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Forum on Immunopathological Diseases and Therapeutics
SJR: 0.309 SNIP: 0.041 CiteScore™: 0.18

ISSN Imprimer: 2151-8017
ISSN En ligne: 2151-8025

Archives: Volume 1, 2010 to Volume 7, 2016

Forum on Immunopathological Diseases and Therapeutics

DOI: 10.1615/ForumImmunDisTher.v2.i1.40
pages 21-34

Dual Role of RKIP in NF-κB Signaling Pathways

Sungdae Park
Department of Biochemistry & Cancer Biology, College of Medicine, University of Toledo, Health Science Campus, Toledo, Ohio, USA
Huihui Tang
Department of Biochemistry & Cancer Biology, College of Medicine, University of Toledo, Health Science Campus, Toledo, Ohio, USA
Kam C. Yeung
Department of Biochemistry & Cancer Biology, College of Medicine, University of Toledo, Toledo, Ohio

RÉSUMÉ

Raf kinase inhibitor protein (RKIP) was first identified as an inhibitor of Raf-1 kinase in the Raf-MEK-ERK signaling pathway. It inhibits the activation phosphorylation of MEK by Raf-1 by competing with MEK for Raf-1 binding. RKIP was also found to play an important role in regulating the NF-κB pathway. Our studies showed that RKIP interacted with multiple components of both canonical and non-canonical pathways. Genetic and biochemical studies demonstrated that RKIP functioned as a scaffold protein facilitating the phos- phorylation of IkκB and NF-κB2/p100 by upstream kinases. However, contrary to what one would expect of a scaffold protein, our results show that RKIP has an overall inhibitory effect on NF-κB transcriptional activities. The regulation of the expression of NF-κB target genes is subject to negative regulation involving the optimal induction of negative regulators, including IkB and p100. Our data thus support a hypothesis that RKIP inhibits the NF-κB activity via an auto-regulatory feedback loop by rapidly inducing the expression and synthesis of inhibitors of NF-κB activation. This mode of action is, therefore, very different from the mechanisms by which RKIP inhibits the Raf-MEK-ERK pathway.


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