title: Nonlinear signalling networks and cell-to-cell variability transform external signals into broadly distributed or bimodal responses.
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.
authors: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland maciej.dobrzynski@ucd.ie.
authors: Maciej
authors: http://orcid.org/0000-0002-0208-7758
authors: M
authors: Dobrzyński
authors: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Lan K
authors: LK
authors: Nguyen
authors: 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.
authors: Marc R
authors: MR
authors: Birtwistle
authors: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Alexander
authors: A
authors: von Kriegsheim
authors: Flow Cytometry Core Technologies, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Alfonso
authors: A
authors: Blanco Fernández
authors: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
authors: Alex
authors: http://orcid.org/0000-0003-2482-9078
authors: A
authors: Cheong
authors: 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.
authors: Walter
authors: W
authors: Kolch
authors: 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.
authors: Boris N
authors: BN
authors: Kholodenko
mesh_terms: D000465:Algorithms; D000600:Amino Acids, Dicarboxylic / Q000737:chemistry; D002450:Cell Communication; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008962:Models, Theoretical; D010100:Oxygen / Q000378:metabolism; D011506:Proteins / Q000737:chemistry*; D015398:Signal Transduction
chemical_list: D000600:Amino Acids, Dicarboxylic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011506:Proteins; D010100:Oxygen; C040947:oxalylglycine
keywords: bimodality; cell heterogeneity; dose–response; signalling networks