USP11 augments TGFβ signaling by deubiquitylating ALK5

The TGFß receptors signal through phosphorylation and nuclear translocation of SMAD2/3. SMAD7, a transcriptional target of TGFß signals, negatively regulates the TGFß pathway by recruiting E3 ubiquitin ligases and targeting TGFß receptors for ubiquitin-mediated degradation. In this report, we identify a deubiquitylating enzyme USP11 as an interactor of SMAD7. USP11 enhances TGFß signalling and can override the negative effects of SMAD7. USP11 interacts with and deubiquitylates the type I TGFß receptor (ALK5), resulting in enhanced TGFß-induced gene transcription. The deubiquitylase activity of USP11 is required to enhance TGFß-induced gene transcription. RNAi-mediated depletion of USP11 results in inhibition of TGFß-induced SMAD2/3 phosphorylation and TGFß-mediated transcriptional responses. Central to TGFß pathway signalling in early embryogenesis and carcinogenesis is TGFß-induced epithelial to mesenchymal transition. USP11 depletion results in inhibition of TGFß-induced epithelial to mesenchymal transition. © 2012 The Authors.