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

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-kappa B pathway. Genetic and biochemical studies demonstrated that RKIP functioned as a scaffold protein facilitating the phosphorylation of I kappa B 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-kappa B transcriptional activities. Since NF-kappa B target gene expression is subject to negative regulation involving the optimal induction of negative regulators, our data support a hypothesis that RKIP inhibits NF-kappa B activity via the auto-regulatory feedback loop by rapidly inducing the expression and synthesis of inhibitors of NF-kappa B activation.