USP11 augments TGFβ signalling by deubiquitylating ALK5

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