Format

Send to

Choose Destination
J R Soc Interface. 2014 Sep 6;11(98):20140383. doi: 10.1098/rsif.2014.0383.

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

Author information

1
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland maciej.dobrzynski@ucd.ie.
2
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
3
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA.
4
Flow Cytometry Core Technologies, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
5
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
6
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
7
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland boris.kholodenko@ucd.ie.

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.

KEYWORDS:

bimodality; cell heterogeneity; dose–response; signalling networks

PMID:
24966234
PMCID:
PMC4233687
DOI:
10.1098/rsif.2014.0383
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center