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. 2019 Mar 29;9:5372. doi: 10.1038/s41598-019-41870-2

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Analog encoding of TGF-β dose information by dose-dependent SMAD signaling and ctgf responses. (A) Schematics of analog and digital responses of individual cells. White filled circles represent the unresponsive single-cells while blue shades represent the response strength. (B) Stimulation dose-response of TGF-β-induced SMAD4 signaling and ctgf response in single cells. At time t = 0, cells were treated with the indicated concentrations of TGF-β and representative traces for active single cells are shown. Left: traces of nuclear to cytoplasmic signal difference in SMAD4; right: ctgf responses in the corresponding single cells. (C,D) Nuclear/cytoplasmic ratio change from stimulation to the peak and ctgf response peak upon treatment with different doses of TGF-β in the iS4 (C) and iS2 (D) cell lines. (E,F) Time lag between TGF-β stimulation and peak of nuclear/cytoplasmic SMAD4/2 ratio (left), between TGF-β stimulation and ctgf response initiation (middle) and peak (right), in the iS4 (E) and iS2 (F) cell lines.