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

Fahd Al-Mulla, Milad S. 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 journalArticle

Abstract

Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor ?B signaling that represses tumor invasion and metastasis. Glycogen synthase kinase-3ß (GSK3ß) 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 GSK3ß 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 GSK3ß by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3ß inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and ß-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3ß 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
Early online date8 Feb 2011
DOIs
Publication statusPublished - 15 Feb 2011

Keywords

  • animals
  • carcinoma
  • cultured cells
  • colorectal neoplasms
  • disease progression
  • enzyme stability
  • glycogen synthase kinase 3
  • humans
  • mice
  • knockout mice
  • oxidative stress
  • phosphatidylethanolamine binding protein
  • phosphorylation
  • protein binding
  • signal transduction
  • up-regulation

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  • Cite this

    Al-Mulla, F., Bitar, M. S., Al-Maghrebi, M., Behbehani, A. I., Al-Ali, W., Rath, O., Doyle, B., Tan, K. Y., Pitt, A., & Kolch, W. (2011). Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β. Cancer Research, 71(4), 1334-1343. https://doi.org/10.1158/0008-5472.CAN-10-3102