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Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation.

The Raf kinase inhibitor protein (RKIP) acts as a negative regulator of the mitogen-activated protein (MAP) kinase (MAPK) cascade initiated by Raf-1. RKIP inhibits the phosphorylation of MAP/extracellular signal-regulated kinase 1 (MEK1) by Raf-1 by disrupting the interaction between these two kinases. We show here that RKIP also antagonizes the signal transduction pathways that mediate the activation of the transcription factor nuclear factor kappa B (NF-kappaB) in response to stimulation with tumor necrosis factor alpha (TNF-alpha) or interleukin 1 beta. Modulation of RKIP expression levels affected NF-kappaB signaling independent of the MAPK pathway. Genetic epistasis analysis involving the ectopic expression of kinases acting in the NF-kappaB pathway indicated that RKIP acts upstream of the kinase complex that mediates the phosphorylation and inactivation of the inhibitor of NF-kappaB (IkappaB). In vitro kinase assays showed that RKIP antagonizes the activation of the IkappaB kinase (IKK) activity elicited by TNF-alpha. RKIP physically interacted with four kinases of the NF-kappaB activation pathway, NF-kappaB-inducing kinase, transforming growth factor beta-activated kinase 1, IKKalpha, and IKKbeta. This mode of action bears striking similarities to the interactions of RKIP with Raf-1 and MEK1 in the MAPK pathway. Emerging data from diverse organisms suggest that RKIP and RKIP-related proteins represent a new and evolutionarily highly conserved family of protein kinase regulators. Since the MAPK and NF-kappaB pathways have physiologically distinct roles, the function of RKIP may be, in part, to coordinate the regulation of these pathways.

Pubmed ID: 11585904

Authors

  • Yeung KC
  • Rose DW
  • Dhillon AS
  • Yaros D
  • Gustafsson M
  • Chatterjee D
  • McFerran B
  • Wyche J
  • Kolch W
  • Sedivy JM

Journal

Molecular and cellular biology

Publication Data

November 4, 2001

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM 41690
  • Agency: NCRR NIH HHS, Id: P20RR15578
  • Agency: NIGMS NIH HHS, Id: R01 GM55435
  • Agency: NIGMS NIH HHS, Id: R01 GM64767

Mesh Terms

  • Androgen-Binding Protein
  • Animals
  • COS Cells
  • Carrier Proteins
  • Cell Line
  • Enzyme Activation
  • Evolution, Molecular
  • Genes, Reporter
  • Humans
  • Interleukin-1
  • Kinetics
  • MAP Kinase Kinase Kinases
  • NF-kappa B
  • Phosphatidylethanolamine Binding Protein
  • Phospholipid Transfer Proteins
  • Phosphorylation
  • Plasmids
  • Precipitin Tests
  • Prostatein
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • Rats
  • Secretoglobins
  • Signal Transduction
  • Transfection
  • Tumor Necrosis Factor-alpha
  • Uteroglobin