Mutually inhibitory Ras-PI(3,4)P(2) feedback loops mediate cell migration.
Mutually inhibitory Ras-PI(3,4)P(2) feedback loops mediate cell migration.
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DOI：
10.1073/pnas.1809039115
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发表时间：
2018-09-25
影响因子：
11.1
通讯作者：
Devreotes PN
中科院分区：
文献类型：
--
作者：
Li X;Edwards M;Swaney KF;Singh N;Bhattacharya S;Borleis J;Long Y;Iglesias PA;Chen J;Devreotes PN
细胞迁移在免疫反应和肿瘤转移等生理和病理状态中起着中心作用。可兴奋网络假说可以解释最近观察到的信号转导和细胞骨架事件的传播波以及迁移细胞的行为。然而，这些网络中涉及的带来兴奋性的分子反馈环却知之甚少。在这里，我们提供了基于RAS和磷脂酰肌醇(3，4)-二磷酸[PI(3，4)P2]之间相互抑制作用的正反馈环的证据。我们的结果揭示了PI(3，4)P2在调节RAS活性中的重要作用，这种作用可能远远超出细胞迁移。信号转导和细胞骨架网络在多种细胞中表现出兴奋性，但其机制尚不清楚。在这里，我们表明，在随机迁移和对化学诱导剂的反应中，细胞保持RAS活性和磷脂酰肌醇(3，4)-二磷酸[PI(3，4)P2]的互补空间和时间分布。此外，通过破坏5-磷酸酶Dd5P4或通过将4-磷酸酶INPP4B重新聚集到质膜上，PI(3，4)P2被耗尽，导致RAS活性增加，细胞扩张，并改变迁移行为。此外，RasGAP2和RapGAP3与PI(3，4)P2结合，缺乏这些基因的细胞的表型与低PI(3，4)P2的表型相似，提供了一种分子机制。这些发现表明，RAS活性促使PI(3，4)P2下降，导致PI(3，4)P2结合间隙从膜上解离，进一步激活RAS，完成对兴奋性至关重要的正反馈回路。在可兴奋网络模型中加入这种反馈回路的计算模型一致地精确地模拟了活性RAS和PI(3，4)P2的动态分布以及细胞的迁移行为。我们在此揭示的相互抑制的Ras-PI(3，4)P2机制为RAS的调节提供了一个框架，该框架可能在许多生理过程中发挥关键作用。
Cell migration is central in physiological and pathological conditions such as immune response and cancer metastasis. The excitable network hypothesis can account for recent observations of propagating waves of signal transduction and cytoskeleton events as well as behaviors of migrating cells. However, the molecular feedback loops involved in these networks that bring about excitability are poorly understood. Here, we provide evidence for a positive-feedback loop based on a mutual inhibitory interaction between Ras and phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2]. Our results uncover an important role of PI(3,4)P2 in the regulation of Ras activity, which may extend well beyond cell migration. Signal transduction and cytoskeleton networks in a wide variety of cells display excitability, but the mechanisms are poorly understood. Here, we show that during random migration and in response to chemoattractants, cells maintain complementary spatial and temporal distributions of Ras activity and phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2]. In addition, depletion of PI(3,4)P2 by disruption of the 5-phosphatase, Dd5P4, or by recruitment of 4-phosphatase INPP4B to the plasma membrane, leads to elevated Ras activity, cell spreading, and altered migratory behavior. Furthermore, RasGAP2 and RapGAP3 bind to PI(3,4)P2, and the phenotypes of cells lacking these genes mimic those with low PI(3,4)P2 levels, providing a molecular mechanism. These findings suggest that Ras activity drives PI(3,4)P2 down, causing the PI(3,4)P2-binding GAPs to dissociate from the membrane, further activating Ras, completing a positive-feedback loop essential for excitability. Consistently, a computational model incorporating such a feedback loop in an excitable network model accurately simulates the dynamic distributions of active Ras and PI(3,4)P2 as well as cell migratory behavior. The mutually inhibitory Ras-PI(3,4)P2 mechanisms we uncovered here provide a framework for Ras regulation that may play a key role in many physiological processes.
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影响因子：
2
作者：
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影响因子：
3.3
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