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. (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),

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
Uncontrolled Keywords: bimodality,cell heterogeneity,dose-response,signalling networks,Biophysics,Biotechnology,Biomaterials,Biochemistry,Bioengineering,Biomedical Engineering
Full Text Link: http://www.scopus.com/inward/record.url?scp=84905055041&partnerID=8YFLogxK Full Text Link: http://rsif.royalsocietypublishing.org/content/11/98/20140383
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Published Date: 2014-06-25
Authors: Dobrzyński, Maciej
Nguyen, Lan K.
Birtwistle, Marc R.
von Kriegsheim, Alexander
Fernández, Alfonso Blanco
Cheong, Alex ( 0000-0003-2482-9078)
Kolch, Walter
Kholodenko, Boris N.

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