Excitable dynamics of Ras triggers spontaneous symmetry breaking of PIP3 signaling in motile cells
Excitable dynamics of Ras triggers spontaneous symmetry breaking of PIP3 signaling in motile cells
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DOI：
10.1242/jcs.224121
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发表时间：
2019-03-01
影响因子：
4
通讯作者：
Ueda, Masahiro
中科院分区：
文献类型：
--
作者：
Fukushima, Seiya;Matsuoka, Satomi;Ueda, Masahiro
自发细胞运动是由信号分子的不对称分布，包括小G蛋白和磷酸肌醇细胞膜上的支持。然而，自发对称破缺所必需的分子网络尚未完全阐明。在这里，我们报告说，在Dictyosteelium discoideum，时空动态的GTP结合Ras（Ras-GTP）打破了对称性，由于其内在的兴奋性，即使在没有细胞外的空间线索和下游信号活动。局部和瞬时Ras激活的随机激发通过与磷酸肌醇3-激酶（PI 3 K）的直接相互作用诱导磷脂酰肌醇（3，4，5）-三磷酸（PIP 3）积累，引起紧密耦合的行波，其沿膜沿着传播。Ras-GTP和PIP 3代谢相关分子波的综合相位分析揭示了可兴奋系统的网络结构，包括下游PIP 3对Ras-GTP的正反馈调节。一个数学模型重建了一系列观察到的破环现象，说明Ras兴奋性在细胞决策过程中的重要参与。
Spontaneous cell movement is underpinned by an asymmetric distribution of signaling molecules including small G proteins and phosphoinositides on the cell membrane. However, the molecular network necessary for spontaneous symmetry breaking has not been fully elucidated. Here, we report that, in Dictyostelium discoideum, the spatiotemporal dynamics of GTP bound Ras (Ras-GTP) breaks the symmetry due its intrinsic excitability even in the absence of extracellular spatial cues and downstream signaling activities. A stochastic excitation of local and transient Ras activation induced phosphatidylinositol (3,4,5)-trisphosphate (PIP3) accumulation via direct interaction with Phosphoinositide 3-kinase (PI3K), causing tightly coupled traveling waves that propagated along the membrane. Comprehensive phase analysis of the waves of Ras-GTP and PIP3 metabolism-related molecules revealed the network structure of the excitable system including positive-feedback regulation of Ras-GTP by the downstream PIP3. A mathematical model reconstituted a series of the observed symmetry-breaking phenomena, illustrating the essential involvement of Ras excitability in the cellular decision-making process.