Raf Kinase Inhibitor Protein RKIP Enhances Signaling by Glycogen Synthase Kinase-3β

Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor kappa beta signaling that represses tumor invasion and metastasis. Glycogen synthase kinase-3 beta (GSK3 beta) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. Here, we show that RKIP binds GSK3 proteins andmaintains GSK3 beta protein levels and its active form. Depletion of RKIP augments oxidative stress-mediated activation of the p38 mitogen activated protein kinase, which, in turn, inactivates GSK3 beta by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3 beta inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and beta-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3 beta expression. These findings reveal the RKIP/GSK3 axis as both a potential therapeutic target and a prognosis-based predictor of cancer progression. Cancer Res; 71(4); 1334-43. (C)2011 AACR.