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首页> 外文期刊>Cellular Signalling >Endocardial cell epithelial-mesenchymal transformation requires Type III TGFβ receptor interaction with GIPC
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Endocardial cell epithelial-mesenchymal transformation requires Type III TGFβ receptor interaction with GIPC

机译：心内膜细胞上皮-间质转化需要III型TGFβ受体与GIPC相互作用

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An early event in heart valve formation is the epithelial-mesenchymal transformation (EMT) of a subpopulation of endothelial cells in specific regions of the heart tube, the endocardial cushions. The Type III TGFβ receptor (TGFβR3) is required for TGFβ2- or BMP-2-stimulated EMT in atrioventricular endocardial cushion (AVC) explants in vitro but the mediators downstream of TGFβR3 are not well described. Using AVC and ventricular explants as an in vitro assay, we found an absolute requirement for specific TGFβR3 cytoplasmic residues, GAIP-interacting protein, C terminus (GIPC), and specific Activin Receptor-Like Kinases (ALK)s for TGFβR3-mediated EMT when stimulated by TGFβ2 or BMP-2. The introduction of TGFβR3 into nontransforming ventricular endocardial cells, followed by the addition of either TGFβ2 or BMP-2, results in EMT. TGFβR3 lacking the entire cytoplasmic domain, or only the 3C-terminal amino acids that are required to bind GIPC, fails to support EMT in response to TGFβ2 or BMP-2. Overexpression of GIPC in AVC endocardial cells enhanced EMT while siRNA-mediated silencing of GIPC in ventricular cells overexpressing TGFβR3 significantly inhibited EMT. Targeting of specific ALKs by siRNA revealed that TGFβR3-mediated EMT requires ALK2 and ALK3, in addition to ALK5, but not ALK4 or ALK6. Taken together, these data identify GIPC, ALK2, ALK3, and ALK5 as signaling components required for TGFβR3-mediated endothelial cell EMT.
机译：心脏瓣膜形成的早期事件是在心管特定区域（心内膜垫层）的内皮细胞亚群的上皮-间充质转化（EMT）。在体外房室心内膜垫层（AVC）外植体中，TGFβ2或BMP-2刺激的EMT需要III型TGFβ受体（TGFβR3），但对TGFβR3下游的介体没有很好的描述。使用AVC和心室外植体作为体外测定法，我们发现当TGFβR3介导的EMT时，对特定TGFβR3细胞质残基，GAIP相互作用蛋白，C末端（GIPC）和特定激活素受体样激酶（ALK）的绝对需求由TGFβ2或BMP-2刺激。将TGFβR3引入非转化性心室心内膜细胞，然后添加TGFβ2或BMP-2，导致EMT。缺乏完整细胞质结构域或仅结合GIPC所需的3C末端氨基酸的TGFβR3无法响应TGFβ2或BMP-2来支持EMT。 GIPC在AVC心内膜细胞中的过度表达增强EMT，而siRNA介导的GIPC在过度表达TGFβR3的心室细胞中的沉默显着抑制EMT。 siRNA对特定ALK的靶向显示，除了ALK5之外，TGFβR3介导的EMT还需要ALK2和ALK3，但不​​需要ALK4或ALK6。综上所述，这些数据将GIPC，ALK2，ALK3和ALK5识别为TGFβR3介导的内皮细胞EMT所需的信号传导成分。

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