Editors' ChoiceCell Biology

AM and FM Tuning of ERK Signaling

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Science Signaling  29 Jan 2013:
Vol. 6, Issue 260, pp. ec28
DOI: 10.1126/scisignal.2004002

Understanding the dynamic range in which the extracellular signal–regulated protein kinase (ERK) pathway functions to stimulate cell proliferation would aid in the rational development of cancer therapies targeting this pathway. Albeck et al. quantitatively analyzed the activation of the ERK pathway by epidermal growth factor (EGF) by monitoring pathway activity in both live and fixed individual cells. Whereas the phosphorylation of ERK and of Rb (a protein associated with entry into the S phase of the cell cycle) exhibited a bimodal response to increasing EGF concentrations, other outputs, such as the abundance of Fra-1, exhibited a graded response. Live-cell imaging of an ERK fluorescent reporter showed that ERK activity was pulsatile and that the frequency and duration of the pulses increased with increasing EGF concentration. Time-lapse analysis of paired cells showed that the cell in the pair that entered mitosis first exhibited longer pulses, greater frequency of pulses, and an increased fraction of time spent with ERK in the active state, suggesting that frequency of the ERK signal regulates proliferation. Live- and fixed-cell analysis indicated that inhibition of the pathway at the level of the receptor resulted in a reduction in the frequency of ERK activity, whereas inhibition of the kinase upstream of ERK (MEK) resulted in a reduction in the amplitude of the ERK signal. Simulations from models of the regulation of Fra-1 by ERK and experimentation indicated that under saturating EGF concentrations, the pathway must be inhibited more than 85% to see an effect on proliferation.

J. G. Albeck, G. B. Mills, J. S. Brugge, Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals. Mol. Cell 49, 249–261(2013). [PubMed]