Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Department of Surgery, University of Toronto, Toronto, ON M5B 1W8, Canada.
Mol Biol Cell. 2011 Dec;22(23):4472-85. doi: 10.1091/mbc.E11-04-0335. Epub 2011 Sep 30.
Injury to the adherens junctions (AJs) synergizes with transforming growth factor-β1 (TGFβ) to activate a myogenic program (α-smooth muscle actin [SMA] expression) in the epithelium during epithelial-myofibroblast transition (EMyT). Although this synergy plays a key role in organ fibrosis, the underlying mechanisms have not been fully defined. Because we recently showed that Smad3 inhibits myocardin-related transcription factor (MRTF), the driver of the SMA promoter and many other CC(A/T)-rich GG element (CArG) box-dependent cytoskeletal genes, we asked whether AJ components might affect SMA expression through interfering with Smad3. We demonstrate that E-cadherin down-regulation potentiates, whereas β-catenin knockdown inhibits, SMA expression. Contact injury and TGFβ enhance the binding of β-catenin to Smad3, and this interaction facilitates MRTF signaling by two novel mechanisms. First, it inhibits the Smad3/MRTF association and thereby allows the binding of MRTF to its myogenic partner, serum response factor (SRF). Accordingly, β-catenin down-regulation disrupts the SRF/MRTF complex. Second, β-catenin maintains the stability of MRTF by suppressing the Smad3-mediated recruitment of glycogen synthase kinase-3β to MRTF, an event that otherwise leads to MRTF ubiquitination and degradation and the consequent loss of SRF/MRTF-dependent proteins. Thus β-catenin controls MRTF-dependent transcription and emerges as a critical regulator of an array of cytoskeletal genes, the "CArGome."
在细胞上皮-成肌纤维转化（EMyT）过程中，黏着连接（AJs）的损伤与转化生长因子-β1（TGFβ）协同作用，激活上皮细胞中的肌生成程序（α-平滑肌肌动蛋白[SMA]表达）。尽管这种协同作用在器官纤维化中起着关键作用，但潜在的机制尚未完全确定。因为我们最近表明 Smad3 抑制肌球蛋白相关转录因子（MRTF），即 SMA 启动子和许多其他 CC（A/T）富含 GG 元件（CArG）盒依赖性细胞骨架基因的驱动因子，所以我们想知道 AJ 成分是否可以通过干扰 Smad3 来影响 SMA 表达。我们证明 E-钙黏蛋白下调增强，而β-连环蛋白下调抑制 SMA 表达。接触损伤和 TGFβ 增强了β-连环蛋白与 Smad3 的结合，这种相互作用通过两种新的机制促进 MRTF 信号传导。首先，它抑制 Smad3/MRTF 复合物的形成，从而允许 MRTF 与肌生成伴侣血清反应因子（SRF）结合。因此，β-连环蛋白下调破坏了 SRF/MRTF 复合物。其次，β-连环蛋白通过抑制 Smad3 介导的糖原合酶激酶-3β向 MRTF 的募集来维持 MRTF 的稳定性，否则会导致 MRTF 泛素化和降解，以及随后丧失 SRF/MRTF 依赖性蛋白。因此，β-连环蛋白控制 MRTF 依赖性转录，并成为一系列细胞骨架基因（“CArGome”）的关键调节因子。
