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转化生长因子-β1通过PP2Ac调节的Raf-MEK-ERK信号通路在内皮细胞中诱导谷氨酰胺分解。

Glutaminolysis Was Induced by TGF-β1 through PP2Ac Regulated Raf-MEK-ERK Signaling in Endothelial Cells.

作者信息

Guo YanYan, Deng YuanJun, Li XiaoQing, Ning Yong, Lin XuePing, Guo ShuiMing, Chen MeiXue, Han Min

机构信息

Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Sicence and Technology, Wuhan, Hubei, China.

出版信息

PLoS One. 2016 Sep 9;11(9):e0162658. doi: 10.1371/journal.pone.0162658. eCollection 2016.

DOI:10.1371/journal.pone.0162658
PMID:27612201
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5017743/
Abstract

Vascular endothelial cells can survive under hypoxic and inflammatory conditions by alterations of the cellular energy metabolism. In addition to high rates of glycolysis, glutaminolysis is another important way of providing the required energy to support cellular sprouting in such situations. However, the exact mechanism in which endothelial cells upregulate glutaminolysis remains unclear. Here we demonstrated that protein phosphatase 2A (PP2A)-mediated Raf-MEK-ERK signaling was involved in glutaminolysis in endothelial cells. Using models of human umbilical vein endothelial cells (HUVECs) treated with transforming growth factor-β1 (TGF-β1), we observed a dramatic induction in cellular glutamate levels accompanied by Raf-MEK-ERK activation. By addition of U0126, the specific inhibitor of MEK1/2, the expression of kidney-type glutaminase (KGA, a critical glutaminase in glutaminolysis) was significantly decreased. Moreover, inhibition of PP2A by okadaic acid (OA), a specific inhibitor of PP2A phosphatase activity or by depletion of its catalytic subunit (PP2Ac), led to a significant inactivation of Raf-MEK-ERK signaling and reduced glutaminolysis in endothelial cells. Taken together, these results indicated that PP2A-dependent Raf-MEK-ERK activation was involved in glutaminolysis and inhibition of PP2A signals was sufficient to block Raf-MEK-ERK pathway and reduced glutamine metabolism in endothelial cells.

摘要

血管内皮细胞可通过改变细胞能量代谢在缺氧和炎症条件下存活。除了高糖酵解率外，谷氨酰胺分解是在这种情况下为细胞发芽提供所需能量的另一种重要方式。然而，内皮细胞上调谷氨酰胺分解的确切机制仍不清楚。在这里，我们证明蛋白磷酸酶2A（PP2A）介导的Raf-MEK-ERK信号传导参与内皮细胞的谷氨酰胺分解。使用用转化生长因子-β1（TGF-β1）处理的人脐静脉内皮细胞（HUVEC）模型，我们观察到细胞谷氨酸水平显著诱导，同时伴有Raf-MEK-ERK激活。通过添加MEK1/2的特异性抑制剂U0126，肾型谷氨酰胺酶（KGA，谷氨酰胺分解中的关键谷氨酰胺酶）的表达显著降低。此外，用冈田酸（OA，PP2A磷酸酶活性的特异性抑制剂）或通过耗尽其催化亚基（PP2Ac）抑制PP2A，导致Raf-MEK-ERK信号传导显著失活，并降低内皮细胞中的谷氨酰胺分解。综上所述，这些结果表明PP2A依赖性Raf-MEK-ERK激活参与谷氨酰胺分解，抑制PP2A信号足以阻断Raf-MEK-ERK途径并减少内皮细胞中的谷氨酰胺代谢。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/72b9d8a4db71/pone.0162658.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/903bafbfcc5f/pone.0162658.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/103c109393c4/pone.0162658.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/25b44b90c29f/pone.0162658.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/154ee1cc68b5/pone.0162658.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/28281f421498/pone.0162658.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/69cabd2e697d/pone.0162658.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/72b9d8a4db71/pone.0162658.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/903bafbfcc5f/pone.0162658.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/103c109393c4/pone.0162658.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/25b44b90c29f/pone.0162658.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/154ee1cc68b5/pone.0162658.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/28281f421498/pone.0162658.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/69cabd2e697d/pone.0162658.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0017/5017743/72b9d8a4db71/pone.0162658.g007.jpg

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