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.
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, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-raf, Rats, Signal Transduction, Transfection, Tumor Necrosis Factor-alpha, Uteroglobin
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, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-raf, Rats, Signal Transduction, Transfection, Tumor Necrosis Factor-alpha, Uteroglobin
Mol. Cell. Biol.
Date: Nov. 01, 2001
PubMed ID: 11585904
View in: Pubmed Google Scholar
Download Curated Data For This Publication
11301
Switch View:
- Interactions 11