Endoglin regulates PI3-kinase/Akt trafficking and signaling to alter endothelial capillary stability during angiogenesis.
Endoglin regulates PI3-kinase/Akt trafficking and signaling to alter endothelial capillary stability during angiogenesis.
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DOI：
10.1091/mbc.e11-12-0993
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发表时间：
2012-07
影响因子：
3.3
通讯作者：
Blobe GC
中科院分区：
文献类型：
--
作者：
Lee NY;Golzio C;Gatza CE;Sharma A;Katsanis N;Blobe GC
Endoglin 通过 GIPC 与 PI3K 相互作用，在细胞膜上募集并激活 PI3K/Akt。 TGF-β1 减弱内皮糖蛋白/GIPC 介导的 PI3K/Akt 膜支架，而 BMP-9 增强，从而在体外改变内皮毛细管稳定性，而 GIPC 在体内发育血管生成过程中介导内皮糖蛋白功能。 Endoglin (CD105) 是一种内皮特异性转化生长因子 β (TGF-β) 辅助受体，对于血管生成和血管稳态至关重要。尽管内皮糖蛋白功能障碍会导致多种血管疾病，但内皮糖蛋白的作用机制仍知之甚少。在这里，我们报告了一种新机制，其中内皮糖蛋白和 Gα 相互作用蛋白 C 端相互作用蛋白 (GIPC) 介导磷脂酰肌醇 3-激酶 (PI3K) 的运输调节内皮信号传导和功能。我们证明内皮糖蛋白通过 GIPC 与 PI3K 亚基 p110α 和 p85 相互作用，在细胞膜上招募并激活 PI3K 和 Akt。观察到相反的配体诱导效应，其中 TGF-β1 减弱，而骨形态发生蛋白 9 增强，内皮糖蛋白/GIPC 介导的 PI3K 和 Akt 膜支架在体外改变内皮毛细管稳定性。此外，我们采用第一个内皮糖蛋白转基因斑马鱼模型来证明GIPC是体内发育血管生成过程中内皮糖蛋白功能的关键组成部分。这些研究定义了内皮糖蛋白和 GIPC 在血管生成过程中调节内皮细胞功能的新的非 Smad 功能。
Endoglin interacts with PI3K via GIPC to recruit and activate PI3K/Akt at the cell membrane. TGF-β1 attenuates, whereas BMP-9 enhances, endoglin/GIPC-mediated membrane scaffolding of PI3K/Akt to alter endothelial capillary tube stability in vitro, and GIPC mediates endoglin function during developmental angiogenesis in vivo. Endoglin (CD105) is an endothelial-specific transforming growth factor β (TGF-β) coreceptor essential for angiogenesis and vascular homeostasis. Although endoglin dysfunction contributes to numerous vascular conditions, the mechanism of endoglin action remains poorly understood. Here we report a novel mechanism in which endoglin and Gα-interacting protein C-terminus–interacting protein (GIPC)–mediated trafficking of phosphatidylinositol 3-kinase (PI3K) regulates endothelial signaling and function. We demonstrate that endoglin interacts with the PI3K subunits p110α and p85 via GIPC to recruit and activate PI3K and Akt at the cell membrane. Opposing ligand-induced effects are observed in which TGF-β1 attenuates, whereas bone morphogenetic protein-9 enhances, endoglin/GIPC-mediated membrane scaffolding of PI3K and Akt to alter endothelial capillary tube stability in vitro. Moreover, we employ the first transgenic zebrafish model for endoglin to demonstrate that GIPC is a critical component of endoglin function during developmental angiogenesis in vivo. These studies define a novel non-Smad function for endoglin and GIPC in regulating endothelial cell function during angiogenesis.