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Dev Cell. 2015 Mar 9;32(5):617-30. doi: 10.1016/j.devcel.2015.01.026. Epub 2015 Feb 26.

TSC1 activates TGF-β-Smad2/3 signaling in growth arrest and epithelial-to-mesenchymal transition.

Author information

1
Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
2
Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands.
3
Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
4
Molecular Immunology (Faculty of Biology), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Molecular Immunology, Max-Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
5
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands; Department for Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany.
6
Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
7
Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands; BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Research Training Group (RTG) 1104, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
8
BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Center for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
9
School of Biological and Biomedical Sciences, Durham University, Durham DH1 3LE, UK.
10
Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Molecular Immunology (Faculty of Biology), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Molecular Immunology, Max-Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
11
Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany; BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Center for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
12
Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Research Training Group (RTG) 1104, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Center for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; ZBMZ Centre for Biochemistry and Molecular Cell Research (Faculty of Medicine), Albert-Ludwigs-University Freiburg, 79106 Freiburg, Germany.
13
Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany. Electronic address: elke.neumann-haefelin@uniklinik-freiburg.de.
14
Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands; BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Department for Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany. Electronic address: k.thedieck@umcg.nl.

Erratum in

  • Dev Cell. 2015 May 4;33(3):366.

Abstract

The tuberous sclerosis proteins TSC1 and TSC2 are key integrators of growth factor signaling. They suppress cell growth and proliferation by acting in a heteromeric complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1). In this study, we identify TSC1 as a component of the transforming growth factor β (TGF-β)-Smad2/3 pathway. Here, TSC1 functions independently of TSC2. TSC1 interacts with the TGF-β receptor complex and Smad2/3 and is required for their association with one another. TSC1 regulates TGF-β-induced Smad2/3 phosphorylation and target gene expression and controls TGF-β-induced growth arrest and epithelial-to-mesenchymal transition (EMT). Hyperactive Akt specifically activates TSC1-dependent cytostatic Smad signaling to induce growth arrest. Thus, TSC1 couples Akt activity to TGF-β-Smad2/3 signaling. This has implications for cancer treatments targeting phosphoinositide 3-kinases and Akt because they may impair tumor-suppressive cytostatic TGF-β signaling by inhibiting Akt- and TSC1-dependent Smad activation.

PMID:
25727005
DOI:
10.1016/j.devcel.2015.01.026
[Indexed for MEDLINE]
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