VEGF Signals through ATF6 and PERK to Promote Endothelial Cell Survival and Angiogenesis in the Absence of ER Stress
VEGF Signals through ATF6 and PERK to Promote Endothelial Cell Survival and Angiogenesis in the Absence of ER Stress
复制标题
DOI：
10.1016/j.molcel.2014.03.022
复制
发表时间：
2014-05-22
期刊：
影响因子：
16
通讯作者：
Fotsis, Theodore
中科院分区：
文献类型：
--
作者：
Karali, Evdoxia;Bellou, Sofia;Fotsis, Theodore
未折叠蛋白在内质网(ER)中的积累启动IRE1α、ATF6和PERK级联反应，导致称为未折叠蛋白反应(UPR)的转录/翻译反应。在这里，我们表明，血管内皮生长因子激活UPR介质通过PLC伽马介导的串扰与mTORC1复合体，而不积累未折叠的蛋白质在内质网。ATF6和PERK的激活通过正向调节mTORC2介导的AKT在Ser473上的磷酸化，从而参与了VEGF对内皮细胞(ECs)的生存效应，而Ser473是AKT充分激活所必需的。低水平的CHOP允许内皮细胞逃避这种UPR产品的促凋亡作用。PLC Gamma、ATF6或eIF2α的缺失显著抑制了血管内皮生长因子诱导的小鼠Matrigel栓中的血管形成，这表明内质网和UPR机制构成了调控EC存活和血管生成的血管内皮生长因子信号通路的组成部分，将它们的作用扩展到对内质网应激适应之外。
Accumulation of unfolded proteins in the endoplasmic reticulum (ER) initiates IRE1 alpha, 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 PLC gamma-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 PLC gamma, ATF6, or eIF2 alpha 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.