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. 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

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

Antje Thien et al. Dev Cell. .
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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.

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