Self-organization of the phosphatidylinositol lipids signaling system for random cell migration
Self-organization of the phosphatidylinositol lipids signaling system for random cell migration
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DOI：
10.1073/pnas.0908278107
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发表时间：
2010-07-06
影响因子：
11.1
通讯作者：
Ueda, Masahiro
中科院分区：
文献类型：
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作者：
Arai, Yoshiyuki;Shibata, Tatsuo;Ueda, Masahiro
磷脂酰肌醇 (PtdIns) 脂质已被确定为随机细胞迁移以及趋化剂诱导的定向迁移的关键信号传导介质。然而，PtdIns 脂质如何在时空上组织以调节细胞运动和极性仍有待阐明。在这里，我们发现在没有化学引诱剂的情况下，盘基网柄菌细胞膜上会自发产生 PtdIns 3,4,5-三磷酸 [PtdIns(3,4,5)P-3] 的自组织波。通过观察单细胞中 PtdIns 脂质波的表型变异性，实验确定了 PtdIns 脂质信号系统内的特征振荡动力学，该信号表现出弛豫振荡器的特征。磷酸酶和张力蛋白同源物 (PTEN) 和磷酸肌醇 3 激酶 (PI3K) 是膜上 PtdIns 脂质浓度的调节因子，对于波的产生至关重要，而功能性肌动蛋白细胞骨架则不然。这些酶的缺陷抑制了波的产生以及基于肌动蛋白的极化和细胞迁移。在这些实验结果的基础上，我们开发了一个反应扩散模型，再现了PtdIns脂质系统的特征弛豫振荡动力学，说明自组织机制为PtdIns脂质信号系统产生随机细胞迁移的自发时空信号提供了基础，而信号成分内随机波动产生的分子噪声引起了这些自发信号的可变性。
Phosphatidylinositol (PtdIns) lipids have been identified as key signaling mediators for random cell migration as well as chemoattractant-induced directional migration. However, how the PtdIns lipids are organized spatiotemporally to regulate cellular motility and polarity remains to be clarified. Here, we found that self-organized waves of PtdIns 3,4,5-trisphosphate [PtdIns(3,4,5)P-3] are generated spontaneously on the membrane of Dictyostelium cells in the absence of a chemoattractant. Characteristic oscillatory dynamics within the PtdIns lipids signaling system were determined experimentally by observing the phenotypic variability of PtdIns lipid waves in single cells, which exhibited characteristics of a relaxation oscillator. The enzymes phosphatase and tensin homolog (PTEN) and phosphoinositide-3-kinase (PI3K), which are regulators for PtdIns lipid concentrations along the membrane, were essential for wave generation whereas functional actin cytoskeleton was not. Defects in these enzymes inhibited wave generation as well as actin-based polarization and cell migration. On the basis of these experimental results, we developed a reaction-diffusion model that reproduced the characteristic relaxation oscillation dynamics of the PtdIns lipid system, illustrating that a self-organization mechanism provides the basis for the PtdIns lipids signaling system to generate spontaneous spatiotemporal signals for random cell migration and that molecular noise derived from stochastic fluctuations within the signaling components gives rise to the variability of these spontaneous signals.