Fructose-1,6-bisphosphate couples glycolytic flux to activation of Ras

Ken Peeters, Frederik Van Leemputte, Baptiste Fischer, Beatriz M. Bonini, Hector Quezada, Maksym Tsytlonok, Dorien Haesen, Ward Vanthienen, Nuno Bernardes, Carmen Bravo Gonzalez-Blas, Veerle Janssens, Peter Tompa, Wim Versées and Johan M. Thevelein ()
Additional contact information
Ken Peeters: Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven
Frederik Van Leemputte: Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven
Baptiste Fischer: VIB-VUB Center for Structural Biology
Beatriz M. Bonini: Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven
Hector Quezada: Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven
Maksym Tsytlonok: VIB-VUB Center for Structural Biology
Dorien Haesen: Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven
Ward Vanthienen: Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven
Nuno Bernardes: Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven
Carmen Bravo Gonzalez-Blas: Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven
Veerle Janssens: Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven
Peter Tompa: VIB-VUB Center for Structural Biology
Wim Versées: VIB-VUB Center for Structural Biology
Johan M. Thevelein: Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Yeast and cancer cells share the unusual characteristic of favoring fermentation of sugar over respiration. We now reveal an evolutionary conserved mechanism linking fermentation to activation of Ras, a major regulator of cell proliferation in yeast and mammalian cells, and prime proto-oncogene product. A yeast mutant (tps1∆) with overactive influx of glucose into glycolysis and hyperaccumulation of Fru1,6bisP, shows hyperactivation of Ras, which causes its glucose growth defect by triggering apoptosis. Fru1,6bisP is a potent activator of Ras in permeabilized yeast cells, likely acting through Cdc25. As in yeast, glucose triggers activation of Ras and its downstream targets MEK and ERK in mammalian cells. Biolayer interferometry measurements show that physiological concentrations of Fru1,6bisP stimulate dissociation of the pure Sos1/H-Ras complex. Thermal shift assay confirms direct binding to Sos1, the mammalian ortholog of Cdc25. Our results suggest that the Warburg effect creates a vicious cycle through Fru1,6bisP activation of Ras, by which enhanced fermentation stimulates oncogenic potency.

Date: 2017
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DOI: 10.1038/s41467-017-01019-z

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