BMP9 Crosstalk with the Hippo Pathway Regulates Endothelial Cell Matricellular and Chemokine Responses.
BMP9 Crosstalk with the Hippo Pathway Regulates Endothelial Cell Matricellular and Chemokine Responses.
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DOI：
10.1371/journal.pone.0122892
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Vary CP
中科院分区：
文献类型：
--
作者：
Young K;Tweedie E;Conley B;Ames J;FitzSimons M;Brooks P;Liaw L;Vary CP
内皮糖蛋白是一种III型TGFβ辅助受体，其在血管生成期间在内皮细胞中上调，并且当在人体中突变时，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粘附有关，但其潜在的分子机制仍知之甚少。在这里，我们表明内皮糖蛋白在内皮细胞中的表达调节了对BMP 9的反应，在粘着斑中zyxin的亚细胞定位。RNA敲低endoglin导致zyxin的错误定位和改变粘着斑的形成。局部粘连的机械传导作用及其通过细胞外基质结合传递调节信号的能力被内皮糖蛋白缺乏改变。BMP/TGFβ转录因子、SMAD和zyxin最近被认为参与了新出现的信号级联，即Hippo通路。Hippo转录辅激活因子YAP 1（yes相关蛋白1）已被认为在机械转导和细胞-细胞接触中起着至关重要的作用。响应内皮糖蛋白表达的YAP 1的BMP 9依赖性核定位的鉴定表明两种途径之间的串扰机制。内皮糖蛋白和YAP 1的抑制改变了YAP 1靶基因CCN 1（富含半胱氨酸的61，CYR 61）和CCN 2（结缔组织生长因子，CTGF）以及趋化因子CCL 2（单核细胞趋化蛋白1，MCP-1）的BMP 9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的协同作用。Hippo通路和内皮糖蛋白之间的直接联系的鉴定可能揭示HHT病因学的新机制。
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.
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影响因子：
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作者：
Duwel, Annette;Eleno, Nelida;Lopez-Novoa, Jose M.
通讯作者：
Lopez-Novoa, Jose M.
影响因子：
2.7
作者：
Arthur, HM;Ure, J;Diamond, AG
通讯作者：
Diamond, AG
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6
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Bourdeau, A;Cymerman, U;Letarte, M
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Letarte, M
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3.8
作者：
Duarte, Christine W.;Murray, Kimberly;Vary, Calvin P. H.
通讯作者：
Vary, Calvin P. H.
影响因子：
64.5
作者：
Alarcón C;Zaromytidou AI;Xi Q;Gao S;Yu J;Fujisawa S;Barlas A;Miller AN;Manova-Todorova K;Macias MJ;Sapkota G;Pan D;Massagué J
通讯作者：
Massagué J