Abstract
The mitogen-activated protein kinase (MAPK) network is a conserved signalling module that regulates cell fate by transducing a myriad of growth-factor signals. The ability of this network to coordinate and process a variety of inputs from different growth-factor receptors into specific biological responses is, however, still not understood. We investigated how the MAPK network brings about signal specificity in PC-12 cells, a model for neuronal differentiation. Reverse engineering by modular-response analysis uncovered topological differences in the MAPK core network dependent on whether cells were activated with epidermal or neuronal growth factor (EGF or NGF). On EGF stimulation, the network exhibited negative feedback only, whereas a positive feedback was apparent on NGF stimulation. The latter allows for bi-stable Erk activation dynamics, which were indeed observed. By rewiring these regulatory feedbacks, we were able to reverse the specific cell responses to EGF and NGF. These results show that growth factor context determines the topology of the MAPK signalling network and that the resulting dynamics govern cell fate.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Cycle / drug effects
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cell Proliferation / drug effects
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Epidermal Growth Factor / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Flow Cytometry
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Intercellular Signaling Peptides and Proteins / pharmacology*
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MAP Kinase Kinase 1 / genetics
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MAP Kinase Kinase 1 / metabolism
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology*
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Models, Biological
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Monte Carlo Method
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Nerve Growth Factor / pharmacology
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PC12 Cells
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Phosphorylation / drug effects
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Proto-Oncogene Proteins c-raf / genetics
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Proto-Oncogene Proteins c-raf / metabolism
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RNA, Small Interfering / genetics
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Rats
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Receptor, trkA / antagonists & inhibitors
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Tetradecanoylphorbol Acetate / pharmacology
Substances
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Intercellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Epidermal Growth Factor
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Nerve Growth Factor
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Receptor, trkA
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Proto-Oncogene Proteins B-raf
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Proto-Oncogene Proteins c-raf
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Protein Kinase C
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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MAP Kinase Kinase 1
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Tetradecanoylphorbol Acetate