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首页> 外文期刊>Cellular Signalling >K-Ras resides on the Arf6-mediated CIE system and its active type interacted with Arf6T27N
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K-Ras resides on the Arf6-mediated CIE system and its active type interacted with Arf6T27N

机译：K-Ras驻留在Arf6介导的CIE系统上，其活跃类型与Arf6T27N相互作用

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摘要

Ras is known as an oncogene transferring signals from the plasma membrane. Recent studies have demonstrated that plasma membrane was not the unique platform for Ras signaling. Ras could also be endocytosed and transported to different endomembrane compartments, evoking different signal pathways there. It is of great significance to exploit the unique intracellular trafficking features of different Ras isoforms to develop new anti-Ras drugs. ADP-ribosylation factor 6 (Arf6) was known to mediate one of the clathrin-independent endocytosis (CIE) pathways. The role of Arf6 in K-Ras dynamic remains largely unknown. In this study, we showed that K-RasG12V co-localized with Arf6 at the plasma membrane, and entered the tubular endosomes or protrusions induced by cytochalasin D or aluminum fluoride in the same way as H-RasG12V does. A subcellular fractionation experiment demonstrated that Arf6 siRNA treatment reduced the plasma membrane presence of both endogenous Ras isoforms and inhibited the phosphorylation of Erk triggered by EGF. When co-expressed with Arf6Q67L, both isoforms were sequestered into the large phosphatidylinositol 4,5-biphosphate [PI(4,5)P2]-enriched vacuoles. However, when co-expressed with Arf6T27N, K-RasG12V co-localized with Arf6T27N at the tubular endosomes significantly than H-RasG12V. Immunoprecipitation and GST fusion protein pull-down studies found out for the first time that K-RasG12V interacted with Arf6T27N. Swapping mutation study showed that the above difference was due to different C-termini. Our study indicated that Arf6 was involved in the dynamic regulation of both Ras isoforms.
机译：Ras被称为致癌基因，可从质膜传递信号。最近的研究表明，质膜不是Ras信号传导的独特平台。还可以将Ras内吞并转运到不同的内膜区室，在那引起不同的信号通路。利用不同的Ras同工型独特的细胞内运输特性开发新的抗Ras药物具有重要意义。已知ADP-核糖基化因子6（Arf6）介导网格蛋白非依赖性内吞（CIE）途径之一。 Arf6在K-Ras动态中的作用仍然未知。在这项研究中，我们显示K-RasG12V与Arf6共定位在质膜上，并以与H-RasG12V相同的方式进入由细胞松弛素D或氟化铝诱导的管状内体或突起。一项亚细胞分离实验表明，Arf6 siRNA处理可减少两种内源性Ras亚型的质膜存在，并抑制EGF触发的Erk磷酸化。当与Arf6Q67L共表达时，两种同工型都被螯合到富含磷脂酰肌醇的4,5-二磷酸[PI（4,5）P2]富集的液泡中。但是，当与Arf6T27N共表达时，K-RasG12V与Arf6T27N共定位于肾小管内体比H-RasG12V显着多。免疫沉淀和GST融合蛋白下拉研究首次发现K-RasG12V与Arf6T27N相互作用。交换突变研究表明，上述差异是由于C末端不同所致。我们的研究表明Arf6参与了两种Ras亚型的动态调节。

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