# Regulation of KRAS plasma membrane targeting by defined glycosphingolipids.

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $396,725

## Abstract

PROJECT SUMMARY
KRAS operates as a molecular switch that oscillates between an active GTP-bound and inactive GDP-bound
state. Active KRAS proteins are required to localize to the plasma membrane within a defined lipid environment
to be functional. Oncogenic KRAS induces metabolic dependence on aerobic glycolysis, a phenomenon known
as the Warburg effect. We recently discovered that aerobic glycolysis, by generating a subset of outer leaflet
glycosphingolipids (GSL), controls KRAS plasma membrane (PM) interactions and therefore KRAS
oncogenesis. Blocking GSL metabolism, using multiple methods including glucose deletion, pharmacological
inhibition and genetic deletion of selected GSL synthetic enzymes all mislocalize KRAS from the PM. Deletion
of key enzymes of the GSL biosynthetic pathways abrogated KRAS oncogenesis in vitro and in vivo. Building
on these exciting findings, we developed our central hypothesis: that a subset of defined glycosphingolipids
regulates localization and nanoscale organization of KRAS through controlling the lipid composition on the PM
and lipid transport at PM-ER membrane contact sites. We will test to what extent do GSLs operate as spatial
organizers of the inner PM and ER-PM contacts sites in Aim1 by using a variety of lipid biosensor and high-
resolution imaging. In Aim 2, we will employ genetic approaches, lipid reconstitution experiments and
molecular dynamics simulation to probe the potential mechanism of inter leaflet coupling between outer leaflet
GSLs and inner leaflet phosphatidylserine on the PM. Finally, in Aim 3 we will rigorously test the relevance of
this novel glycosphingolipid-centered mechanism in multiple mouse KRAS cancer models. In sum, using a
multidisciplinary approach, this proposal will yield new insights into the molecular mechanism of how surface
GSLs regulate PM lipid composition and lipid transport, and the role of inter leaflet lipid coupling. This is highly
significant to basic membrane biology and biophysics. The connection of GSL metabolism through PM lipid
organization to KRAS function will identify a novel vulnerability to KRAS oncogenesis that may have
therapeutic potential.

## Key facts

- **NIH application ID:** 10894128
- **Project number:** 5R01GM151280-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Alemayehu A. Gorfe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $396,725
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894128

## Citation

> US National Institutes of Health, RePORTER application 10894128, Regulation of KRAS plasma membrane targeting by defined glycosphingolipids. (5R01GM151280-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10894128. Licensed CC0.

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