CHMP6 and VPS4A mediate the recycling of Ras to the plasma membrane to promote growth factor signaling.
CHMP6 and VPS4A mediate the recycling of Ras to the plasma membrane to promote growth factor signaling.
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DOI：
10.1038/onc.2011.607
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发表时间：
2012-10-25
期刊：
影响因子：
8
通讯作者：
Chang EC
中科院分区：
文献类型：
--
作者：
Zheng ZY;Cheng CM;Fu XR;Chen LY;Xu L;Terrillon S;Wong ST;Bar-Sagi D;Songyang Z;Chang EC
虽然Ras在质膜（PM）上起作用以介导生长因子信号传导，但越来越多的证据表明Ras在细胞质中具有复杂的作用。为了揭示这些作用，我们筛选了一个cDNA文库，并分离出了也影响Ras功能的H-Ras结合蛋白。许多分离的蛋白质调节涉及内体的运输; CHMP 6/VPS 20和VPS 4A与ESCRT-III相互作用，被选择用于进一步研究。我们发现，结合是直接的，并发生在内体中。此外，当H-Ras具有功能性效应物结合环并且是GTP结合的和泛素化的时，结合是最有效的。CHMP 6和VPS 4A也结合N-Ras，但不结合K-Ras。抑制CHMP 6和VPS 4A阻断Ras诱导的转化，这与通过细胞分级分离和光漂白测量的Ras在PM上的低效定位相关。此外，沉默CHMP 6和VPS 4A也阻断EGFR再循环。这些数据表明，Ras与关键的ESCRT-III组分相互作用，以促进自身和EGFR再循环回到PM，从而产生正反馈回路，以增强生长因子信号传导。
While Ras is well-known to function on the plasma membrane (PM) to mediate growth factor signaling, increasing evidence suggests that Ras has complex roles in the cytoplasm. To uncover these roles, we screened a cDNA library and isolated H-Ras-binding proteins that also influence Ras functions. Many isolated proteins regulate trafficking involving endosomes; CHMP6/VPS20 and VPS4A, which interact with ESCRT-III, were chosen for further study. We showed that the binding is direct and occurs in endosomes. Furthermore, the binding is most efficient when H-Ras has a functional effector-binding-loop and is GTP-bound and ubiquitylated. CHMP6 and VPS4A also bound N-Ras, but not K-Ras. Repressing CHMP6 and VPS4A blocked Ras-induced transformation, which correlated with inefficient Ras localization to the PM as measured by cell fractionation and photobleaching. Moreover, silencing CHMP6 and VPS4A also blocked EGFR recycling. These data suggest that Ras interacts with key ESCRT-III components to promote recycling of itself and EGFR back to the PM to create a positive feedback loop to enhance growth factor signaling.
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