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- Title
Temporal perturbation of ERK dynamics reveals network architecture of FGF2/MAPK signaling.
- Authors
Blum, Yannick; Mikelson, Jan; Dobrzyński, Maciej; Ryu, Hyunryul; Jacques, Marc‐Antoine; Jeon, Noo Li; Khammash, Mustafa; Pertz, Olivier
- Abstract
Stimulation of PC‐12 cells with epidermal (EGF) versus nerve (NGF) growth factors (GFs) biases the distribution between transient and sustained single‐cell ERK activity states, and between proliferation and differentiation fates within a cell population. We report that fibroblast GF (FGF2) evokes a distinct behavior that consists of a gradually changing population distribution of transient/sustained ERK signaling states in response to increasing inputs in a dose response. Temporally controlled GF perturbations of MAPK signaling dynamics applied using microfluidics reveal that this wider mix of ERK states emerges through the combination of an intracellular feedback, and competition of FGF2 binding to FGF receptors (FGFRs) and heparan sulfate proteoglycan (HSPG) co‐receptors. We show that the latter experimental modality is instructive for model selection using a Bayesian parameter inference. Our results provide novel insights into how different receptor tyrosine kinase (RTK) systems differentially wire the MAPK network to fine‐tune fate decisions at the cell population level. Synopsis: Analyses of single‐cell MAPK/ERK signaling dynamics in response to temporally controlled EGF, NGF, FGF2 stimulations show that FGF2 evokes distinct signaling dynamics compared to EGF/NGF. A mathematical model that accounts for these responses is presented. FGF2 leads to distinct population distributions of dynamic ERK states compared to EGF/NGF.Increasing FGF2 inputs gradually shifts the population distribution of ERK states.Temporal perturbations provide new insights into FGF2/MAPK signaling network structure.FGFR/HSPG interactions enable the gradually changing distributions of ERK states.
- Subjects
HEPARAN sulfate; PROTEIN-tyrosine kinases; CELL determination; CELL populations; EXTRACELLULAR signal-regulated kinases
- Publication
Molecular Systems Biology, 2019, Vol 15, Issue 11, pN.PAG
- ISSN
1744-4292
- Publication type
Article
- DOI
10.15252/msb.20198947