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Cell-specific responses to the cytokine TGFβ are determined by variability in protein levels

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Item Type:Article
Title:Cell-specific responses to the cytokine TGFβ are determined by variability in protein levels
Creators Name:Strasen, J. and Sarma, U. and Jentsch, M. and Bohn, S. and Sheng, C. and Horbelt, D. and Knaus, P. and Legewie, S. and Loewer, A.
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.
Keywords:Cellular Heterogeneity, Mathematical Modeling, Signaling Dynamics, Single-Cell Analysis, TGFβ-SMAD Signaling
Source:Molecular Systems Biology
Publisher:EMBO Press / Wiley
Page Range:e7733
Date:25 January 2018
Official Publication:https://doi.org/10.15252/msb.20177733
PubMed:View item in PubMed

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