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TSC1 Activates TGF-β-Smad2/3 Signaling in Growth Arrest and Epithelial-to-Mesenchymal Transition

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Kläsener,  Kathrin
Molecular Immunology (Faculty of Biology), Albert-Ludwigs-University Freiburg;
BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg;
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Reth,  Michael
Molecular Immunology (Faculty of Biology), Albert-Ludwigs-University Freiburg;
BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg;
Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg;
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Thien, A., Prentzell, M. T., Holzwarth, B., Kläsener, K., Kuper, I., Boehlke, C., et al. (2015). TSC1 Activates TGF-β-Smad2/3 Signaling in Growth Arrest and Epithelial-to-Mesenchymal Transition. Developmental Cell, 32, 617-630. doi:doi: 10.1016/j.devcel.2015.01.026.


Cite as: http://hdl.handle.net/someHandle/test/escidoc:902686
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.