Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β

Fahd Al-Mulla, Milad Sami Bitar, May Al-Maghrebi, Abdulla I. Behbehani, Waleed Al-Ali, Oliver Rath, Brendan Doyle, Kit Yee Tan, Andrew Pitt, Walter Kolch

Research output: Contribution to journalArticlepeer-review

97 Citations (Scopus)

Abstract

Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor κB signaling that represses tumor invasion and metastasis. Glycogen synthase kinase-3β (GSK3β) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. Here, we show that RKIP binds GSK3 proteins and maintains GSK3β 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 GSK3β by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3β inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and β-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3β expression. These findings reveal the RKIP/GSK3 axis as both a potential therapeutic target and a prognosis-based predictor of cancer progression.

Original languageEnglish
Pages (from-to)1334-1343
Number of pages10
JournalCancer Research
Volume71
Issue number4
DOIs
Publication statusPublished - 15 Feb 2011

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