# Regulation of KRAS Trafficking and Signaling by GPR31

> **NIH NIH R03** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $169,500

## Abstract

PROJECT SUMMARY
KRAS is the oncogene most frequently mutated in human cancer. KRAS functions as a
molecular switch that regulates signaling pathways only when associated with cellular
membranes. KRAS associates with membranes as a consequence of farnesylation that
operates in conjunction with a polybasic C-terminus. Efforts to defeat KRAS by blocking
farnesylation failed because of alternative enzymes capable of prenylating KRAS. We
therefore took an unbiased approach to identify previously unrecognized genes that
participate in the membrane association of KRAS. We devised a dual luciferase assay
that reports loss of KRAS affinity for membranes and used this assay in a genome-wide
siRNA screen. Among the 13 genes identified we were surprised to find a G protein
coupled receptor (GPCR) designated GPR31, which is a high affinity receptor for 12-(S)-
HETE and has been shown to stimulate MAPK signaling. GPR31 is an understudied
GPCR that is included in the Illuminating the Druggable Genome project. We were
also surprised to find by co-immunoprecipitation a physical interaction between GPR31
and KRAS, suggesting that GPR31 might act as a secretory pathway chaperone for KRAS
as it traffics from endomembrane to the plasma membrane (PM). In preliminary studies
we have found that GRP31 and KRAS colocalized on endomembrane and PM and that
silencing of GPR31 with siRNA inhibits KRAS dependent cell proliferation and
macropinocytosis. We now propose to determine if 12-(S)-HETE signaling through
GPR31 regulates KRAS trafficking and signaling with three Specific Aims. Aim 1.
Ligation of GPR31 with 12-(S)-HETE and Interaction of GPR31 with KRAS. We will
measure the interaction between GPR31 and KRAS by co-immunoprecipitation and FRET
± 12-(S)-HETE or control eicosinoids. Aim 2. Ligation of GPR31 with 12-(S)-HETE and
Trafficking of KRAS. We will study KRAS trafficking from endomembrane to PM using
live cell imaging ± 12-(S)-HETE. Aim 3. Ligation of GPR31 with 12-(S)-HETE and KRAS
activation. We will study KRAS signaling ± 12-(S)-HETE. The prosecution of these aims
will determine if GPR31 signaling regulates KRAS and thereby prioritize GPR31 for anti-
cancer drug discovery.
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## Key facts

- **NIH application ID:** 10047185
- **Project number:** 1R03TR003358-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** MARK Reid PHILIPS
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,500
- **Award type:** 1
- **Project period:** 2020-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047185

## Citation

> US National Institutes of Health, RePORTER application 10047185, Regulation of KRAS Trafficking and Signaling by GPR31 (1R03TR003358-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10047185. Licensed CC0.

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