Department of Digestive Disease, The First Affiliated Hospital of University of Science and Technology of China, Anhui Provincial Hospital, Hefei, China; MOE Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei, China.
MOE Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei, China.
J Biol Chem. 2022 Nov;298(11):102561. doi: 10.1016/j.jbc.2022.102561. Epub 2022 Oct 2.
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.
癌细胞在不同的细胞周期阶段对葡萄糖代谢中间产物有独特的需求，用于生物合成和能量。然而，细胞周期调节剂和糖酵解酶如何协调来协调这些必要的代谢过程，仍知之甚少。在这里，我们报告了细胞周期的间期中有丝分裂激酶 Aurora A 与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 苏氨酸 45 位的磷酸化显著降低了 PKM2 的酶活性，减少了其四聚体化，并促进了糖酵解通量和分支合成代谢途径。用非磷酸化的 PKM2 T45A 突变体替代内源性 PKM2 可抑制糖酵解、糖酵解分支途径和在体外和体内模型中的肿瘤生长。总之，我们的研究揭示了 Aurora A 通过调节限速糖酵解酶 PKM2 发挥新的促肿瘤功能，主要是在细胞周期的 S 期。我们的研究结果还表明，尽管 Aurora A 和 Aurora B 激酶都在相同的残基上磷酸化 PKM2，但特定激酶和 PKM2 相互作用的时空调节是依赖于上下文的，这表明细胞周期和糖酵解调节剂之间存在错综复杂的相互联系。
