Dataset Information

USP11 augments TGF? signalling by deubiquitylating ALK5.

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

SUBMITTER: Al-Salihi MA

PROVIDER: S-EPMC3390794 | biostudies-other | 2012 Jun

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

USP11 augments TGFβ signalling by deubiquitylating ALK5.

Al-Salihi Mazin A MA Herhaus Lina L Macartney Thomas T Sapkota Gopal P GP

Open biology 20120601 6

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 re ...[more]

PMID: 22773947

Similar Datasets

Project description:BackgroundRadiotherapy is widely used to treat cancer. While rapidly dividing cancer cells are naturally considered the main target of radiotherapy, emerging evidence indicates that radiotherapy also affects endothelial cell functions, and possibly also their angiogenic capacity. In spite of its clinical relevance, such putative anti-angiogenic effect of radiotherapy has not been thoroughly characterized. We have investigated the effect of ionizing radiation on angiogenesis using in vivo, ex vivo and in vitro experimental models in combination with genetic and pharmacological interventions.Principal findingsHere we show that high doses ionizing radiation locally suppressed VEGF- and FGF-2-induced Matrigel plug angiogenesis in mice in vivo and prevented endothelial cell sprouting from mouse aortic rings following in vivo or ex vivo irradiation. Quiescent human endothelial cells exposed to ionizing radiation in vitro resisted apoptosis, demonstrated reduced sprouting, migration and proliferation capacities, showed enhanced adhesion to matrix proteins, and underwent premature senescence. Irradiation induced the expression of P53 and P21 proteins in endothelial cells, but p53 or p21 deficiency and P21 silencing did not prevent radiation-induced inhibition of sprouting or proliferation. Radiation induced Smad-2 phosphorylation in skin in vivo and in endothelial cells in vitro. Inhibition of the TGF-beta type I receptor ALK5 rescued deficient endothelial cell sprouting and migration but not proliferation in vitro and restored defective Matrigel plug angiogenesis in irradiated mice in vivo. ALK5 inhibition, however, did not rescue deficient proliferation. Notch signaling, known to hinder angiogenesis, was activated by radiation but its inhibition, alone or in combination with ALK5 inhibition, did not rescue suppressed proliferation.ConclusionsThese results demonstrate that irradiation of quiescent endothelial cells suppresses subsequent angiogenesis and that ALK5 is a critical mediator of this suppression. These results extend our understanding of radiotherapy-induced endothelial dysfunctions, relevant to both therapeutic and unwanted effects of radiotherapy.

Dataset Information

USP11 augments TGF? signalling by deubiquitylating ALK5.

Publications

USP11 augments TGFβ signalling by deubiquitylating ALK5.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets