Hyunryul Ryu1,2, Minhwan Chung1, Maciej Dobrzyński3, Dirk Fey3, Yannick Blum4, Sung Sik Lee5, Matthias Peter5, Boris N Kholodenko*,3, Noo Li Jeon*,1,2 and Olivier Pertz*,4, 6
1School of Mechanical and Aerospace Engineering Seoul National University, Seoul, Korea
2Institute of Advanced Machinery and Design Seoul National University, Seoul, Korea
3System Biology Ireland, University College Dublin, Belfield Dublin, Ireland
4Department of Biomedicine, University of Basel, Basel, Switzerland
5Institute of Biochemistry, Zurich, Switzerland
6Institute of Cell Biology University of Bern, Bern, Switzerland
* Corresponding author : Boris N Kholodenko, Noo Li Jeon, Olivier Pertz
Abstract
Transient versus sustained ERK MAP kinase (MAPK) activation dynamics induce proliferation versus differentiation in response to epidermal (EGF) or nerve (NGF) growth factors in PC-12 cells. Duration of ERK activation has therefore been proposed to specify cell fate decisions. Using a biosensor to measure ERK activation dynamics in single living cells reveals that sustained EGF/NGF application leads to a heterogeneous mix of transient and sustained ERK activation dynamics in distinct cells of the population, different than the population average. EGF biases toward transient, while NGF biases toward sustained ERK activation responses. In contrast, pulsed growth factor application can repeatedly and homogeneously trigger ERK activity transients across the cell population. These datasets enable mathematical modeling to reveal salient features inherent to the MAPK network. Ultimately, this predicts pulsed growth factor stimulation regimes that can bypass the typical feedback activation to rewire the system toward cell differentiation irrespective of growth factor identity.