Glycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids

Junchen Liu, Ransome Hoeven, Walaa E. Kattan, Jeffrey T. Chang, Dina Montufar-Solis, Wei Chen, Maurice Wong, Yong Zhou, Carlito B. Lebrilla and John F. Hancock ()
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Junchen Liu: University of Texas Health Science Center
Ransome Hoeven: The University of Texas Health Science Center at Houston
Walaa E. Kattan: University of Texas Health Science Center
Jeffrey T. Chang: University of Texas Health Science Center
Dina Montufar-Solis: University of Texas Health Science Center
Wei Chen: University of Texas Health Science Center
Maurice Wong: University of California
Yong Zhou: University of Texas Health Science Center
Carlito B. Lebrilla: University of California
John F. Hancock: University of Texas Health Science Center

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Oncogenic KRAS expression generates a metabolic dependency on aerobic glycolysis, known as the Warburg effect. We report an effect of increased glycolytic flux that feeds into glycosphingolipid biosynthesis and is directly linked to KRAS oncogenic function. High resolution imaging and genetic approaches show that a defined subset of outer leaflet glycosphingolipids, including GM3 and SM4, is required to maintain KRAS plasma membrane localization, with GM3 engaging in cross-bilayer coupling to maintain inner leaflet phosphatidylserine content. Thus, glycolysis is critical for KRAS plasma membrane localization and nanoscale spatial organization. Reciprocally oncogenic KRAS selectively upregulates cellular content of these same glycosphingolipids, whose depletion in turn abrogates KRAS oncogenesis in pancreatic cancer models. Our findings expand the role of the Warburg effect beyond ATP generation and biomass building to high-level regulation of KRAS function. The positive feedforward loop between oncogenic KRAS signaling and glycosphingolipid synthesis represents a vulnerability with therapeutic potential.

Date: 2023
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DOI: 10.1038/s41467-023-36128-5

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