biostudies-literatureWang YYoung Scientific and Technological Talents Support Project of Jilin ProvinceMOST | National Natural Science Foundation of China (NSFC)China Postdoctoral Science FoundationMOST | National Natural Science Foundation of ChinaChina Postdoctoral Science Foundation (China Postdoctoral Foundation Project)2368-2396https://www.ebi.ac.uk/biostudies/studies/S-EPMC11183095biostudies-literatureUnknown43(12)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 phosThe EMBO journalPKM2 functions as a histidine kinase to phosphorylate PGAM1 and increase glycolysis shunts in cancer.PMC11183095320708962020T1300903207075832101048QT2021052019M661190Liu JJin XPeng WTian MHao MFeng YBa XShu HZhao ZWang LZhang WWei MXia MDong KHao FXia CQu YWang YDi YfalsePKM2 functions as a histidine kinase to phosphorylate PGAM1 and increase glycolysis shunts in cancer.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 phos2024-01-01T00:00:00Z2024 Jun2026-06-01T11:21:43.66Z2024-10-15T14:29:32.117ZS-EPMC111830953875025910.1038/s44318-024-00110-8