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

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

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.

Publication DOI: https://doi.org/10.1098/rsif.2014.0383
Divisions: Life & Health Sciences > Pharmacy
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Uncontrolled Keywords: bimodality,cell heterogeneity,dose-response,signalling networks,Biophysics,Biotechnology,Biomaterials,Biochemistry,Bioengineering,Biomedical Engineering

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