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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Blotting, Western
  • Cell Proliferation*
  • Cells, Cultured
  • Epithelial-Mesenchymal Transition*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction
  • Smad2 Protein / metabolism*
  • Smad3 Protein / metabolism*
  • TOR Serine-Threonine Kinases / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Multiprotein Complexes
  • Receptors, Transforming Growth Factor beta
  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • TSC1 protein, human
  • TSC2 protein, human
  • Transforming Growth Factor beta
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt