficient fibroblast cells, we found that MEKK3 plays a critical role in TNF-induced NF-kappaB activation. We have shown that MEKK3 is required for IKK activation and functions downstream of receptor-interacting protein (RIP) and TNF receptor- associated factor 2. We have also shown that MEKK3 interacts with RIP and directly phosphorylates IKK. The kinase activity of MEKK3 is pivotal to its function and, therefore, MEKK3 links RIP and IKK in TNF-induced NF-kappaB activation.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Cells, Cultured
  • Enzyme Activation
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • I-kappa B Kinase
  • MAP Kinase Kinase Kinase 3
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / physiology*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • NF-kappa B
  • Proteins
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • Protein-Serine-Threonine Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • MAP Kinase Kinase Kinase 3
  • MAP Kinase Kinase Kinases
  • Map3k3 protein, mouse