Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals.
Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals.
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DOI：
10.1016/j.molcel.2012.11.002
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发表时间：
2013-01-24
期刊：
影响因子：
16
通讯作者：
Brugge JS
中科院分区：
文献类型：
--
作者：
Albeck JG;Mills GB;Brugge JS
EGF刺激的ERK/MAPK通路是细胞增殖信号的关键通道，也是许多癌症的治疗靶点。在这里，我们描述了这一途径的两个主要的定量方面：信号强度编码的机制和信号输出与增殖相关的响应曲线。在稳态条件下，我们发现，ERK被激活的离散，异步脉冲的频率和持续时间由细胞外浓度的EGF跨越生理范围。在遗传上相同的姐妹细胞中，细胞间脉冲动力学的变异性影响进入S期的决定。虽然EGFR的靶向抑制降低了ERK活性脉冲的频率，但MEK的抑制降低了它们的振幅。在多个细胞系中测量的连续响应曲线显示，仅当ERK途径输出福尔斯下降到低于约10%的阈值时，增殖才被有效沉默，这表明高剂量靶向该途径是实现治疗功效所必需的。
The EGF-stimulated ERK/MAPK pathway is a key conduit for cellular proliferation signals and a therapeutic target in many cancers. Here, we characterize two central quantitative aspects of this pathway: the mechanism by which signal strength is encoded and the response curve relating signal output to proliferation. Under steady-state conditions, we find that ERK is activated in discrete, asynchronous pulses with frequency and duration determined by extracellular concentrations of EGF spanning the physiological range. In genetically identical sister cells, cell-to-cell variability in pulse dynamics influences the decision to enter S-phase. While targeted inhibition of EGFR reduces the frequency of ERK activity pulses, inhibition of MEK reduces their amplitude. Continuous response curves measured in multiple cell lines reveal that proliferation is effectively silenced only when ERK pathway output falls below a threshold of ~10%, indicating that high-dose targeting of the pathway is necessary to achieve therapeutic efficacy.
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