Journal article
Glycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids
Nature communications, Vol.14(1), pp.465-465
01/28/2023
DOI: 10.1038/s41467-023-36128-5
PMCID: PMC9884228
PMID: 36709325
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.
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.
Details
- Title: Subtitle
- Glycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids
- Creators
- Junchen Liu - The University of Texas Health Science Center at HoustonRansome van der Hoeven - The University of Texas Health Science Center at HoustonWalaa E. Kattan - The University of Texas Health Science Center at HoustonJeffrey T. Chang - The University of Texas Health Science Center at HoustonDina Montufar-Solis - Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science CenterWei Chen - The University of Texas Health Science Center at HoustonMaurice Wong - University of California, DavisYong Zhou - The University of Texas MD Anderson Cancer CenterCarlito B. Lebrilla - University of California, DavisJohn F. Hancock - The University of Texas MD Anderson Cancer Center
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.14(1), pp.465-465
- DOI
- 10.1038/s41467-023-36128-5
- PMID
- 36709325
- PMCID
- PMC9884228
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Nature Publishing Group UK
- Grant note
- RP200047 / Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas) (https://doi.org/10.13039/100004917)
- Language
- English
- Date published
- 01/28/2023
- Academic Unit
- Dental Research; Periodontics
- Record Identifier
- 9984737966302771
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