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Sensitivity control through attenuation of signal transfer efficiency by negative regulation of cellular signalling

Author

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  • Yu Toyoshima

    (Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.)

  • Hiroaki Kakuda

    (Graduate School of Frontier Sciences, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.)

  • Kazuhiro A. Fujita

    (Graduate School of Frontier Sciences, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
    Present address: The Systems Biology Institute, Shirokanaedai 5-6-9, Minato-ku, Tokyo 108-0071, Japan.)

  • Shinsuke Uda

    (Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.)

  • Shinya Kuroda

    (Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
    Graduate School of Frontier Sciences, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
    CREST, Japan Science and Technology Corporation)

Abstract

Sensitivity is one of the hallmarks of biological and pharmacological responses. However, the principle of controlling sensitivity remains unclear. Here we theoretically analyse a simple biochemical reaction and find that the signal transfer efficiency of the transient peak amplitude attenuates depending on the strength of negative regulation. We experimentally find that many signalling pathways in various cell lines, including the Akt and ERK pathways, can be approximated by simple biochemical reactions and that the same property of the attenuation of signal transfer efficiency was observed for such pathways. Because of this property, a downstream molecule should show higher sensitivity to an activator and lower sensitivity to an inhibitor than an upstream molecule. Indeed, we experimentally verify that S6, which lies downstream of Akt, shows lower sensitivity to an epidermal growth factor receptor inhibitor than Akt. Thus, cells can control downstream sensitivity through the attenuation of signal transfer efficiency by changing the expression level of negative regulators.

Suggested Citation

  • Yu Toyoshima & Hiroaki Kakuda & Kazuhiro A. Fujita & Shinsuke Uda & Shinya Kuroda, 2012. "Sensitivity control through attenuation of signal transfer efficiency by negative regulation of cellular signalling," Nature Communications, Nature, vol. 3(1), pages 1-8, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1745
    DOI: 10.1038/ncomms1745
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    Cited by:

    1. Juliane Liepe & Sarah Filippi & Michał Komorowski & Michael P H Stumpf, 2013. "Maximizing the Information Content of Experiments in Systems Biology," PLOS Computational Biology, Public Library of Science, vol. 9(1), pages 1-13, January.
    2. Kaoru Ohashi & Hisako Komada & Shinsuke Uda & Hiroyuki Kubota & Toshinao Iwaki & Hiroki Fukuzawa & Yasunori Komori & Masashi Fujii & Yu Toyoshima & Kazuhiko Sakaguchi & Wataru Ogawa & Shinya Kuroda, 2015. "Glucose Homeostatic Law: Insulin Clearance Predicts the Progression of Glucose Intolerance in Humans," PLOS ONE, Public Library of Science, vol. 10(12), pages 1-19, December.

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