CD109-mediated degradation of TGF-ß receptors and inhibition of TGF-ß responses involve regulation of SMAD7 and Smurf2 localization and function
CD109-mediated degradation of TGF-ß receptors and inhibition of TGF-ß responses involve regulation of SMAD7 and Smurf2 localization and function
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DOI：
10.1002/jcb.23349
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发表时间：
2012-01-01
影响因子：
4
通讯作者：
Philip, Anie
中科院分区：
文献类型：
--
作者：
Bizet, Albane A.;Tran-Khanh, Nicolas;Philip, Anie
转化生长因子-β是一种多功能细胞因子，调节多种细胞过程，包括增殖、分化和细胞外基质沉积。转化生长因子-β信号的失调与多种疾病有关，如癌症和组织纤维化。转化生长因子-β通过两种跨膜蛋白，即I型受体(TGFBR1)和II型受体(TGFBR2)传递信号。这些受体在细胞表面的水平受到几种机制的严格调控，包括Smad7招募E3泛素连接酶SMAD泛素化调节因子(SMurf)2后的降解。此外，转化生长因子-β共受体可以细胞特异性的方式调节转化生长因子-β信号受体的活性。我们以前已经发现了一种新的转化生长因子-β共受体CD109，它是一种糖基磷脂酰肌醇(GPI)锚定蛋白，可以负向调节转化生长因子-β信号。尽管CD109在体内可能作为转化生长因子-β作用的调节因子，但其调控转化生长因子-β信号的机制仍不完全清楚。此前，我们已经证明，CD109通过促进转化生长因子-β受体定位于脂筏/小窝和促进转化生长因子-β受体的降解而下调转化生长因子-β信号转导。在这里，我们证明CD109以配体依赖的方式增强Smad7/S-2介导的TGFBR1的降解。此外，我们还发现CD109调节Smad7/SMurf2与TGFBR1的定位和关联。最后，我们证明CD109‘S对转化生长因子-β信号和反应的抑制作用需要Smad7的表达和S-2泛素连接酶的活性。综上所述，这些结果表明CD109是Smad7/SMurf2介导的TGFBR1降解的重要调节因子。J.细胞。生物化学。2012年，113：238246。(C)2011年威利期刊公司。
Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates a wide variety of cellular processes including proliferation, differentiation, and extracellular matrix deposition. Dysregulation of TGF-beta signaling is associated with several diseases such as cancer and tissue fibrosis. TGF-beta signals through two transmembrane proteins known as the type I (TGFBR1) and type II (TGFBR2) receptors. The levels of these receptors at the cell surface are tightly regulated by several mechanisms, including degradation following recruitment of the E3 ubiquitin ligase SMAD ubiquitination regulatory factor (Smurf) 2 by SMAD7. In addition, TGF-beta co-receptors can modulate TGF-beta signaling receptor activity in a cell-specific manner. We have previously identified a novel TGF-beta co-receptor, CD109, a glycosyl phosphatidylinositol (GPI)-anchored protein that negatively regulates TGF-beta signaling. Despite CD109's potential relevance as a regulator of TGF-beta action in vivo, the mechanisms by which CD109 regulates TGF-beta signaling are still incompletely understood. Previously, we have shown that CD109 downregulates TGF-beta signaling by promoting TGF-beta receptor localization into the lipid raft/caveolae compartment and by enhancing TGF-beta receptor degradation. Here, we demonstrate that CD109 enhances SMAD7/Smurf2-mediated degradation of TGFBR1 in a ligand-dependent manner. Moreover, we show that CD109 regulates the localization and the association of SMAD7/Smurf2 with TGFBR1. Finally, we demonstrate that CD109's inhibitory effect on TGF-beta signaling and responses require SMAD7 expression and Smurf2 ubiquitin ligase activity. Taken together, these results suggest that CD109 is an important regulator of SMAD7/Smurf2-mediated degradation of TGFBR1. J. Cell. Biochem. 113: 238246, 2012. (C) 2011 Wiley Periodicals, Inc.