Nonlinear signalling networks and cell-to-cell variability transform external signals into broadly distributed or bimodal responses

Maciej Dobrzyński*, Lan K. Nguyen, Marc R. Birtwistle, Alexander von Kriegsheim, Alfonso Blanco Fernández, Alex Cheong, Walter Kolch, Boris N. Kholodenko

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

We show theoretically and experimentally a mechanismbehind the emergence of wide or bimodal protein distributions in biochemical networks with nonlinear input-output characteristics (the dose-response curve) and variability in protein abundance. Large cell-to-cell variation in the nonlinear dose-response characteristics can be beneficial to facilitate two distinct groups of response levels as opposed to a graded response. Under the circumstances that we quantify mathematically, the two distinct responses can coexist within a cellular population, leading to the emergence of a bimodal protein distribution. Using flow cytometry, we demonstrate the appearance of wide distributions in the hypoxia-inducible factor-mediated response network in HCT116 cells. With help of our theoretical framework, we perform a novel calculation of the magnitude of cell-to-cell heterogeneity in the dose-response obtained experimentally.

Original languageEnglish
Article number20140383
JournalJournal of the Royal Society Interface
Volume11
Issue number98
DOIs
Publication statusPublished - 25 Jun 2014

Keywords

  • bimodality
  • cell heterogeneity
  • dose-response
  • signalling networks

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    Dobrzyński, M., Nguyen, L. K., Birtwistle, M. R., von Kriegsheim, A., Fernández, A. B., Cheong, A., Kolch, W., & Kholodenko, B. N. (2014). Nonlinear signalling networks and cell-to-cell variability transform external signals into broadly distributed or bimodal responses. Journal of the Royal Society Interface, 11(98), [20140383]. https://doi.org/10.1098/rsif.2014.0383