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

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
Life & Health Sciences > Cellular and Molecular Biomedicine
Life & Health Sciences
Uncontrolled Keywords: bimodality,cell heterogeneity,dose-response,signalling networks,Biophysics,Biotechnology,Biomaterials,Biochemistry,Bioengineering,Biomedical Engineering
Full Text Link: http://rsif.roy ... /11/98/20140383
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
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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