The cytokine TGFβ provides important information during embryonic development, adult tissue homeostasis, and regeneration. Alterations in the cellular response to TGFβ are involved in severe human diseases. To understand how cells encode the extracellular input and transmit its information to elicit appropriate responses, we acquired quantitative time-resolved measurements of pathway activation at the single-cell level. We established dynamic time warping to quantitatively compare signaling dynamics of thousands of individual cells and described heterogeneous single-cell responses by mathematical modeling. Our combined experimental and theoretical study revealed that the response to a given dose of TGFβ is determined cell specifically by the levels of defined signaling proteins. This heterogeneity in signaling protein expression leads to decomposition of cells into classes with qualitatively distinct signaling dynamics and phenotypic outcome. Negative feedback regulators promote heterogeneous signaling, as a SMAD7 knock-out specifically affected the signal duration in a subpopulation of cells. Taken together, we propose a quantitative framework that allows predicting and testing sources of cellular signaling heterogeneity.
PubMed Central Full Text PDF:C\:\\Users\\SL\\Zotero\\storage\\FEGEGA2B\\Strasen et al. - 2018 - Cell-specific responses to the cytokine TGFβ are determined by variability in protein levels.pdf:application/pdf
%0 Journal Article
%1 strasen_cell-specific_2018
%A Strasen, Jette
%A Sarma, Uddipan
%A Jentsch, Marcel
%A Bohn, Stefan
%A Sheng, Caibin
%A Horbelt, Daniel
%A Knaus, Petra
%A Legewie, Stefan
%A Loewer, Alexander
%D 2018
%J Molecular Systems Biology
%K Analysis, Biology, Cell Factor Growth Humans, Line, Models, Nucleus, Organ Protein, Signal Single-Cell Smad2 Smad4 Specificity, Systems TGFβ‐SMAD Theoretical, Transduction, Transforming analysis, beta cellular dynamics, heterogeneity, mathematical modeling, signaling signaling, single‐cell
%N 1
%P e7733
%R 10.15252/msb.20177733
%T Cell-specific responses to the cytokine TGFβ are determined by variability in protein levels
%V 14
%X The cytokine TGFβ provides important information during embryonic development, adult tissue homeostasis, and regeneration. Alterations in the cellular response to TGFβ are involved in severe human diseases. To understand how cells encode the extracellular input and transmit its information to elicit appropriate responses, we acquired quantitative time-resolved measurements of pathway activation at the single-cell level. We established dynamic time warping to quantitatively compare signaling dynamics of thousands of individual cells and described heterogeneous single-cell responses by mathematical modeling. Our combined experimental and theoretical study revealed that the response to a given dose of TGFβ is determined cell specifically by the levels of defined signaling proteins. This heterogeneity in signaling protein expression leads to decomposition of cells into classes with qualitatively distinct signaling dynamics and phenotypic outcome. Negative feedback regulators promote heterogeneous signaling, as a SMAD7 knock-out specifically affected the signal duration in a subpopulation of cells. Taken together, we propose a quantitative framework that allows predicting and testing sources of cellular signaling heterogeneity.
@article{strasen_cell-specific_2018,
abstract = {The cytokine TGFβ provides important information during embryonic development, adult tissue homeostasis, and regeneration. Alterations in the cellular response to TGFβ are involved in severe human diseases. To understand how cells encode the extracellular input and transmit its information to elicit appropriate responses, we acquired quantitative time-resolved measurements of pathway activation at the single-cell level. We established dynamic time warping to quantitatively compare signaling dynamics of thousands of individual cells and described heterogeneous single-cell responses by mathematical modeling. Our combined experimental and theoretical study revealed that the response to a given dose of TGFβ is determined cell specifically by the levels of defined signaling proteins. This heterogeneity in signaling protein expression leads to decomposition of cells into classes with qualitatively distinct signaling dynamics and phenotypic outcome. Negative feedback regulators promote heterogeneous signaling, as a SMAD7 knock-out specifically affected the signal duration in a subpopulation of cells. Taken together, we propose a quantitative framework that allows predicting and testing sources of cellular signaling heterogeneity.},
added-at = {2025-03-05T15:52:38.000+0100},
author = {Strasen, Jette and Sarma, Uddipan and Jentsch, Marcel and Bohn, Stefan and Sheng, Caibin and Horbelt, Daniel and Knaus, Petra and Legewie, Stefan and Loewer, Alexander},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/21a7065fc3c72c12fbc94e58ca051d7f9/slegewie},
doi = {10.15252/msb.20177733},
file = {PubMed Central Full Text PDF:C\:\\Users\\SL\\Zotero\\storage\\FEGEGA2B\\Strasen et al. - 2018 - Cell-specific responses to the cytokine TGFβ are determined by variability in protein levels.pdf:application/pdf},
interhash = {c7b488275f920e5ddf86add6c490236c},
intrahash = {1a7065fc3c72c12fbc94e58ca051d7f9},
issn = {1744-4292},
journal = {Molecular Systems Biology},
keywords = {Analysis, Biology, Cell Factor Growth Humans, Line, Models, Nucleus, Organ Protein, Signal Single-Cell Smad2 Smad4 Specificity, Systems TGFβ‐SMAD Theoretical, Transduction, Transforming analysis, beta cellular dynamics, heterogeneity, mathematical modeling, signaling signaling, single‐cell},
language = {eng},
month = jan,
number = 1,
pages = {e7733},
pmcid = {PMC5787704},
pmid = {29371237},
timestamp = {2025-03-05T15:52:38.000+0100},
title = {Cell-specific responses to the cytokine {TGFβ} are determined by variability in protein levels},
volume = 14,
year = 2018
}
