# Investigating the Mechanism of Activation of EphA4

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2024 · $48,974

## Abstract

Project Summary/Abstract
Many therapeutics for proliferative and neurodegenerative disorders, such as cancer and amyotrophic lateral
sclerosis (ALS), aim to disrupt or inhibit downstream signaling pathways components such as the MAPK cascade.
A critical barrier in therapeutic development against Receptor Tyrosine Kinases (RTKs) is that oftentimes
signaling pathways are interconnected, and this may lead to off-target side-effects. One method to mitigate these
challenges is to determine the mechanism of activation of membrane receptors that actively play a role in
abnormal cellular functions. RTKs, such as Erythropoietin-producing hepatoma (Eph) receptor 4, have been of
particular interest as potential drug targets. However, there is a lack of structural information on EphA4 that
provides insight into receptor activation. In this work, we aim to determine key structural differences during
activation of dimeric EphA4 as well investigate the activity of loss-of-function EphA4 mutants using
complementary fluorescence-based and structural studies to validate our findings. In aim one, we propose to
elucidate critical structural differences resulting in wild type EphA4 activation using cryo-electron microscopy
(cryo-EM). In aim 2, we propose to characterize aberrant activity and oligomerization of known EphA4 cancer
mutants through fluorescence-based studies, biophysical, and biochemical assays. The results of these aims will
contribute significantly to our underlying understanding of RTKs and will aid in efforts to develop EphA4
structure-based drug designs for proliferative and neurodegenerative disorders.

## Key facts

- **NIH application ID:** 10835871
- **Project number:** 5F31GM150212-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Briana Whitehead
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10835871

## Citation

> US National Institutes of Health, RePORTER application 10835871, Investigating the Mechanism of Activation of EphA4 (5F31GM150212-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10835871. Licensed CC0.

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