Cell-specific responses to the cytokine TGFβ are determined by variability in protein levels.
Cell-specific responses to the cytokine TGFβ are determined by variability in protein levels.
复制标题
细胞特异性对细胞因子TGFβ的反应取决于蛋白质水平的变异性。
DOI：
10.15252/msb.20177733
复制
发表时间：
2018-01-25
影响因子：
9.9
通讯作者：
Loewer A
中科院分区：
文献类型：
--
作者：
Strasen J;Sarma U;Jentsch M;Bohn S;Sheng C;Horbelt D;Knaus P;Legewie S;Loewer A
细胞因子 TGFβ 在胚胎发育、成体组织稳态和再生过程中提供重要信息。细胞对 TGFβ 反应的改变与严重的人类疾病有关。为了了解细胞如何编码细胞外输入并传输其信息以引起适当的反应，我们获得了单细胞水平上通路激活的定量时间分辨测量。我们建立了动态时间扭曲来定量比较数千个单个细胞的信号动力学，并通过数学模型描述异质单细胞反应。我们的实验和理论相结合的研究表明，细胞对给定剂量的 TGFβ 的反应具体取决于特定信号蛋白的水平。信号蛋白表达的这种异质性导致细胞分解为具有性质不同的信号动力学和表型结果的类别。负反馈调节器促进异质信号传导，因为 SMAD7 敲除特别影响细胞亚群中的信号持续时间。综上所述，我们提出了一个定量框架，可以预测和测试细胞信号异质性的来源。
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.
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影响因子：
2.9
作者：
ABE, M;HARPEL, JG;RIFKIN, DB
通讯作者：
RIFKIN, DB
影响因子：
64.5
作者：
Goolam M;Scialdone A;Graham SJL;Macaulay IC;Jedrusik A;Hupalowska A;Voet T;Marioni JC;Zernicka-Goetz M
通讯作者：
Zernicka-Goetz M
影响因子：
7.3
作者：
Gonzalez DM;Medici D
通讯作者：
Medici D
影响因子：
19
作者：
Clarke, David C.;Liu, Xuedong
通讯作者：
Liu, Xuedong
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM