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

Maciej Dobrzynski, Lan K Nguyen, Marc R Birtwistle, Alex Von Kriegsheim, Alfonso Blanco Fernandez, Alex Cheong, Walter Kolch, Boris Kholodenko

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20 Citations (Scopus)


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.
Original languageEnglish
Number of pages10
JournalJournal of the Royal Society Interface
Issue number98
Publication statusPublished - 6 Sept 2014
Externally publishedYes

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