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.
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http://dx.doi.org/10.1038/s44318-024-00110-8 | DOI Listing |
Bioorg Med Chem
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Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 1050 Boyles St., Frederick, MD 21702, USA.
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View Article and Find Full Text PDFBiochem Biophys Rep
March 2025
College of Biomedical Sciences, Larkin University, Miami, FL, 33169, USA.
Nucleic Acids Res
December 2024
Department of Biology, Massachusetts Institute of Technology, Building 68, 31 Ames St., Cambridge, MA 02139, USA.
The eukaryotic microrchidia (MORC) protein family are DNA gyrase, Hsp90, histidine kinase, MutL (GHKL)-type ATPases involved in gene expression regulation and chromatin compaction. The molecular mechanisms underlying these activities are incompletely understood. Here, we studied the full-length human MORC2 protein biochemically.
View Article and Find Full Text PDFMethods Mol Biol
December 2024
Systems, Synthetic, and Physical Biology Program, Rice University, Houston, TX, USA.
Optogenetics enables precise control of gene expression in a variety of organisms. We recently developed the first system for optogenetic control of transcription in Bacillus subtilis. This system is based on CcaSR, a light-responsive two-component regulatory system originally derived from Synechocystis PCC 6803.
View Article and Find Full Text PDFPLoS Genet
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Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
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