Oscillatory signal decoding within the ERK cascade

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 Ca²⁺ 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 Ca²⁺ signals at its multiple levels to regulate cellular function is poorly understood. Here, we investigated the dynamics of Ca²⁺-induced ERK pathway activation in a pancreatic β-cell line using genetically encoded fluorescent biosensors. By carefully manipulating Ca²⁺ input signals and directly monitoring the activity dynamics of individual ERK pathway components, we reveal that β-cell Ca²⁺ 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 Ca²⁺-responsive pathways operate within a hybrid network architecture to achieve both hierarchical and parallel processing of β-cell Ca²⁺ oscillations, providing important insights into dynamic signal decoding by this crucial signaling network.