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Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate

Nature Cell Biology volume 9, pages 324–330 (2007)Cite this article

An Addendum to this article was published on 01 May 2007

Abstract

The mitogen-activated protein kinase (MAPK) network is a conserved signalling module that regulates cell fate by transducing a myriad of growth-factor signals1. 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 differentiation2. Reverse engineering by modular-response analysis3 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.

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Figure 1: MRA reveals differences in MAPK-network topology.
Figure 2: Dose-response profiles of Erk1/2 activation.
Figure 3: Irreversibility in MAPK network activation on NGF stimulation.
Figure 4: Rewiring MAPK-network topology redirects phenotypic response of PC-12 cells.

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Acknowledgements

We are thankful to G. Nolan for FACS protocols and to A. Riddell (Flow Cytometry Core Facility, EMBL) for technical assistance. We also thank P. Cohen, A. Squire, P. Beltrao and A. Kinkhabwala for very helpful discussions. S. Santos is supported by an 'E-STAR' fellowship funded by the ECs FP6 Marie Curie Host fellowship for Early Stage Research Training under contract number MEST-CT-2004-504640.

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Authors and Affiliations

  1. European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics, Meyerhofstrasse 1, Heidelberg, D-69117, Germany

    Silvia D. M. Santos, Peter J. Verveer & Philippe I. H. Bastiaens

  2. Department of Systemic Biology, MPI for Molecular Physiology, Otto-Hahn Strasse -11, Dortmund, 44227, Germany

    Peter J. Verveer & Philippe I. H. Bastiaens

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  1. Silvia D. M. Santos
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Correspondence to Philippe I. H. Bastiaens.

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Supplementary figures S1, S2, S3 and S4 (PDF 1624 kb)

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Santos, S., Verveer, P. & Bastiaens, P. Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nat Cell Biol 9, 324–330 (2007). https://doi.org/10.1038/ncb1543

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