Endothelial-to-mesenchymal transition (EndMT) is the biological process through which endothelial cells transdifferentiate into mesenchymal cells. During embryo development, EndMT regulates endocardial cushion formation via TGFβ/BMP signaling. In adults, EndMT is mainly activated during pathological conditions. Hence, it is necessary to characterize molecular regulators cooperating with TGFβ signaling in driving EndMT, to identify potential novel therapeutic targets to treat these pathologies. Here, we studied YAP, a transcriptional co-regulator involved in several biological processes, including epithelial-to-mesenchymal transition (EMT). As EndMT is the endothelial-specific form of EMT, and YAP (herein referring to YAP1) and TGFβ signaling cross-talk in other contexts, we hypothesized that YAP contributes to EndMT by modulating TGFβ signaling. We demonstrate that YAP is required to trigger TGFβ-induced EndMT response, specifically contributing to SMAD3-driven EndMT early gene transcription. We provide novel evidence that YAP acts as SMAD3 transcriptional co-factor and prevents GSK3β-mediated SMAD3 phosphorylation, thus protecting SMAD3 from degradation. YAP is therefore emerging as a possible candidate target to inhibit pathological TGFβ-induced EndMT at early stages.

中文翻译：

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YAP 在驱动 TGFβ 介导的内皮间质转化中的双重作用。

内皮-间充质转化 (EndMT) 是内皮细胞转分化为间充质细胞的生物学过程。在胚胎发育过程中，EndMT 通过 TGFβ/BMP 信号传导调节心内膜垫的形成。在成人中，EndMT 主要在病理状态下被激活。因此，有必要表征与 TGFβ 信号协同驱动 EndMT 的分子调节剂，以确定治疗这些病理的潜在新治疗靶点。在这里，我们研究了 YAP，一种参与多种生物过程的转录共调节因子，包括上皮间质转化 (EMT)。由于 EndMT 是 EMT 的内皮特异性形式，而 YAP（此处指的是 YAP1）和 TGFβ 信号在其他情况下会相互影响，我们假设 YAP 通过调节 TGFβ 信号传导对 EndMT 做出贡献。我们证明 YAP 是触发 TGFβ 诱导的 EndMT 反应所必需的，特别有助于 SMAD3 驱动的 EndMT 早期基因转录。我们提供了新的证据，表明 YAP 作为 SMAD3 转录辅因子并阻止 GSK3β 介导的 SMAD3 磷酸化，从而保护 SMAD3 免于降解。因此，YAP 正在成为在早期抑制病理性 TGFβ 诱导的 EndMT 的可能候选目标。