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.
Yeung
K C
KC
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912, USA. kyeung@mco.edu
Rose
D W
DW
Dhillon
A S
AS
Yaros
D
D
Gustafsson
M
M
Chatterjee
D
D
McFerran
B
B
Wyche
J
J
Kolch
W
W
Sedivy
J M
JM
D000727:Androgen-Binding Protein; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology*; D002460:Cell Line; D004789:Enzyme Activation; D019143:Evolution, Molecular; D017930:Genes, Reporter; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007700:Kinetics; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D049488:Phosphatidylethanolamine Binding Protein; D049294:Phospholipid Transfer Proteins; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D060789:Prostatein; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D051381:Rats; D060765:Secretoglobins; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014598:Uteroglobin; D000097782:NF-kappaB-Inducing Kinase; D000099151:MAP Kinase Kinase Kinase 7; D060788:Mammaglobin B
D000727:Androgen-Binding Protein; D002352:Carrier Proteins; D007375:Interleukin-1; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D049488:Phosphatidylethanolamine Binding Protein; D049294:Phospholipid Transfer Proteins; D060789:Prostatein; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D060765:Secretoglobins; D014409:Tumor Necrosis Factor-alpha; D014598:Uteroglobin; D000097782:NF-kappaB-Inducing Kinase; D000099151:MAP Kinase Kinase Kinase 7; C511482:PEBP1 protein, human; C511484:Scgb1d2 protein, rat; C511483:Scgb1d4 protein, rat; C556468:Scgb2a1 protein, rat; D060788:Mammaglobin B