Medical Research Council - Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow St., Dundee DD1 5EH, UK.
Open Biol. 2012 Jun;2(6):120063. doi: 10.1098/rsob.120063.
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 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.
TGFβ 受体通过磷酸化和 SMAD2/3 的核转位信号转导。SMAD7 是 TGFβ 信号的转录靶标，通过招募 E3 泛素连接酶并靶向 TGFβ 受体进行泛素介导的降解，负调控 TGFβ 途径。在本报告中，我们确定去泛素化酶 USP11 是 SMAD7 的相互作用蛋白。USP11 增强 TGFβ 信号转导，并能克服 SMAD7 的负效应。USP11 与 I 型 TGFβ 受体（ALK5）相互作用并去泛素化，导致增强的 TGFβ 诱导基因转录。USP11 的去泛素酶活性对于增强 TGFβ 诱导的基因转录是必需的。RNAi 介导的 USP11 耗竭导致 TGFβ 诱导的 SMAD2/3 磷酸化和 TGFβ 介导的转录反应受到抑制。TGFβ 通路信号在胚胎发生和癌发生早期的核心是 TGFβ 诱导的上皮到间充质转化。USP11 耗竭导致 TGFβ 诱导的上皮到间充质转化受到抑制。
