Young Kira, Tweedie Eric, Conley Barbara, Ames Jacquelyn, FitzSimons MaryLynn, Brooks Peter, Liaw Lucy, Vary Calvin P H
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine 04074, United States of America; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine 04469, United States of America.
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine 04074, United States of America.
PLoS One. 2015 Apr 24;10(4):e0122892. doi: 10.1371/journal.pone.0122892. eCollection 2015.
Endoglin is a type III TGFβ auxiliary receptor that is upregulated in endothelial cells during angiogenesis and, when mutated in humans, results in the vascular disease hereditary hemorrhagic telangiectasia (HHT). Though endoglin has been implicated in cell adhesion, the underlying molecular mechanisms are still poorly understood. Here we show endoglin expression in endothelial cells regulates subcellular localization of zyxin in focal adhesions in response to BMP9. RNA knockdown of endoglin resulted in mislocalization of zyxin and altered formation of focal adhesions. The mechanotransduction role of focal adhesions and their ability to transmit regulatory signals through binding of the extracellular matrix are altered by endoglin deficiency. BMP/TGFβ transcription factors, SMADs, and zyxin have recently been implicated in a newly emerging signaling cascade, the Hippo pathway. The Hippo transcription coactivator, YAP1 (yes-associated protein 1), has been suggested to play a crucial role in mechanotransduction and cell-cell contact. Identification of BMP9-dependent nuclear localization of YAP1 in response to endoglin expression suggests a mechanism of crosstalk between the two pathways. Suppression of endoglin and YAP1 alters BMP9-dependent expression of YAP1 target genes CCN1 (cysteine-rich 61, CYR61) and CCN2 (connective tissue growth factor, CTGF) as well as the chemokine CCL2 (monocyte chemotactic protein 1, MCP-1). These results suggest a coordinate effect of endoglin deficiency on cell matrix remodeling and local inflammatory responses. Identification of a direct link between the Hippo pathway and endoglin may reveal novel mechanisms in the etiology of HHT.
内皮糖蛋白是一种III型转化生长因子β（TGFβ）辅助受体，在血管生成过程中在内皮细胞中上调，在人类中发生突变时会导致血管疾病遗传性出血性毛细血管扩张症（HHT）。尽管内皮糖蛋白与细胞黏附有关，但其潜在的分子机制仍知之甚少。在这里，我们表明内皮细胞中内皮糖蛋白的表达响应骨形态发生蛋白9（BMP9）调节桩蛋白在粘着斑中的亚细胞定位。内皮糖蛋白的RNA敲低导致桩蛋白定位错误并改变粘着斑的形成。粘着斑的机械转导作用及其通过细胞外基质结合传递调节信号的能力因内皮糖蛋白缺乏而改变。BMP/TGFβ转录因子、SMAD蛋白和桩蛋白最近与一个新出现的信号级联反应——Hippo通路有关。Hippo转录共激活因子YAP1（Yes相关蛋白1）被认为在机械转导和细胞间接触中起关键作用。鉴定出响应内皮糖蛋白表达的BMP9依赖性YAP1核定位，提示了这两条通路之间的串扰机制。内皮糖蛋白和YAP1的抑制改变了YAP1靶基因CCN1（富含半胱氨酸61，CYR61）和CCN2（结缔组织生长因子，CTGF）以及趋化因子CCL2（单核细胞趋化蛋白1，MCP-1）的BMP9依赖性表达。这些结果表明内皮糖蛋白缺乏对细胞基质重塑和局部炎症反应具有协同作用。鉴定Hippo通路与内皮糖蛋白之间的直接联系可能揭示HHT病因学中的新机制。
