2. Academic Validation
  3. PKM2 functions as a histidine kinase to phosphorylate PGAM1 and increase glycolysis shunts in cancer

PKM2 functions as a histidine kinase to phosphorylate PGAM1 and increase glycolysis shunts in cancer

  • EMBO J. 2024 May 15. doi: 10.1038/s44318-024-00110-8.
Yang Wang # 1,  Hengyao Shu # 1,  Yanzhao Qu 1,  Xin Jin 1,  Jia Liu 1,  Wanting Peng 1,  Lihua Wang 1,  Miao Hao 2,  Mingjie Xia 1,  Zhexuan Zhao 1,  Kejian Dong 1,  Yao Di 1,  Miaomiao Tian 1,  Fengqi Hao 1,  Chaoyi Xia 1,  Wenxia Zhang 1,  Xueqing Ba 3,  Yunpeng Feng 4,  Min Wei 5
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), Northeast Normal University, 5268 Renmin Street, 130024, Changchun, Jilin, China.
  • 2 Science Research Center, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, 130033, Changchun, Jilin, China.
  • 3 Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), Northeast Normal University, 5268 Renmin Street, 130024, Changchun, Jilin, China. baxq755@nenu.edu.cn.
  • 4 Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), Northeast Normal University, 5268 Renmin Street, 130024, Changchun, Jilin, China. fengyp0108@nenu.edu.cn.
  • 5 Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), Northeast Normal University, 5268 Renmin Street, 130024, Changchun, Jilin, China. weim750@nenu.edu.cn.
  • # Contributed equally.
PMID: 38750259 DOI: 10.1038/s44318-024-00110-8
Abstract

Phosphoglycerate mutase 1 (PGAM1) is a key node Enzyme that diverts the metabolic reactions from glycolysis into its shunts to support macromolecule biosynthesis for rapid and sustainable cell proliferation. It is prevalent that PGAM1 activity is upregulated in various tumors; however, the underlying mechanism remains unclear. Here, we unveil that Pyruvate Kinase M2 (PKM2) moonlights as a histidine kinase in a phosphoenolpyruvate (PEP)-dependent manner to catalyze PGAM1 H11 phosphorylation, that is essential for PGAM1 activity. Moreover, monomeric and dimeric but not tetrameric PKM2 are efficient to phosphorylate and activate PGAM1. In response to epidermal growth factor signaling, Src-catalyzed PGAM1 Y119 phosphorylation is a prerequisite for PKM2 binding and the subsequent PGAM1 H11 phosphorylation, which constitutes a discrepancy between tumor and normal cells. A PGAM1-derived pY119-containing cell-permeable peptide or Y119 mutation disrupts the interaction of PGAM1 with PKM2 and PGAM1 H11 phosphorylation, dampening the glycolysis shunts and tumor growth. Together, these results identify a function of PKM2 as a histidine kinase, and illustrate the importance of Enzyme crosstalk as a regulatory mode during metabolic reprogramming and tumorigenesis.

Keywords

Glycolysis Shunts; Histidine Kinase; Phosphoglycerate Mutase 1 (PGAM1); Phosphorylation; Pyruvate Kinase M2 (PKM2).

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