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Cell Syst. 2018 Jan 24;6(1):75-89.e11. doi: 10.1016/j.cels.2017.11.010. Epub 2017 Dec 13.

Resolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression.

Author information

1
Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany.
2
Institute of Physics, University of Freiburg, 79104 Freiburg, Germany; Center for Biological Systems Analysis, University of Freiburg, 79104 Freiburg, Germany.
3
Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany; Molecular Structure Analysis, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
4
Institute of Pathology, University of Basel, 4003 Basel, Switzerland.
5
Division Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
6
Department of General and Transplantation Surgery, Ruprecht Karls University Heidelberg, 69120 Heidelberg, Germany.
7
Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany.
8
Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, 13353 Berlin, Germany; Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, 04103 Leipzig, Germany.
9
Medical Research Center, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
10
Molecular Structure Analysis, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
11
Institute of Physics, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
12
Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany; Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), 69120 Heidelberg, Germany. Electronic address: u.klingmueller@dkfz.de.

Abstract

Upon stimulation of cells with transforming growth factor β (TGF-β), Smad proteins form trimeric complexes and activate a broad spectrum of target genes. It remains unresolved which of the possible Smad complexes are formed in cellular contexts and how these contribute to gene expression. By combining quantitative mass spectrometry with a computational selection strategy, we predict and provide experimental evidence for the three most relevant Smad complexes in the mouse hepatoma cell line Hepa1-6. Utilizing dynamic pathway modeling, we specify the contribution of each Smad complex to the expression of representative Smad target genes, and show that these contributions are conserved in human hepatoma cell lines and primary hepatocytes. We predict, based on gene expression data of patient samples, increased amounts of Smad2/3/4 proteins and Smad2 phosphorylation as hallmarks of hepatocellular carcinoma and experimentally verify this prediction. Our findings demonstrate that modeling approaches can disentangle the complexity of transcription factor complex formation and its impact on gene expression.

KEYWORDS:

L1 regularization; Smad proteins and complexes; TGF-β signal transduction; dynamic pathway modeling; hepatocellular carcinoma; liver; mathematical modeling; quantitative mass spectrometry; regulation of gene expression; systems biology

PMID:
29248373
DOI:
10.1016/j.cels.2017.11.010
[Indexed for MEDLINE]
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