Raf Kinase Inhibitor Protein RKIP Enhances Signaling by Glycogen Synthase Kinase-3β
Raf Kinase Inhibitor Protein RKIP Enhances Signaling by Glycogen Synthase Kinase-3β
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DOI：
10.1158/0008-5472.can-10-3102
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发表时间：
2011-02-15
期刊：
影响因子：
11.2
通讯作者：
Kolch, Walter
中科院分区：
文献类型：
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作者：
Al-Mulla, Fahd;Bitar, Milad S.;Kolch, Walter
Raf激酶抑制蛋白（RKIP）是c-RAF激酶和核因子κ β信号传导的生理抑制剂，其抑制肿瘤侵袭和转移。糖原合成酶激酶-3 β（GSK3 β）通过下调多种致癌途径（包括Wnt信号传导和细胞周期蛋白D1激活）抑制肿瘤进展。在这里，我们表明RKIP结合GSK 3蛋白并维持GSK 3 β蛋白水平及其活性形式。RKIP的消耗增强了氧化应激介导的p38促分裂原活化蛋白激酶的活化，这反过来又通过在抑制性T390残基磷酸化使GSK 3 β失活。该途径解除GSK3 β对致癌底物的抑制，从而引起细胞周期蛋白D的稳定，其诱导细胞周期进展和β-连环蛋白、SNAIL和SLUG，其促进上皮向间充质转化。人结直肠癌中的RKIP水平与GSK 3 β表达正相关。这些发现揭示了RKIP/GSK 3轴既是潜在的治疗靶点，也是基于肿瘤进展的预测因子。Cancer Res; 71（4）; 1334 - 43.（c）2011年《非洲标准化评论》。
Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor kappa beta signaling that represses tumor invasion and metastasis. Glycogen synthase kinase-3 beta (GSK3 beta) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. Here, we show that RKIP binds GSK3 proteins andmaintains GSK3 beta 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 GSK3 beta by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3 beta inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and beta-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3 beta 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. (C)2011 AACR.