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.

Public Health Relevance

EphA2 is a cell membrane receptor that has been implicated in a number of diseases, including cancer, cataracts, inflammation, atherosclerosis and infections. We have obtained evidence that three activating ligands promote the formation of three distinct EphA2 assemblies, leading to different signaling responses. We propose to study the mechanisms behind this ?ligand functional selectivity?, which will advance the general understanding of signal transduction and inform the design of ?pathway-biased? targeted drugs with improved specificity and safety profiles.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM131374-02
Application #
9840491
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Koduri, Sailaja
Project Start
2019-01-01
Project End
2022-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Sanford Burnham Prebys Medical Discovery Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037