# GPCR - Linked RhoGEFs in Tumor Growth and Metastasis

> **NIH NIH R01** · PURDUE UNIVERSITY · 2020 · $355,725

## Abstract

PROJECT SUMMARY
G protein-coupled receptors (GPCRs) are well known for their ability to convert extracellular information
encoded in hormones, odorants, and peptides into rapid changes in cellular homeostasis by modulating the
function of effector enzymes and channels in the cell. However, analysis of human cancer genomes indicates
that some GPCR signaling pathways lead to sustained signals that in pathological settings are linked to tumor
growth and metastasis. A common feature of such pathways is the activation of Rho GTPases by Dbl family
Rho guanine nucleotide exchange factors (RhoGEFs). The TrioC subfamily (composed of Trio, Kalirin, and
p63RhoGEF) is directly activated by heterotrimeric Gαq subunits and is strongly implicated in ocular melanoma
and leukemia. The P-Rex subfamily (composed of P-Rex1 and 2) is activated synergistically by direct
interactions with G and the lipid PIP3, and is overexpressed in many breast and prostate tumors where it
plays a metastatic role. Trio and P-Rex1/2 have thus emerged as important chemotherapeutic targets. The fact
that the molecular and cellular mechanisms underlying regulation of these enzymes are as of yet poorly
understood prevents a rational approach to the design of novel therapeutic approaches. By determining
crystallographic and cryo-EM structures of members from these RhoGEF subfamilies, this proposal seeks to
define molecular mechanisms of activation and to test these hypotheses through a battery of functional assays.
In parallel, we extend our functional analysis into model cell systems to understand how constitutively active
heterotrimeric G proteins and GPCRs promote cancer cell growth (as in ocular melanoma) and metastasis (as
in breast cancer) via TrioC and P-Rex subfamily RhoGEFs. By understanding the basis for regulation of
RhoGEF activity by heterotrimeric G proteins both in vitro and in relevant cellular contexts, we will accelerate
discovery of new biological insights and novel therapeutic strategies that can be used to combat cancer.

## Key facts

- **NIH application ID:** 9870899
- **Project number:** 5R01CA221289-03
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** John Tesmer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,725
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870899

## Citation

> US National Institutes of Health, RePORTER application 9870899, GPCR - Linked RhoGEFs in Tumor Growth and Metastasis (5R01CA221289-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9870899. Licensed CC0.

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