Tran Nguyen H N, Frascoli Federico, Clayton Andrew H A
Department of Physics and Astronomy, Optical Sciences Centre, School of Science, Computing and Engineering Technologies, Swinburne University of Technology, Melbourne, VIC 3122, Australia.
Department of Mechanical Engineering and Mechanics, Drexel University, Philadelphia, PA 19094, USA.
Biology (Basel). 2025 Apr 5;14(4):374. doi: 10.3390/biology14040374.
The ERK pathway is an important biochemical cascade and acts as a master regulator of myriad cell processes including cell proliferation, differentiation, and survival. Early biochemical work established that the timing of ERK phosphorylation was an important determinant of PC12 cell fate, with extended phosphorylation (with nerve growth factor treatment) linked to differentiation but rapid on-off ERK phosphorylation kinetics (with epidermal growth factor treatment) linked to cell proliferation. Recent work from several laboratories has revealed that periodic forcing the phosphorylation of ERK with growth factors, light (optogenetics) or electronically can switch cell fate from proliferative to differentiated depending on type of stimulus (amplitude and frequency). Here, we take an ERK model and analyze it from the frequency domain perspective. The key is the transfer function, which provides a compact description of input (growth factor)-output (ERK activation) behavior over a range of input frequencies, allowing an understanding of system dynamics in terms of amplitude modulations, phase shifts, and signaling bandwidths. Our analysis of transfer functions indicates that, at normal receptor levels, the ERK pathway acts as a negative feedback amplifier to growth factor fluctuations, amplifying them at low receptor occupancy but suppressing them at high receptor occupancy. The frequency dependence is best described as a resonant low pass filter, which selectively filters out high frequency input oscillations. We use the transfer function to predict how different growth factor input dynamics shape ERK activation.
ERK通路是一个重要的生化级联反应，是众多细胞过程（包括细胞增殖、分化和存活）的主要调节因子。早期的生化研究表明，ERK磷酸化的时间是PC12细胞命运的一个重要决定因素，延长的磷酸化（用神经生长因子处理）与分化相关，而快速的ERK磷酸化开关动力学（用表皮生长因子处理）与细胞增殖相关。几个实验室最近的研究表明，通过生长因子、光（光遗传学）或电周期性地促使ERK磷酸化，可根据刺激类型（幅度和频率）将细胞命运从增殖转变为分化。在这里，我们采用一个ERK模型并从频域角度对其进行分析。关键是传递函数，它在一系列输入频率上提供了输入（生长因子）-输出（ERK激活）行为的简洁描述，从而能够从幅度调制、相移和信号带宽方面理解系统动态。我们对传递函数的分析表明，在正常受体水平下，ERK通路对生长因子波动起负反馈放大器的作用，在低受体占有率时放大波动，而在高受体占有率时抑制波动。频率依赖性最好描述为一个共振低通滤波器，它能选择性地滤除高频输入振荡。我们利用传递函数预测不同生长因子输入动态如何塑造ERK激活。
