Common pathways regulate Type III TGFβ receptor-dependent cell invasion in epicardial and endocardial cells.
Common pathways regulate Type III TGFβ receptor-dependent cell invasion in epicardial and endocardial cells.
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DOI：
10.1016/j.cellsig.2016.03.004
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发表时间：
2016-06
影响因子：
4.8
通讯作者：
Barnett JV
中科院分区：
文献类型：
--
作者：
Clark CR;Robinson JY;Sanchez NS;Townsend TA;Arrieta JA;Merryman WD;Trykall DZ;Olivey HE;Hong CC;Barnett JV
在心脏发育过程中，上皮-间充质转化（Epithelial-Mesenchymal Transformation， EMT）和随后的心外膜和心内膜细胞的侵袭对冠状动脉和心脏瓣膜的发育至关重要。转化后的细胞分别产生心脏成纤维细胞和血管平滑肌细胞或瓣膜间质细胞。III型转化生长因子β (TGFβR3)受体调节两种细胞类型的EMT和细胞侵袭，但TGFβR3下游的信号传导机制尚不清楚。在这里，我们使用心外膜和心内膜细胞进行体外细胞侵袭实验，以确定TGFβR3下游调节细胞侵袭的共同机制。抑制NF-κB活性可阻断心外膜和心内膜细胞的侵袭。在Tgfbr3−/−心外膜细胞中发现NF-κB信号通路失调，并表现出对配体的细胞侵袭受损。tgf β r3依赖性细胞侵袭也依赖于激活素受体样激酶（ALK） 2、ALK3和ALK5活性。TGFβR3突变体在841残基上含有苏氨酸到丙氨酸的取代（TGFβR3- t841a）在体外诱导心外膜和心内膜细胞中不依赖配体的细胞侵袭。这些发现揭示了NF-κB信号在心外膜和心内膜细胞侵袭调节中的作用，并鉴定了TGFβR3中刺激配体非依赖性信号传导的突变。
Epithelial-Mesenchymal Transformation (EMT) and the subsequent invasion of epicardial and endocardial cells during cardiac development is critical to the development of the coronary vessels and heart valves. The transformed cells give rise to cardiac fibroblasts and vascular smooth muscle cells or valvular interstitial cells, respectively. The Type III Transforming Growth Factor β (TGFβR3) receptor regulates EMT and cell invasion in both cell types, but the signaling mechanisms downstream of TGFβR3 are not well understood. Here we use epicardial and endocardial cells in in vitro cell invasion assays to identify common mechanisms downstream of TGFβR3 that regulate cell invasion. Inhibition of NF-κB activity blocked cell invasion in epicardial and endocardial cells. NF-κB signaling was found to be dysregulated in Tgfbr3−/− epicardial cells which also show impaired cell invasion in response to ligand. TGFβR3-dependent cell invasion is also dependent upon Activin Receptor-Like Kinase (ALK) 2, ALK3, and ALK5 activity. A TGFβR3 mutant that contains a threonine to alanine substitution at residue 841 (TGFβR3-T841A) induces ligand-independent cell invasion in both epicardial and endocardial cells in vitro. These findings reveal a role for NF-κB signaling in the regulation of epicardial and endocardial cell invasion and identify a mutation in TGFβR3 which stimulates ligand-independent signaling.