Receptor Level Mechanisms Are Required for Epidermal Growth Factor (EGF)-stimulated Extracellular Signal-regulated Kinase (ERK) Activity Pulses

摘要: In both physiological and cell culture systems, EGF-stimulated ERK activity occurs in discrete pulses within individual cells. Many feedback loops are present the EGF receptor (EGFR)-ERK network, but mechanisms driving pulsatile kinetics unknown. Here, we find that cells respond to with frequency-modulated activity, stimulation through a heterologous TrkA system results non-pulsatile, amplitude-modulated activation of ERK. We further dissect pulse using combination FRET- translocation-based reporters EGFR is required maintain throughout 10–20-minute lifetime pulses. Together, these data indicate feedbacks operating core Ras-Raf-MEK-ERK cascade insufficient drive instead implicate acting at level EGFR.