Extracellular signal-regulated kinase (ERK) has long been studied as a key driver of both essential cellular processes and disease. A persistent question has been how this single pathway is able to direct multiple cell behaviors, including growth, proliferation, and death. Modern biosensor studies have revealed that the temporal pattern of ERK activity is highly variable and heterogeneous, and critically, that these dynamic differences modulate cell fate. This two-part review discusses the current understanding of dynamic activity in the ERK pathway, how it regulates cellular decisions, and how these cell fates lead to tissue regulation and pathology. In part 1, we cover the optogenetic and live-cell imaging technologies that first revealed the dynamic nature of ERK, as well as current challenges in biosensor data analysis. We also discuss advances in mathematical models for the mechanisms of ERK dynamics, including receptor-level regulation, negative feedback, cooperativity, and paracrine signaling. While hurdles still remain, it is clear that higher temporal and spatial resolution provide mechanistic insights into pathway circuitry. Exciting new algorithms and advanced computational tools enable quantitative measurements of single-cell ERK activation, which in turn inform better models of pathway behavior. However, the fact that current models still cannot fully recapitulate the diversity of ERK responses calls for a deeper understanding of network structure and signal transduction in general.

中文翻译：

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ERK 动力学指南，第 1 部分：机制和模型

细胞外信号调节激酶 (ERK) 长期以来一直被研究为重要细胞过程和疾病的关键驱动因素。一个持续存在的问题是，这条单一途径如何能够指导多种细胞行为，包括生长、增殖和死亡。现代生物传感器研究表明，ERK 活性的时间模式具有高度可变性和异质性，而且至关重要的是，这些动态差异会调节细胞命运。这篇由两部分组成的综述讨论了目前对 ERK 通路动态活动的理解、它如何调节细胞决策，以及这些细胞命运如何导致组织调节和病理学。在第 1 部分中，我们介绍了首次揭示 ERK 动态性质的光遗传学和活细胞成像技术，以及当前生物传感器数据分析中的挑战。我们还讨论了 ERK 动力学机制数学模型的进展，包括受体水平调节、负反馈、协同性和旁分泌信号传导。虽然障碍仍然存在，但很明显，更高的时间和空间分辨率可以提供对通路电路的机械见解。令人兴奋的新算法和先进的计算工具可以定量测量单细胞 ERK 激活，从而为更好的通路行为模型提供信息。然而，当前模型仍然无法完全概括 ERK 反应的多样性，这一事实需要对网络结构和信号转导有更深入的了解。