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

Author:

Dobrzyński Maciej1ORCID,Nguyen Lan K.1,Birtwistle Marc R.12,von Kriegsheim Alexander1,Blanco Fernández Alfonso3,Cheong Alex14ORCID,Kolch Walter156,Kholodenko Boris N.156

Affiliation:

1. Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland

2. Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA

3. Flow Cytometry Core Technologies, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland

4. School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK

5. Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland

6. School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland

Abstract

We show theoretically and experimentally a mechanism behind 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.

Publisher

The Royal Society

Subject

Biomedical Engineering,Biochemistry,Biomaterials,Bioengineering,Biophysics,Biotechnology

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