Molecular and Cellular Pathobiology Raf Kinase Inhibitor Protein RKIP Enhances Signaling by Glycogen Synthase Kinase-3b

Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor kB signaling that represses tumor invasion andmetastasis.Glycogen synthase kinase-3b (GSK3b) suppresses tumorprogression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. Here, we show thatRKIPbindsGSK3proteins andmaintainsGSK3bprotein levels and its active form.Depletion ofRKIP augments oxidative stress–mediated activation of the p38 mitogen activated protein kinase, which, in turn, inactivates GSK3b by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3b inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and b-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3b 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. 2011 AACR.