Origins of cell-to-cell variability, kinetic proof-reading and the robustness of MAPK signal transduction

Cellular signalling processes can exhibit pronounced cell-to-cell variability in genetically identical cells. This affects how individual cells respond differentially to the same environmental stimulus. However, the origins of cell-to-cell variability in cellular signalling systems remain poorly understood. Here we measure the temporal evolution of phosphorylated MEK and ERK dynamics across populations of cells and quantify the levels of population heterogeneity over time using high-throughput image cytometry. We use a statistical modelling framework to show that upstream noise is the dominant factor causing cell-to-cell variability in ERK phosphorylation, rather than stochasticity in the phosphorylation/dephosphorylation of ERK. In particular, the cell-to-cell variability during sustained phosphorylation stems from random fluctuations in the background upstream signalling processes, while during transient phosphorylation, the heterogeneity is primarily due to noise in the intensity of the upstream signal(s). We show that the core MEK/ERK system uses kinetic proof-reading to faithfully and robustly transmits these variable inputs. The MAPK cascade thus propagates cell-to-cell variability at the population level, rather than attenuating or increasing it.