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.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis*
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Blotting, Western
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Cell Proliferation*
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Cells, Cultured
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Epithelial-Mesenchymal Transition*
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Flow Cytometry
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Fluorescent Antibody Technique
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Humans
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Immunoenzyme Techniques
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Immunoprecipitation
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Mechanistic Target of Rapamycin Complex 1
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Multiprotein Complexes / metabolism
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction
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Smad2 Protein / metabolism*
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Smad3 Protein / metabolism*
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TOR Serine-Threonine Kinases / metabolism
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Transforming Growth Factor beta / metabolism*
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / metabolism*
Substances
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Multiprotein Complexes
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Receptors, Transforming Growth Factor beta
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SMAD2 protein, human
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SMAD3 protein, human
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Smad2 Protein
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Smad3 Protein
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TSC1 protein, human
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TSC2 protein, human
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Transforming Growth Factor beta
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases