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Prediction and validation of the distinct dynamics of transient and sustained ERK activation

Nature Cell Biology volume 7, pages 365–373 (2005)Cite this article

Abstract

To elucidate the hidden dynamics of extracellular-signal-regulated kinase (ERK) signalling networks, we developed a simulation model of ERK signalling networks by constraining in silico dynamics based on in vivo dynamics in PC12 cells. We predicted and validated that transient ERK activation depends on rapid increases of epidermal growth factor and nerve growth factor (NGF) but not on their final concentrations, whereas sustained ERK activation depends on the final concentration of NGF but not on the temporal rate of increase. These ERK dynamics depend on Ras and Rap1 dynamics, the inactivation processes of which are growth-factor-dependent and -independent, respectively. Therefore, the Ras and Rap1 systems capture the temporal rate and concentration of growth factors, and encode these distinct physical properties into transient and sustained ERK activation, respectively.

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Figure 1: Schematic overview of EGF- and NGF-dependent ERK signalling networks.
Figure 2: In vivo and in silico dynamics of ERK signalling networks.
Figure 3: Distinct dynamics of transient and sustained ERK activation.
Figure 4: In silico and in vivo ERK activation in response to stepwise increases of EGF and to stepwise decreases of NGF.
Figure 5: Distinct dynamics of EGF- and NGF-dependent Ras and Rap1 activation.
Figure 6: Characteristics of Ras and Rap1 activation in the simple Ras and Rap1 models.
Figure 7: Transient Ras activation, and Ras, Rap1 and ERK activation at steady state.
Figure 8: The distinct temporal dynamics of transient and sustained ERK activation via Ras and Rap1 activation.

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Acknowledgements

We thank K. Kaibuchi, Y. Gotoh, M. Kawato and M. Arita for critically reading this manuscript, and R. Kettunen and R. Kunihiro for their technical assistance. This work was supported in part by a grant in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a grant in-aid from Uehara Memorial Foundation.

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  1. Satoru Sasagawa and Yu-ichi Ozaki: These authors contributed equally to this work.

Authors and Affiliations

  1. Undergraduate Program for Bioinformatics and Systems Biology, Graduate School of Information Science and Technology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Satoru Sasagawa, Yu-ichi Ozaki & Shinya Kuroda

  2. Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, 277-8583, Japan

    Kazuhiro Fujita & Shinya Kuroda

  3. PRESTO, Japan Science and Technology Agency, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Shinya Kuroda

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  1. Satoru Sasagawa
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Correspondence to Shinya Kuroda.

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Supplementary Figures S1, S2, S3, S4 and S5 (PDF 726 kb)

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Sasagawa, S., Ozaki, Yi., Fujita, K. et al. Prediction and validation of the distinct dynamics of transient and sustained ERK activation. Nat Cell Biol 7, 365–373 (2005). https://doi.org/10.1038/ncb1233

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