Robustness of MEK-ERK Dynamics and Origins of Cell-to-Cell Variability in MAPK Signaling.
Cellular signaling 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 signaling systems remain poorly understood. Here, we measure the dynamics of phosphorylated MEK and ERK across cell populations and quantify the levels of population heterogeneity over time using high-throughput image cytometry. We use a statistical modeling framework to show that extrinsic noise, particularly that from upstream MEK, is the dominant factor causing cell-to-cell variability in ERK phosphorylation, rather than stochasticity in the phosphorylation/dephosphorylation of ERK. We furthermore show that without extrinsic noise in the core module, variable (including noisy) signals would be faithfully reproduced downstream, but the within-module extrinsic variability distorts these signals and leads to a drastic reduction in the mutual information between incoming signal and ERK activity.
Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London SW7 2AZ, UK.
Sarah
S
Filippi
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK; Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK.
Chris P
CP
Barnes
Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London SW7 2AZ, UK.
Paul D W
PD
Kirk
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-8654, Japan.
Takamasa
T
Kudo
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-8654, Japan.
Katsuyuki
K
Kunida
Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London SW7 2AZ, UK.
Siobhan S
SS
McMahon
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-8654, Japan.
Takaho
T
Tsuchiya
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-8654, Japan.
Takumi
T
Wada
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-8654, Japan; CREST, Japan Science and Technology Agency, Bunkyo-ku, Tokyo 113-0033, Japan.
Shinya
S
Kuroda
Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London SW7 2AZ, UK; Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK. Electronic address: m.stumpf@imperial.ac.uk.
Michael P H
MP
Stumpf
D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D008954:Models, Biological; D015233:Models, Statistical; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D013997:Time Factors
D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases