Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Yeung, K.C. et al.

Yeung, Rose, Dhillon, Yaros, Gustafsson, Chatterjee, McFerran, Wyche, Kolch, Sedivy,

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.[1]

References

Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation. Yeung, K.C., Rose, D.W., Dhillon, A.S., Yaros, D., Gustafsson, M., Chatterjee, D., McFerran, B., Wyche, J., Kolch, W., Sedivy, J.M. Mol. Cell. Biol. (2001) [Pubmed]

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