RKIP inhibits NF-κB in cancer cells by regulating upstream signaling components of the IκB kinase complex

Tang, Huihui; Park, Sungdae; Sun, Shao-Cong; Trumbly, Robert; Ren, Gang; Tsung, Eric; Yeung, Kam C.

doi:10.1016/j.febslet.2009.12.051

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Volume 584, Issue 4 , Pages 662-668, 19 February 2010

RKIP inhibits NF-κB in cancer cells by regulating upstream signaling components of the IκB kinase complex

Editor by Angel Nebreda

Huihui Tang
- Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Health Science Campus, 3035 Arlington Avenue, Toledo, OH 43614-5804, United States
Sungdae Park
- Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Health Science Campus, 3035 Arlington Avenue, Toledo, OH 43614-5804, United States
Shao-Cong Sun
- Department of Immunology, SCRB 4.2019, University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, United States
Robert Trumbly
- Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Health Science Campus, 3035 Arlington Avenue, Toledo, OH 43614-5804, United States
Gang Ren
- Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Health Science Campus, 3035 Arlington Avenue, Toledo, OH 43614-5804, United States
Eric Tsung
- Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Health Science Campus, 3035 Arlington Avenue, Toledo, OH 43614-5804, United States
Kam C. Yeung
- Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Health Science Campus, 3035 Arlington Avenue, Toledo, OH 43614-5804, United States
- Corresponding author. Fax: +1 4193836228.

Received 29 September 2009; received in revised form 17 December 2009; accepted 19 December 2009. published online 29 December 2009.

Abstract

RKIP was first identified as an inhibitor of the Raf-MEK-ERK signaling pathway. RKIP was also found to play an important role in the NF-κB pathway. Genetic and biochemical studies demonstrated that RKIP functioned as a scaffold protein facilitating the phosphorylation of IκB 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 the NF-κB transcriptional activities. Since NF-κB target gene expression is subject to negative regulation involving the optimal induction of negative regulators, our data support a hypothesis that RKIP inhibits NF-κB activity via the auto-regulatory feedback loop by rapidly inducing the expression and synthesis of inhibitors of NF-κB activation.

Structured summary

MINT-7386121: TRAF6 (uniprotkb:Q9Y4K3) physically interacts (MI:0915) with RKIP (uniprotkb:P30086) by anti bait co-immunoprecipitation (MI:0006)

Keywords: RKIP, Raf-MEK-ERK, NF-κB, scaffold, Negative regulatory loop