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

Nature Cell Biology volume 9, pages 324330 (2007) | Download Citation

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  • 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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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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Affiliations

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

    • Silvia D. M. Santos
    • , Peter J. Verveer
    •  & Philippe I. H. Bastiaens
  2. MPI for Molecular Physiology, Department of Systemic Biology, Otto-Hahn Strasse -11, 44227 Dortmund, Germany.

    • Peter J. Verveer
    •  & Philippe I. H. Bastiaens

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Philippe I. H. Bastiaens.

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DOI

https://doi.org/10.1038/ncb1543

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