USP 11 augments TGF b signalling by deubiquitylating ALK 5

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