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Glycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids

Author

Listed:
  • 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
    M. D. Anderson Cancer Center and 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
    M. D. Anderson Cancer Center and University of Texas Health Science Center)

  • Carlito B. Lebrilla

    (University of California)

  • John F. Hancock

    (University of Texas Health Science Center
    M. D. Anderson Cancer Center and University of Texas Health Science Center)

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.

Suggested Citation

  • Junchen Liu & Ransome Hoeven & Walaa E. Kattan & Jeffrey T. Chang & Dina Montufar-Solis & Wei Chen & Maurice Wong & Yong Zhou & Carlito B. Lebrilla & John F. Hancock, 2023. "Glycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36128-5
    DOI: 10.1038/s41467-023-36128-5
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    as
    1. Caroline R. Amendola & James P. Mahaffey & Seth J. Parker & Ian M. Ahearn & Wei-Ching Chen & Mo Zhou & Helen Court & Jie Shi & Sebastian L. Mendoza & Michael J. Morten & Eli Rothenberg & Eyal Gottlieb, 2019. "KRAS4A directly regulates hexokinase 1," Nature, Nature, vol. 576(7787), pages 482-486, December.
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