TY - JOUR
T1 - Nonlinear signalling networks and cell-to-cell variability transform external signals into broadly distributed or bimodal responses
AU - Dobrzynski, Maciej
AU - Nguyen, Lan K
AU - Birtwistle, Marc R
AU - Von Kriegsheim, Alex
AU - Fernandez, Alfonso Blanco
AU - Cheong, Alex
AU - Kolch, Walter
AU - Kholodenko, Boris
PY - 2014/9/6
Y1 - 2014/9/6
N2 - 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.
AB - 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.
UR - http://www.ncbi.nlm.nih.gov/pubmed/24966234
U2 - 10.1098/rsif.2014.0383
DO - 10.1098/rsif.2014.0383
M3 - Article
VL - 11
JO - Journal of the Royal Society Interface
JF - Journal of the Royal Society Interface
SN - 1742-5689
IS - 98
ER -