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Molecular and Cellular Biology, November 2001, p. 7207-7217, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7207-7217.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Raf Kinase Inhibitor Protein Interacts with NF-kappa B-Inducing Kinase and TAK1 and Inhibits NF-kappa B Activation

Kam C. Yeung,1,* David W. Rose,2 Amardeep S. Dhillon,3 Diane Yaros,1,dagger Marcus Gustafsson,1 Devasis Chatterjee,1 Brian McFerran,3 James Wyche,1 Walter Kolch,3 and John M. Sedivy1

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 029121; Department of Medicine and Whittier Diabetes Program, University of California---San Diego, La Jolla, California 92093-06732; and Beatson Institute for Cancer Research, CRC Beatson Laboratories, Bearsden, Glasgow G61 1BD, United Kingdom3

Received 8 January 2001/Returned for modification 14 March 2001/Accepted 2 August 2001

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-kappa B) in response to stimulation with tumor necrosis factor alpha (TNF-alpha ) or interleukin 1 beta. Modulation of RKIP expression levels affected NF-kappa B signaling independent of the MAPK pathway. Genetic epistasis analysis involving the ectopic expression of kinases acting in the NF-kappa B pathway indicated that RKIP acts upstream of the kinase complex that mediates the phosphorylation and inactivation of the inhibitor of NF-kappa B (Ikappa B). In vitro kinase assays showed that RKIP antagonizes the activation of the Ikappa B kinase (IKK) activity elicited by TNF-alpha . RKIP physically interacted with four kinases of the NF-kappa B activation pathway, NF-kappa B-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-kappa B pathways have physiologically distinct roles, the function of RKIP may be, in part, to coordinate the regulation of these pathways.

* Corresponding author. Present address: Medical College of Ohio, Department of Biochemistry & Molecular Biology, 3035 Arlington Ave., Toledo, OH 43614-5804. Phone: (419) 383-6658. Fax: (419) 383-6228. E-mail: kyeung{at}mco.edu.

dagger Present address: Rhode Island Hospital, Providence, RI 02903.

Molecular and Cellular Biology, November 2001, p. 7207-7217, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7207-7217.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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