Aurora A-mediated pyruvate kinase M2 phosphorylation promotes biosynthesis with glycolytic metabolites and tumor cell cycle progression.
Aurora A-mediated pyruvate kinase M2 phosphorylation promotes biosynthesis with glycolytic metabolites and tumor cell cycle progression.
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DOI：
10.1016/j.jbc.2022.102561
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发表时间：
2022-11
影响因子：
4.8
通讯作者：
Yang, Zhenye
中科院分区：
文献类型：
--
作者：
Jiang, Ya;Wang, Ting;Sheng, Dandan;Han, Chaoqiang;Xu, Tian;Zhang, Peng;You, Weiyi;Fan, Weiwei;Zhang, Zhiyong;Jin, Tengchuan;Duan, Xiaotao;Yuan, Xiao;Liu, Xing;Zhang, Kaiguang;Ruan, Ke;Shi, Jue;Guo, Jing;Cheng, Aoxing;Yang, Zhenye
癌细胞在不同的细胞周期阶段对葡萄糖代谢中间产物的生物合成和能量有不同的需求。然而，细胞周期调节因子和糖酵解酶是如何协调协调基本代谢过程的，目前还没有得到很好的描述。在这里，我们报道了细胞周期间期有丝分裂酶Aurora A和糖酵解酶丙酮酸激酶M2(PKM2)之间的一种新的相互作用。我们发现Aurora A介导的PKM2在苏氨酸45处的磷酸化。这种磷酸化显著降低了PKM2的酶活性，减少了它的四聚反应，并促进了糖酵解通量和分支合成代谢途径。在体外和体内模型中，用非磷酸化的PKM2 T45A突变体取代内源性PKM2可以抑制糖酵解、糖酵解分支途径和肿瘤生长。总之，我们的研究揭示了Aurora A通过调节限速糖酵解酶PKM2的新的促肿瘤功能，该酶主要在细胞周期的S阶段。我们的研究结果还表明，虽然Aurora A和Aurora B两个蛋白激酶都在相同的残基上磷酸化PKM2，但特定的蛋白激酶和PKM2相互作用的空间和时间调节是上下文依赖的，这表明细胞周期和糖酵解调节之间存在复杂的相互联系。
Cancer cells have distinctive demands for intermediates from glucose metabolism for biosynthesis and energy in different cell cycle phases. However, how cell cycle regulators and glycolytic enzymes coordinate to orchestrate the essential metabolic processes are still poorly characterized. Here, we report a novel interaction between the mitotic kinase, Aurora A, and the glycolytic enzyme, pyruvate kinase M2 (PKM2), in the interphase of the cell cycle. We found Aurora A–mediated phosphorylation of PKM2 at threonine 45. This phosphorylation significantly attenuated PKM2 enzymatic activity by reducing its tetramerization and also promoted glycolytic flux and the branching anabolic pathways. Replacing the endogenous PKM2 with a nonphosphorylated PKM2 T45A mutant inhibited glycolysis, glycolytic branching pathways, and tumor growth in both in vitro and in vivo models. Together, our study revealed a new protumor function of Aurora A through modulating a rate-limiting glycolytic enzyme, PKM2, mainly during the S phase of the cell cycle. Our findings also showed that although both Aurora A and Aurora B kinase phosphorylate PKM2 at the same residue, the spatial and temporal regulations of the specific kinase and PKM2 interaction are context dependent, indicating intricate interconnectivity between cell cycle and glycolytic regulators.
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影响因子：
13.8
作者：
Olson KA;Schell JC;Rutter J
通讯作者：
Rutter J
影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
影响因子：
29
作者：
Pavlova NN;Thompson CB
通讯作者：
Thompson CB
影响因子：
16.6
作者：
Jiang, Yuhui;Wang, Yugang;Wang, Ting;Hawke, David H.;Zheng, Yanhua;Li, Xinjian;Zhou, Qin;Majumder, Sadhan;Bi, Erfei;Liu, David X.;Huang, Suyun;Lu, Zhimin
通讯作者：
Lu, Zhimin
影响因子：
20.3
作者：
den Hollander, Juergen;Rimpi, Sara;Keller, Ulrich
通讯作者：
Keller, Ulrich