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Glycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids
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Journal Article
Glycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids
2023
Overview
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.
KRAS is a small GTPase that regulates cell proliferation. Here, the authors show that a subset of cell surface glycosphingolipids regulate KRAS plasma membrane localization by modulating inner leaflet lipid composition, uncovering a requirement for KRAS oncogenesis that may have therapeutic potential.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/28
/ 38/44
/ 59/5
/ 64/11
/ 64/60
/ 82/1
/ 82/58
/ 96/10
/ 96/35
/ Glycosphingolipids - metabolism
/ Humanities and Social Sciences
/ Humans
/ Lipids
/ Pancreatic Neoplasms - genetics
/ Pancreatic Neoplasms - metabolism
/ Plasma
/ Proto-Oncogene Proteins p21(ras) - genetics
/ Proto-Oncogene Proteins p21(ras) - metabolism
/ Science
