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Mol Syst Biol. 2015 Nov 27;11(11):838. doi: 10.15252/msb.20156458.

Frequency modulation of ERK activation dynamics rewires cell fate.

Author information

1
School of Mechanical and Aerospace Engineering Seoul National University, Seoul, Korea Institute of Advanced Machinery and Design Seoul National University, Seoul, Korea.
2
School of Mechanical and Aerospace Engineering Seoul National University, Seoul, Korea.
3
System Biology Ireland, University College Dublin, Belfield Dublin, Ireland.
4
Department of Biomedicine, University of Basel, Basel, Switzerland.
5
Institute of Biochemistry, Zurich, Switzerland.
6
System Biology Ireland, University College Dublin, Belfield Dublin, Ireland boris.kholodenko@ucd.ie njeon@snu.ac.kr olivier.pertz@izb.unibe.ch.
7
School of Mechanical and Aerospace Engineering Seoul National University, Seoul, Korea Institute of Advanced Machinery and Design Seoul National University, Seoul, Korea boris.kholodenko@ucd.ie njeon@snu.ac.kr olivier.pertz@izb.unibe.ch.
8
Department of Biomedicine, University of Basel, Basel, Switzerland boris.kholodenko@ucd.ie njeon@snu.ac.kr olivier.pertz@izb.unibe.ch.

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.

KEYWORDS:

ERK activity dynamics; FRET biosensor; cell fate decisions; signaling heterogeneity; single cell biology

PMID:
26613961
PMCID:
PMC4670727
[Indexed for MEDLINE]
Free PMC Article

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