Raf Kinase Inhibitor Protein RKIP Enhances Signaling by Glycogen Synthase Kinase-3β
| Autor: | Milad S. Bitar, Abdulla Behbehani, Andrew R. Pitt, Fahd Al-Mulla, Walter Kolch, Oliver Rath, Brendan Doyle, May Al-Maghrebi, Kit Yee Tan, Waleed Al-Ali |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Cyclin D Phosphatidylethanolamine Binding Protein Biology Glycogen Synthase Kinase 3 Mice Cyclin D1 GSK-3 Enzyme Stability Animals Humans Phosphorylation Glycogen synthase Cells Cultured Mice Knockout Glycogen Synthase Kinase 3 beta Kinase Carcinoma Wnt signaling pathway Up-Regulation Cell biology Oxidative Stress Oncology Tumor progression Disease Progression Cancer research biology.protein Signal transduction Colorectal Neoplasms Protein Binding Signal Transduction |
| Zdroj: | Cancer Research. 71:1334-1343 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-10-3102 |
| Popis: | 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. Cancer Res; 71(4); 1334–43. ©2011 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|