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 Ca(2+) 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(2+) signals at its multiple levels to regulate cellular function is poorly understood. Here, we investigated the dynamics of Ca(2+)-induced ERK pathway activation in a pancreatic β-cell line using genetically encoded fluorescent biosensors. By carefully manipulating Ca(2+) input signals and directly monitoring the activity dynamics of individual ERK pathway components, we reveal that β-cell Ca(2+) 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(2+)-responsive pathways operate within a hybrid network architecture to achieve both hierarchical and parallel processing of β-cell Ca(2+) oscillations, providing important insights into dynamic signal decoding by this crucial signaling network.