Ganesan Ambhighainath, Lee Ha Neul, Tenner Brian, Mehta Sohum, Levchenko Andre, Zhang Jin
Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Pharmacology, University of California San Diego, La Jolla, CA 92093, USA.
bioRxiv. 2025 Jul 28:2025.07.24.666680. doi: 10.1101/2025.07.24.666680.
Extracellular-signal-regulated kinase (ERK) integrates multiple growth factor and hormone stimuli to control essential cellular processes such as proliferation, survival, and migration. In electrically excitable cells, the ERK pathway also interfaces with intracellular Ca dynamics to achieve non-canonical, cell-type specific functions, having been implicated in neuronal synaptic plasticity, cardiac hypertrophy, and pancreatic insulin secretion. Yet how the classical Ras/MEK/ERK cascade responds to and decodes dynamic Ca signals at its multiple levels to regulate cellular function is poorly understood. Here, we investigated the dynamics of Ca-induced ERK pathway activation in a pancreatic β-cell line using genetically encoded fluorescent biosensors. By carefully manipulating Ca input signals and directly monitoring the activity dynamics of individual ERK pathway components, we reveal that β-cell Ca oscillations undergo sequential signal processing along the ERK cascade, mediated by the characteristic response kinetics at each pathway step. We further demonstrate that the ERK cascade and possibly other Ca-responsive pathways operate within a hybrid network architecture to achieve both hierarchical and parallel processing of β-cell Ca oscillations, providing important insights into dynamic signal decoding by this crucial signaling network.
细胞外信号调节激酶（ERK）整合多种生长因子和激素刺激，以控制细胞增殖、存活和迁移等基本细胞过程。在电可兴奋细胞中，ERK信号通路还与细胞内钙动态相互作用，以实现非经典的、细胞类型特异性功能，这与神经元突触可塑性、心脏肥大和胰腺胰岛素分泌有关。然而，经典的Ras/MEK/ERK级联如何在多个水平上响应并解码动态钙信号以调节细胞功能，目前仍知之甚少。在这里，我们使用基因编码的荧光生物传感器研究了胰腺β细胞系中钙诱导的ERK信号通路激活的动力学。通过仔细操纵钙输入信号并直接监测单个ERK信号通路组件的活性动态，我们发现β细胞钙振荡沿着ERK级联进行顺序信号处理，这是由每个信号通路步骤的特征响应动力学介导的。我们进一步证明，ERK级联以及可能的其他钙响应信号通路在混合网络架构中运行，以实现β细胞钙振荡的分级和平行处理，为这个关键信号网络的动态信号解码提供了重要见解。
