Aurora A–mediated pyruvate kinase M2 phosphorylation promotes biosynthesis with glycolytic metabolites and tumor cell cycle progression

Ya Jiang, Ting Wang, Dandan Sheng, Chaoqiang Han, Tian Xu, Peng Zhang, Weiyi You, Weiwei Fan, Zhiyong Zhang, Tengchuan Jin, Xiaotao Duan, Xiao Yuan, Xing Liu, Kaiguang Zhang, Ke Ruan, Jue Shi, Jing Guo, Aoxing Cheng*, Zhenye Yang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number102561
Number of pages11
JournalJournal of Biological Chemistry
Volume298
Issue number11
DOIs
Publication statusPublished - Nov 2022

Scopus Subject Areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

User-Defined Keywords

  • Aurora A
  • biosynthesis
  • cell cycle progression
  • phosphorylation
  • PKM2

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