Division of Biomedical Research, Foundation of Research and Technology-Hellas, Institute of Molecular Biology and Biotechnology, University Campus, 45110 Ioannina, Greece; Laboratory of Biological Chemistry, Medical School, University of Ioannina, 45110 Ioannina, Greece.
Department of Informatics and Telecommunications Engineering, University of Western Macedonia, 50100 Kozani, Greece; Division of Biomedical Research, Foundation of Research and Technology-Hellas, Institute of Molecular Biology and Biotechnology, University Campus, 45110 Ioannina, Greece.
Mol Cell. 2014 May 22;54(4):559-72. doi: 10.1016/j.molcel.2014.03.022. Epub 2014 Apr 17.
Accumulation of unfolded proteins in the endoplasmic reticulum (ER) initiates IRE1α, ATF6, and PERK cascades, leading to a transcriptional/translational response known as unfolded protein response (UPR). Here we show that VEGF activates UPR mediators through a PLCγ-mediated crosstalk with the mTORC1 complex without accumulation of unfolded proteins in the ER. Activation of ATF6 and PERK contributes to the survival effect of VEGF on endothelial cells (ECs) by positively regulating mTORC2-mediated phosphorylation of AKT on Ser473, which is required for full activity of AKT. Low levels of CHOP allow ECs to evade the proapoptotic effect of this UPR product. Depletion of PLCγ, ATF6, or eIF2α dramatically inhibited VEGF-induced vascularization in mouse Matrigel plugs, suggesting that the ER and the UPR machinery constitute components of the VEGF signaling circuit that regulates EC survival and angiogenesis, extending their role beyond adaptation to ER stress.
内质网中未折叠蛋白的积累会引发 IRE1α、ATF6 和 PERK 级联反应，导致一种被称为未折叠蛋白反应 (UPR) 的转录/翻译反应。在这里，我们发现 VEGF 通过与 mTORC1 复合物的 PLCγ 介导的串扰而无需内质网中未折叠蛋白的积累来激活 UPR 介质。ATF6 和 PERK 的激活通过正向调节 AKT 在 Ser473 上的 mTORC2 介导的磷酸化，从而促进 VEGF 对血管内皮细胞 (ECs) 的存活作用，AKT 的完全活性需要 Ser473 的磷酸化。CHOP 的低水平允许 ECs 逃避这种 UPR 产物的促凋亡作用。PLCγ、ATF6 或 eIF2α 的耗竭显著抑制了 VEGF 在小鼠 Matrigel 塞中的血管生成作用，这表明 ER 和 UPR 机制构成了调节 EC 存活和血管生成的 VEGF 信号通路的组成部分，从而将其作用扩展到适应 ER 应激之外。
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