Strasen2018 – TGFβ SMAD Signalling Class 5

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  • Cell‐specific responses to the cytokine TGFβ are determined by variability in protein levels
  • Jette Strasen1,†, Uddipan Sarma2,†, Marcel Jentsch1,3,†, Stefan Bohn3, Caibin Sheng1,3, Daniel Horbelt4, Petra Knaus4, Stefan Legewie (*,2 and Alexander Loewer (*,1,3
  • Molecular Systems Biology , 1/ 2018 , Volume 14 , pages: e7733
  • 1Berlin Institute for Medical Systems Biology, Max Delbrueck Center in the Helmholtz Association, Berlin, Germany 2Institute of Molecular Biology (IMB), Mainz, Germany 3Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany 4Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany * Corresponding author. Tel: +49 6131 39 21430; E‐mail: Corresponding author. Tel: +49 6151 16 28060; E‐mail: † These authors contributed equally to this work
  • The cytokine TGFβ provides important information during embryonic development, adult tissue homeostasis, and regeneration. Alterations in the cellular response to TGFβ are involved in severe human diseases. To understand how cells encode the extracellular input and transmit its information to elicit appropriate responses, we acquired quantitative time‐resolved measurements of pathway activation at the single‐cell level. We established dynamic time warping to quantitatively compare signaling dynamics of thousands of individual cells and described heterogeneous single‐cell responses by mathematical modeling. Our combined experimental and theoretical study revealed that the response to a given dose of TGFβ is determined cell specifically by the levels of defined signaling proteins. This heterogeneity in signaling protein expression leads to decomposition of cells into classes with qualitatively distinct signaling dynamics and phenotypic outcome. Negative feedback regulators promote heterogeneous signaling, as a SMAD7 knock‐out specifically affected the signal duration in a subpopulation of cells. Taken together, we propose a quantitative framework that allows predicting and testing sources of cellular signaling heterogeneity.
uddipan sarma, Rahuman Sheriff

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Figure_5A_class5.xml SBML L2V4 representation of Strasen2018 – TGFβ SMAD Signalling Class 5 93.47 KB Preview | Download

  • Model originally submitted by : uddipan sarma
  • Submitted: Dec 5, 2017 1:40:01 PM
  • Last Modified: Apr 10, 2018 4:36:28 PM
  • Version: 5 public model Download this version
    • Submitted on: Apr 10, 2018 4:36:28 PM
    • Submitted by: Rahuman Sheriff
    • With comment: Edited model metadata online.
  • Version: 3 public model Download this version
    • Submitted on: Jan 26, 2018 6:25:11 AM
    • Submitted by: uddipan sarma
    • With comment: Model revised without commit message
  • Version: 1 unpublished model Download this version
    • Submitted on: Dec 5, 2017 1:40:01 PM
    • Submitted by: uddipan sarma
    • With comment: Import of Signaling_class_5