Smad7 Protein Interacts with Receptor-regulated Smads (R-Smads) to Inhibit Transforming Growth Factor-β (TGF-β/Smad Signaling
Smad7 Protein Interacts with Receptor-regulated Smads (R-Smads) to Inhibit Transforming Growth Factor-β (TGF-β/Smad Signaling
复制标题
Smad7 蛋白与受体调节的 Smad (R-Smad) 相互作用，抑制转化生长因子-β (TGF-β)/Smad 信号转导
DOI：
10.1074/jbc.m115.694281
复制
发表时间：
2016-01-01
影响因子：
4.8
通讯作者：
Chen, Ye-Guang
中科院分区：
文献类型：
--
作者：
Yan, Xiaohua;Liao, Hongwei;Chen, Ye-Guang
转化生长因子-β是一种多效性细胞因子，调节广泛的细胞活动和病理生理过程。转化生长因子-β信号在时空上是微调的。Smad7作为转化生长因子-β信号转导的关键负性调节因子，通过阻断受体活性、诱导受体降解或干扰Smad-DNA结合发挥抑制作用。然而，Smad7在转化生长因子-β信号转导中的作用和分子机制仍不完全清楚。在这项研究中，我们报道了一种新的机制，Smad7在Smad水平上拮抗转化生长因子-β信号。Gal4-荧光素酶报告实验表明，Smad7在转化生长因子-β信号传导过程中与R-Smad蛋白发生寡聚反应，并直接抑制R-Smad的活性。在机制上，Smad7与Smad4竞争与R-Smads结合，并招募E3泛素连接酶NEDD4L激活R-Smads，导致其多泛素化和蛋白酶体降解。与R-Smad-Smad4齐聚相似，R-Smad与Smad7之间的相互作用是由它们的MAD同源2(MH2)结构域介导的。Smad7的MH2结构域中有一个带正电的碱性区域，包括L3/β8环链模块和邻近的氨基酸，这是相互作用所必需的。这些结果为Smad7对转化生长因子-β信号的调控提供了新的线索。
TGF-beta is a pleiotropic cytokine that regulates a wide range of cellular actions and pathophysiological processes. TGF-beta signaling is spatiotemporally fine-tuned. As a key negative regulator of TGF-beta signaling, Smad7 exerts its inhibitory effects by blocking receptor activity, inducing receptor degradation or interfering with Smad-DNA binding. However, the functions and the molecular mechanisms underlying the actions of Smad7 in TGF-beta signaling are still not fully understood. In this study we report a novel mechanism whereby Smad7 antagonizes TGF-beta signaling at the Smad level. Smad7 oligomerized with R-Smad proteins upon TGF-beta signaling and directly inhibited R-Smad activity, as assessed by Gal4-luciferase reporter assays. Mechanistically, Smad7 competes with Smad4 to associate with R-Smads and recruits the E3 ubiquitin ligase NEDD4L to activated R-Smads, leading to their polyubiquitination and proteasomal degradation. Similar to the R-Smad-Smad4 oligomerization, the interaction between R-Smads and Smad7 is mediated by their mad homology 2 (MH2) domains. A positive-charged basic region including the L3/beta 8 loop-strand module and adjacent amino acids in the MH2 domain of Smad7 is essential for the interaction. These results shed new light on the regulation of TGF-beta signaling by Smad7.