线粒体易位的磷酸甘油酸激酶1作为一种蛋白激酶，在肿瘤发生过程中协调糖酵解和三羧酸循环。
Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis.
作者信息
Li Xinjian, Jiang Yuhui, Meisenhelder Jill, Yang Weiwei, Hawke David H, Zheng Yanhua, Xia Yan, Aldape Kenneth, He Jie, Hunter Tony, Wang Liwei, Lu Zhimin
机构信息
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Institute of Cell Metabolism and Disease, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
出版信息
Mol Cell. 2016 Mar 3;61(5):705-719. doi: 10.1016/j.molcel.2016.02.009.
It is unclear how the Warburg effect that exemplifies enhanced glycolysis in the cytosol is coordinated with suppressed mitochondrial pyruvate metabolism. We demonstrate here that hypoxia, EGFR activation, and expression of K-Ras G12V and B-Raf V600E induce mitochondrial translocation of phosphoglycerate kinase 1 (PGK1); this is mediated by ERK-dependent PGK1 S203 phosphorylation and subsequent PIN1-mediated cis-trans isomerization. Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex. This reduces mitochondrial pyruvate utilization, suppresses reactive oxygen species production, increases lactate production, and promotes brain tumorigenesis. Furthermore, PGK1 S203 and PDHK1 T338 phosphorylation levels correlate with PDH S293 inactivating phosphorylation levels and poor prognosis in glioblastoma patients. This work highlights that PGK1 acts as a protein kinase in coordinating glycolysis and the tricarboxylic acid (TCA) cycle, which is instrumental in cancer metabolism and tumorigenesis.
目前尚不清楚，体现了胞质溶胶中糖酵解增强的瓦氏效应是如何与受抑制的线粒体丙酮酸代谢协调的。我们在此证明，缺氧、表皮生长因子受体（EGFR）激活以及K-Ras G12V和B-Raf V600E的表达会诱导磷酸甘油酸激酶1（PGK1）向线粒体转位；这是由细胞外信号调节激酶（ERK）依赖的PGK1 S203磷酸化以及随后PIN1介导的顺反异构化介导的。线粒体PGK1作为一种蛋白激酶，在苏氨酸338位点磷酸化丙酮酸脱氢酶激酶1（PDHK1），从而激活PDHK1磷酸化并抑制丙酮酸脱氢酶（PDH）复合体。这会减少线粒体丙酮酸的利用，抑制活性氧的产生，增加乳酸的产生，并促进脑肿瘤的发生。此外，PGK1 S203和PDHK1 T338的磷酸化水平与胶质母细胞瘤患者中PDH S293失活磷酸化水平及不良预后相关。这项工作突出表明，PGK1作为一种蛋白激酶，在协调糖酵解和三羧酸（TCA）循环中发挥作用，这在癌症代谢和肿瘤发生过程中至关重要。
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