Stochastic ERK Activation Induced by Noise and Cell-to-Cell Propagation Regulates Cell Density-Dependent Proliferation
Stochastic ERK Activation Induced by Noise and Cell-to-Cell Propagation Regulates Cell Density-Dependent Proliferation
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DOI：
10.1016/j.molcel.2013.09.015
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发表时间：
2013-11-21
期刊：
影响因子：
16
通讯作者：
Matsuda, Michiyuki
中科院分区：
文献类型：
--
作者：
Aoki, Kazuhiro;Kumagai, Yuka;Matsuda, Michiyuki
细胞外信号调节激酶(ERK)在细胞生长的信号级联中起着核心作用。在这里，我们展示了随机ERK活性脉冲以一种依赖于细胞密度的方式调节细胞增殖率。荧光共振能量转移(FRET)生物传感器显示，随机ERK活性脉冲自发激发或从相邻细胞传播。ERK活动脉冲的频率，而不是幅度，对细胞密度呈钟形响应，并与细胞增殖率相关。持续不断的是，由光可切换CRAF蛋白产生的合成ERK活性脉冲加速了细胞的增殖。数学模型表明，80%和20%的ERK活动脉冲分别由噪声和细胞间传播产生。最后，对受人工合成的ERK活性脉冲作用的细胞的RNA测序分析表明，血清反应因子(SRF)转录因子参与了ERK活性脉冲驱动的基因表达。
The extracellular signal-regulated kinase (ERK) plays a central role in the signaling cascades of cell growth. Here, we show that stochastic ERK activity pulses regulate cell proliferation rates in a cell density-dependent manner. A fluorescence resonance energy transfer (FRET) biosensor revealed that stochastic ERK activity pulses fired spontaneously or propagated from adjacent cells. Frequency, but not amplitude, of ERK activity pulses exhibited a bell-shaped response to the cell density and correlated with cell proliferation rates. Consistently, synthetic ERK activity pulses generated by a light-switchable CRaf protein accelerated cell proliferation. A mathematical model clarified that 80% and 20% of ERK activity pulses are generated by the noise and cell-to-cell propagation, respectively. Finally, RNA sequencing analysis of cells subjected to the synthetic ERK activity pulses suggested the involvement,of serum responsive factor (SRF) transcription factors in the gene expression driven by the ERK activity pulses.