title: Frequency modulation of ERK activation dynamics rewires cell fate.
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.
authors.affiliation: School of Mechanical and Aerospace Engineering Seoul National University, Seoul, Korea Institute of Advanced Machinery and Design Seoul National University, Seoul, Korea.
authors.forename: Hyunryul
authors.initials: H
authors.lastname: Ryu
authors.affiliation: School of Mechanical and Aerospace Engineering Seoul National University, Seoul, Korea.
authors.forename: Minhwan
authors.initials: M
authors.lastname: Chung
authors.affiliation: System Biology Ireland, University College Dublin, Belfield Dublin, Ireland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Dobrzyński
authors.affiliation: System Biology Ireland, University College Dublin, Belfield Dublin, Ireland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Fey
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Blum
authors.affiliation: Institute of Biochemistry, Zurich, Switzerland.
authors.forename: Sung Sik
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Institute of Biochemistry, Zurich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Peter
authors.affiliation: System Biology Ireland, University College Dublin, Belfield Dublin, Ireland boris.kholodenko@ucd.ie njeon@snu.ac.kr olivier.pertz@izb.unibe.ch.
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
authors.affiliation: 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.
authors.forename: Noo Li
authors.initials: NL
authors.lastname: Jeon
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland boris.kholodenko@ucd.ie njeon@snu.ac.kr olivier.pertz@izb.unibe.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Pertz
mesh_terms: D000818:Animals; D015374:Biosensing Techniques; D002454:Cell Differentiation / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D046210:Microfluidic Analytical Techniques; D008954:Models, Biological; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D049490:Systems Biology / Q000379:methods*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ERK activity dynamics; FRET biosensor; cell fate decisions; signaling heterogeneity; single cell biology