# Ligand functional selectivity in EphA2 receptor signaling

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $459,877

## Abstract

SUMMARY
The mechanism behind the phenomenon of "ligand functional selectivity”, defined as the ability
of different ligands to differentially activate distinct signaling pathways through a common
receptor, is not understood for receptor tyrosine kinases. Here we seek to obtain such
mechanistic information for EphA2, a transmembrane receptor tyrosine kinase that is critically
important for human health. We will investigate EphA2 signaling responses to three ligands:
dimeric ephrinA1-Fc, monomeric m-ephrinA1, and the engineered monomeric YSA peptide
ligand using biochemical and biophysical approaches in the context of live cells. We have
already discovered differences in the extracellular configuration of the EphA2/YSA, EphA2/m-
ephrinA1 and EphA2/ephrinA1-Fc oligomers in live cells, and in Aim 1 we will investigate
whether these differences are transmitted across the plasma membrane, leading to differences
in the configuration of the EphA2 intracellular regions. In Aim 2, we will compare EphA2
signaling responses to the three ligands to test the hypothesis that differences in downstream
signaling correlate with differential phosphorylation of some of the EphA2 tyrosines and/or
different kinetics of EphA2 activation/inactivation. This work will advance the general
understanding of receptor tyrosine kinase signal transduction, and inform the design of
“pathway-biased” targeted drugs with improved specificity and safety profiles.

## Key facts

- **NIH application ID:** 9840491
- **Project number:** 5R01GM131374-02
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Kalina Hristova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $459,877
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840491

## Citation

> US National Institutes of Health, RePORTER application 9840491, Ligand functional selectivity in EphA2 receptor signaling (5R01GM131374-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840491. Licensed CC0.

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