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Amplitude, duration, and frequency of activation of the extracellular-signal-regulated kinase (ERK) pathway code distinct information to instruct cells to migrate, proliferate, or differentiate. Synchronized frequency control of ERK activation would provide a powerful approach to regulate cell behaviors. Here we demonstrated modulation of ERK activities using alternative current (AC) electric fields (EFs) applied through high-k dielectric passivated microelectrodes. Both the amplitude and frequency of ERK activation can be precisely synchronized and modulated. ERK activation in our system is independent of Faradaic currents and electroporation, thus excluding mechanisms of changes in pH, reactive oxygen species, and other electrochemical reaction. Further experiments pinpointed a mechanism of phosphorylation site of epidermal growth factor (EGF) receptor to activate the EGFR-ERK pathway, and independent of EGF. AC EFs thus provide a powerful platform for practical and precise control of EGFR-ERK pathway.

Controlling ERK Activation Dynamics in Mammary Epithelial Cells with Alternating Electric Fields through Microelectrodes