USP11 augments TGFβ signalling by deubiquitylating ALK5

Open Biol. 2012 Jun;2(6):120063. doi: 10.1098/rsob.120063.

Abstract

The TGFβ receptors signal through phosphorylation and nuclear translocation of SMAD2/3. SMAD7, a transcriptional target of TGFβ signals, negatively regulates the TGFβ pathway by recruiting E3 ubiquitin ligases and targeting TGFβ receptors for ubiquitin-mediated degradation. In this report, we identify a deubiquitylating enzyme USP11 as an interactor of SMAD7. USP11 enhances TGFβ signalling and can override the negative effects of SMAD7. USP11 interacts with and deubiquitylates the type I TGFβ receptor (ALK5), resulting in enhanced TGFβ-induced gene transcription. The deubiquitylase activity of USP11 is required to enhance TGFβ-induced gene transcription. RNAi-mediated depletion of USP11 results in inhibition of TGFβ-induced SMAD2/3 phosphorylation and TGFβ-mediated transcriptional responses. Central to TGFβ pathway signalling in early embryogenesis and carcinogenesis is TGFβ-induced epithelial to mesenchymal transition. USP11 depletion results in inhibition of TGFβ-induced epithelial to mesenchymal transition.

Keywords: ALK5; TGFβ; USP11; USP15; cancer; ubiquitin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epithelial-Mesenchymal Transition / physiology*
  • HEK293 Cells
  • Humans
  • Mice
  • Phosphorylation / physiology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction / physiology*
  • Smad Proteins / genetics
  • Smad Proteins / metabolism
  • Thiolester Hydrolases / genetics
  • Thiolester Hydrolases / metabolism*
  • Transcription, Genetic / physiology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / physiology*

Substances

  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Transforming Growth Factor beta
  • USP11 protein, human
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse
  • Thiolester Hydrolases