title: Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β.
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.
authors.affiliation: Department of Pathology, Faculty of Medicine, Health Sciences Center, Kuwait University, Safat, Kuwait, UK. fahd@al-mulla.org
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
authors.forename: Milad S
authors.initials: MS
authors.lastname: Bitar
authors.forename: May
authors.initials: M
authors.lastname: Al-Maghrebi
authors.forename: Abdulla I
authors.initials: AI
authors.lastname: Behbehani
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Ali
authors.forename: Oliver
authors.initials: O
authors.lastname: Rath
authors.forename: Brendan
authors.initials: B
authors.lastname: Doyle
authors.forename: Kit Yee
authors.initials: KY
authors.lastname: Tan
authors.forename: Andrew
authors.initials: A
authors.lastname: Pitt
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004795:Enzyme Stability; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology
chemical_list: C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3