Park Su-hyun, Jung Eun-Ho, Kim Geun-Young, Kim Byung-Chul, Lim Jae Hyang, Woo Chang-Hoon
Department of Pharmacology, Yeungnam University College of Medicine, Daegu 705-717, Korea.
Mol Cells. 2015 Jan 31;38(1):20-5. doi: 10.14348/molcells.2015.2120. Epub 2014 Dec 16.
TGF-β regulates pleiotropic cellular responses including cell growth, differentiation, migration, apoptosis, extracellular matrix production, and many other biological processes. Although non-Smad signaling pathways are being increasingly reported to play many roles in TGF-β-mediated biological processes, Smads, especially receptor-regulated Smads (R-Smads), still play a central mediatory role in TGF-β signaling for epithelial-mesenchymal transition. Thus, the biological activities of R-Smads are tightly regulated at multiple points. Inhibitory Smad (I-Smad also called Smad7) acts as a critical endogenous negative feedback regulator of Smad-signaling pathways by inhibiting R-Smad phosphorylation and by inducing activated type I TGF-β receptor degradation. Roles played by Smad7 in health and disease are being increasingly reported, but the molecular mechanisms that regulate Smad7 are not well understood. In this study, we show that E3 ubiquitin ligase Itch acts as a positive regulator of TGF-β signaling and of subsequent EMT-related gene expression. Interestingly, the Itch-mediated positive regulation of TGF-β signaling was found to be dependent on Smad7 ubiquitination and its subsequent degradation. Further study revealed Itch acts as an E3 ubiquitin ligase for Smad7 polyubiquitination, and thus, that Itch is an important regulator of Smad7 activity and a positive regulator of TGF-β signaling and of TGF-β-mediated biological processes. Accordingly, the study uncovers a novel regulatory mechanism whereby Smad7 is controlled by Itch.
转化生长因子-β（TGF-β）可调节多种细胞反应，包括细胞生长、分化、迁移、凋亡、细胞外基质生成以及许多其他生物学过程。尽管越来越多的报道表明非Smad信号通路在TGF-β介导的生物学过程中发挥多种作用，但Smad蛋白，尤其是受体调节型Smad（R-Smad），在TGF-β信号传导介导上皮-间质转化过程中仍发挥核心介导作用。因此，R-Smad的生物学活性在多个环节受到严格调控。抑制性Smad（I-Smad，也称为Smad7）通过抑制R-Smad磷酸化以及诱导活化的I型TGF-β受体降解，作为Smad信号通路关键的内源性负反馈调节因子。越来越多的报道阐述了Smad7在健康和疾病中的作用，但调控Smad7的分子机制尚未完全明确。在本研究中，我们发现E3泛素连接酶Itch作为TGF-β信号传导及后续上皮-间质转化相关基因表达的正向调节因子。有趣的是，发现Itch对TGF-β信号传导的正向调节作用依赖于Smad7的泛素化及其随后的降解。进一步研究表明，Itch作为Smad7多聚泛素化的E3泛素连接酶，因此，Itch是Smad7活性的重要调节因子，也是TGF-β信号传导及TGF-β介导生物学过程的正向调节因子。相应地，本研究揭示了一种由Itch调控Smad7的新型调节机制。
