2. Academic Validation
  3. Disentangling Pro-mitotic Signaling during Cell Cycle Progression using Time-Resolved Single-Cell Imaging

Disentangling Pro-mitotic Signaling during Cell Cycle Progression using Time-Resolved Single-Cell Imaging

  • Cell Rep. 2020 Apr 14;31(2):107514. doi: 10.1016/j.celrep.2020.03.078.
Manuela Benary 1,  Stefan Bohn 2,  Mareen Lüthen 3,  Ilias K Nolis 4,  Nils Blüthgen 5,  Alexander Loewer 6
Affiliations

Affiliations

  • 1 Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; Institute for Theoretical Biology, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany; Integrative Research Institute Life Sciences, Humboldt University Berlin, 10115 Berlin, Germany.
  • 2 Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
  • 3 Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 4 Berlin Institute for Medical Systems Biology, Max Delbrueck Center in the Helmholtz Association, 13125 Berlin, Germany.
  • 5 Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; Institute for Theoretical Biology, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany; Integrative Research Institute Life Sciences, Humboldt University Berlin, 10115 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: nils.bluethgen@charite.de.
  • 6 Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany; Berlin Institute for Medical Systems Biology, Max Delbrueck Center in the Helmholtz Association, 13125 Berlin, Germany. Electronic address: loewer@bio.tu-darmstadt.de.
PMID: 32294432 DOI: 10.1016/j.celrep.2020.03.078
Abstract

Cells rely on input from extracellular growth factors to control their proliferation during development and adult homeostasis. Such mitogenic inputs are transmitted through multiple signaling pathways that synergize to precisely regulate cell cycle entry and progression. Although the architecture of these signaling networks has been characterized in molecular detail, their relative contribution, especially at later cell cycle stages, remains largely unexplored. By combining quantitative time-resolved measurements of fluorescent reporters in untransformed human cells with targeted pharmacological inhibitors and statistical analysis, we quantify epidermal growth factor (EGF)-induced signal processing in individual cells over time and dissect the dynamic contribution of downstream pathways. We define signaling features that encode information about extracellular ligand concentrations and critical time windows for inducing cell cycle transitions. We show that both extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) activity are necessary for initial cell cycle entry, whereas only PI3K affects the duration of S phase at later stages of mitogenic signaling.

Keywords

MAPK pathway; PI3K pathway; cell-cycle; information theory; mitogenic signaling; scRNA-seq; signaling dynamics; single-cell analysis; time-lapse microscopy.

Figures
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