TSC1 activates TGF-β-Smad2/3 signaling in growth arrest and epithelial-to-mesenchymal transition.
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.
Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
Antje
A
Thien
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.
Mirja Tamara
MT
Prentzell
Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
Birgit
B
Holzwarth
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.
Kathrin
K
Kläsener
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.
Ineke
I
Kuper
Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
Christopher
C
Boehlke
Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
Annika G
AG
Sonntag
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.
Stefanie
S
Ruf
Bioinformatics and Molecular Genetics (Faculty of Biology), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
Lars
L
Maerz
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.
Roland
R
Nitschke
School of Biological and Biomedical Sciences, Durham University, Durham DH1 3LE, UK.
Sushma-Nagaraja
SN
Grellscheid
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.
Michael
M
Reth
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.
Gerd
G
Walz
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.
Ralf
R
Baumeister
Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany. Electronic address: elke.neumann-haefelin@uniklinik-freiburg.de.
Elke
E
Neumann-Haefelin
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.
Kathrin
K
Thedieck
D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D046912:Multiprotein Complexes; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D016212:Transforming Growth Factor beta; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases