Ras nanoclusters: a new drug target?
Ras nanoclusters: a new drug target?
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DOI：
10.4161/sgtp.23145
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发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Hancock, John F
中科院分区：
文献类型：
--
作者：
Cho, Kwang-Jin;Hancock, John F
质膜上的Ras蛋白横向分离成瞬时纳米簇，这对于Ras/MAPK级联的高保真信号传输至关重要。Ras纳米簇组装和拆卸的动力学控制着MAPK信号的输出。BRaf抑制剂矛盾地激活ras转化细胞中的CRaf和MAPK信号。在我们最近的研究中，我们发现BRaf抑制通过增加Ras纳米簇形成的频率，显著增强了致癌的K-和N-Ras的纳米簇，而不是H-Ras。这种破坏Ras纳米簇的时空动态完全解释了Raf抑制剂对Ras信号传输的影响。结合其他研究，我们提出Ras纳米簇的动力学可能代表未来治疗干预的新靶点。
Ras proteins on the plasma membrane are laterally segregated into transient nanoclusters that are essential for high-fidelity signal transmission by the Ras/MAPK cascade. The dynamics of Ras nanocluster assembly and disassembly control MAPK signal output. BRaf inhibitors paradoxically activate CRaf and MAPK signaling in Ras-transformed cells. In our recent study, we showed that BRaf inhibition significantly enhances nanoclustering of oncogenic K- and N-Ras, but not H-Ras by increasing the frequency of Ras nanocluster formation. This disrupted spatiotemporal dynamics of Ras nanocluster fully accounts for the observed effects of Raf inhibitors on Ras signal transmission. Here together with other studies, we propose that the dynamics of Ras nanoclusters may represent a novel target for future therapeutic intervention.