RKTG对Raf激酶信号传导的空间调控
Spatial regulation of Raf kinase signaling by RKTG.
作者信息
Feng Lin, Xie Xiaoduo, Ding Qiurong, Luo Xiaolin, He Jing, Fan Fengjuan, Liu Weizhong, Wang Zhenzhen, Chen Yan
机构信息
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China.
出版信息
Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14348-53. doi: 10.1073/pnas.0701298104. Epub 2007 Aug 27.
Subcellular compartmentalization has become an important theme in cell signaling such as spatial regulation of Ras by RasGRP1 and MEK/ERK by Sef. Here, we report spatial regulation of Raf kinase by RKTG (Raf kinase trapping to Golgi). RKTG is a seven-transmembrane protein localized at the Golgi apparatus. RKTG expression inhibits EGF-stimulated ERK and RSK phosphorylation, blocks NGF-mediated PC12 cell differentiation, and antagonizes Ras- and Raf-1-stimulated Elk-1 transactivation. Through interaction with Raf-1, RKTG changes the localization of Raf-1 from cytoplasm to the Golgi apparatus, blocks EGF-stimulated Raf-1 membrane translocation, and reduces the interaction of Raf-1 with Ras and MEK1. In RKTG-null mice, the basal ERK phosphorylation level is increased in the brain and liver. In RKTG-deleted mouse embryonic fibroblasts, EGF-induced ERK phosphorylation is enhanced. Collectively, our results reveal a paradigm of spatial regulation of Raf kinase by RKTG via sequestrating Raf-1 to the Golgi apparatus and thereby inhibiting the ERK signaling pathway.
亚细胞区室化已成为细胞信号传导中的一个重要主题，例如RasGRP1对Ras的空间调控以及Sef对MEK/ERK的空间调控。在此，我们报道了RKTG（Raf激酶滞留于高尔基体）对Raf激酶的空间调控。RKTG是一种定位于高尔基体的七次跨膜蛋白。RKTG的表达抑制表皮生长因子（EGF）刺激的细胞外信号调节激酶（ERK）和核糖体S6激酶（RSK）磷酸化，阻断神经生长因子（NGF）介导的嗜铬细胞瘤（PC12）细胞分化，并拮抗Ras和Raf-1刺激的Elk-1反式激活。通过与Raf-1相互作用，RKTG使Raf-1的定位从细胞质改变至高尔基体，阻断EGF刺激的Raf-1向膜的转位，并减少Raf-1与Ras和MEK1的相互作用。在RKTG基因敲除小鼠中，脑和肝中的基础ERK磷酸化水平升高。在缺失RKTG的小鼠胚胎成纤维细胞中，EGF诱导的ERK磷酸化增强。总体而言,我们的结果揭示了一种RKTG对Raf激酶进行空间调控的模式，即通过将Raf-1隔离于高尔基体从而抑制ERK信号通路。
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