Department of Life Science, The University of Seoul, Seoul, Korea.
Oncogene. 2013 Jul 11;32(28):3390-6. doi: 10.1038/onc.2012.373. Epub 2012 Aug 20.
It has been shown that inhibition of GTPase-activating protein of ADP-ribosylation factor (Arf), ArfGAP, with a small molecule (QS11) results in synergistic activation of Wnt/β-catenin signaling. However, the role of Arf in Wnt/β-catenin signaling has not yet been elucidated. Here, we show that activation of Arf is essential for Wnt/β-catenin signaling. The level of the active form of Arf (Arf-GTP) transiently increased in the presence of Wnt, and this induction event was abrogated by blocking the interaction between Wnt and Frizzled (Fzd). In addition, knockdown of Fzds, Dvls or LRP6 blocked the Wnt-mediated activation of Arf. Consistently, depletion of Arf led to inhibition of Wnt-mediated membrane PtdIns (4,5)P2 (phosphatidylinositol 4, 5-bisphosphate) synthesis and LRP6 phosphorylation. Overall, our data suggest that transient activation of Arf modulates LRP6 phosphorylation for the transduction of Wnt/β-catenin signaling.
已经表明，ADP-核糖基化因子（Arf）的 GTP 酶激活蛋白（ArfGAP）的小分子抑制剂（QS11）可协同激活 Wnt/β-catenin 信号通路。然而，Arf 在 Wnt/β-catenin 信号通路中的作用尚未阐明。本文显示，Arf 的激活对于 Wnt/β-catenin 信号通路是必需的。在 Wnt 存在的情况下，Arf 的活性形式（Arf-GTP）的水平短暂增加，并且该诱导事件通过阻断 Wnt 与 Frizzled（Fzd）之间的相互作用而被阻断。此外，Fzds、Dvls 或 LRP6 的敲低阻断了 Wnt 介导的 Arf 激活。一致地，Arf 的耗竭导致 Wnt 介导的膜 PtdIns（4,5）P2（磷脂酰肌醇 4,5-二磷酸）合成和 LRP6 磷酸化的抑制。总体而言，我们的数据表明，Arf 的短暂激活调节 LRP6 的磷酸化以转导 Wnt/β-catenin 信号通路。
