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