Glycolysis Regulates Kras Plasma Membrane Localization and Function Through Defined Glycosphingolipids

Authors

Junchen Liu
Ransome van der Hoeven
Walaa E Kattan
Jeffrey T Chang
Dina Montufar-Solis
Wei Chen
Maurice Wong
Yong Zhou
Carlito B Lebrilla
John F Hancock

Publication Date

1-28-2023

Journal

Nature Communications

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.

Keywords

Humans, Proto-Oncogene Proteins p21(ras), Pancreatic Neoplasms, Cell Membrane, Signal Transduction, Glycolysis, Glycosphingolipids