Abstract
SummaryThe 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.
Highlights
The signalling pathways downstream of the transforming growth factor b (TGFb) family of receptors play critical roles in regulating cellular proliferation, apoptosis, differentiation and migration [1,2,3]
SMURF1/2, WWP1 and NEDD4L have previously been reported to interact with SMAD7 and modulate the TGFb pathway [7,17,18]
While the regulation of TGFb signalling by SMAD7-associated E3 ubiquitin ligases has been extensively investigated and reported, we were drawn to the novel deubiquitylating enzymes (DUBs) interactors of SMAD7
Summary
The signalling pathways downstream of the transforming growth factor b (TGFb) family of receptors play critical roles in regulating cellular proliferation, apoptosis, differentiation and migration [1,2,3]. Signalling is initiated when TGFb ligands bind to their transmembrane serine/threonine kinase cognate receptors. Ligand binding induces specific pairing of type I (ALK1-7) and type II (ACVR-IIA, ACVR-IIB, BMPR-II, AMHR-II and TGFbR-II) receptors in a quaternary complex. SMAD proteins are the intracellular signal transducers of activated receptor complexes and are divided into three groups: receptor-regulated (R-) SMADs (1–3, 5 and 8), the co-SMAD (4) and the inhibitory (I-) SMADs (6 and 7). Type I receptors phosphorylate different R-SMADs at their C-terminal SXS motif depending on the receptor pairing and the ligand. This induces R-SMAD complex formation with SMAD4 and translocation to the nucleus, where along with other cofactors they regulate transcription of more than 500 target genes.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
