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首页> 外文学位 >The identification of TGF-beta signaling pathways that regulate endocardial cell epithelial-to-mesenchymal transformation.
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The identification of TGF-beta signaling pathways that regulate endocardial cell epithelial-to-mesenchymal transformation.

机译：调节心内膜细胞上皮到间充质转化的TGF-β信号通路的鉴定。

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摘要

Valvular heart disease due to congenital abnormalities or pathology is a major cause of mortality and morbidity. Understanding the cellular processes and molecules that regulate valve formation and remodeling is required to develop effective therapies. In the developing heart, epithelial-to-mesenchymal transformation (EMT) in a subpopulation of endocardial cells in the atrioventricular cushion (AVC) is an important step in valve formation. Transforming Growth Factor beta (TGFbeta) has been shown to be an important regulator of AVC endocardial cell EMT in vitro and mesenchymal cell differentiation in vivo. TGFbeta signals through three high affinity cell surface receptors, the TGFbeta Type I (TGFbetaR1, also known as ALKs), Type II (TGFbetaR2), and Type III (TGFbetaR3) receptors. We have used targeted overexpression and knockdown experiments in the ventricle and AVC to score for gain- and loss-of-function respectively to determine the molecules that regulate EMT in vitro. First, we have demonstrated that a Par6/Smurf1/RhoA pathway is operative downstream of ALK5 to mediate endocardial cell EMT. Second, we identified BMP-2 as a ligand for TGFbetaR3 and demonstrated that BMP-2 can mediate EMT. Third, although dispensable for ligand presentation, we demonstrate that the cytoplasmic domain of TGFbetaR3 is absolutely required for TGFbeta2-stimulated EMT in vitro. Within this cytoplasmic domain, the three C-terminal amino acids comprise a Class I PDZ binding motif that binds to the PDZ domain containing protein GIPC to stabilize TGFbetaR3 surface expression. Deletion of the Class I PDZ binding motif is sufficient to abolish TGFbeta2-stimulated ventricular EMT in vitro, suggesting a role for GIPC in TGFbetaR3-mediated EMT. Consistent with GIPC interaction with TGFbetaR3 mediating EMT, overexpression of GIPC leads to an enhancement of AVC transformation, whereas targeting GIPC via siRNA inhibited TGFbetaR3-stimulated EMT. We establish that the Class I PDZ domain of TGFbetaR3 and interaction with GIPC are required for endocardial cell EMT in vitro. These data identify a novel ligand for TGFbetaR3 and reveal an essential role for TGFbetaR3 in mediating non-canonical signaling downstream of TGFbeta.
机译：由于先天性异常或病理引起的瓣膜性心脏病是死亡率和发病率的主要原因。需要了解调节瓣膜形成和重塑的细胞过程和分子，以开发有效的疗法。在发育中的心脏中，房室垫（AVC）中心内膜细胞亚群中的上皮-间充质转化（EMT）是瓣膜形成的重要步骤。转化生长因子β（TGFbeta）已被证明是体外AVC心内膜细胞EMT和体内间充质细胞分化的重要调节剂。 TGFbeta通过三种高亲和力细胞表面受体，即I型TGFbeta（TGFbetaR1，也称为ALKs），II型（TGFbetaR2）和III型（TGFbetaR3）受体发出信号。我们已经在心室和AVC中使用针对性的过表达和敲低实验分别对功能的获得和丧失进行评分，以确定在体外调节EMT的分子。首先，我们证明了Par6 / Smurf1 / RhoA途径在ALK5下游起作用，以介导心内膜细胞EMT。其次，我们确定BMP-2为TGFbetaR3的配体，并证明BMP-2可以介导EMT。第三，尽管配体呈递是不可缺少的，但我们证明了TGFbetaR3的EMT在体外绝对需要TGFbetaR3的胞质域。在该胞质结构域内，三个C末端氨基酸包含I类PDZ结合基序，该基序与包含蛋白质GIPC的PDZ结构域结合以稳定TGFbetaR3表面表达。删除I类PDZ结合基序足以在体外废除TGFbeta2刺激的心室EMT，提示GIPC在TGFbetaR3介导的EMT中起作用。与GIPC与TGFbetaR3介导的EMT相互作用一致，GIPC的过表达导致AVC转化增强，而通过siRNA靶向GIPC则抑制了TGFbetaR3刺激的EMT。我们建立了心内膜细胞EMT体外需要TGFbetaR3的I类PDZ域和与GIPC的相互作用。这些数据确定了TGFbetaR3的新型配体，并揭示了TGFbetaR3在介导TGFbeta下游的非规范信号传导中的重要作用。

著录项

  • 作者

    Townsend, Todd Andrew.;

  • 作者单位

    Vanderbilt University.;

  • 授予单位 Vanderbilt University.;
  • 学科 Biology Cell.Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 159 p.
  • 总页数 159
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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