# Molecular mechanisms of Eph receptor signaling

> **NIH NIH R35** · OHIO STATE UNIVERSITY · 2024 · $297,513

## Abstract

PROJECT SUMMARY
The survival of every multicellular organism relies on effective cell-cell communication. Despite the diversity of
signals that cells need to communicate to their neighbors, evolution appears to have settled on only a few
physical mechanisms for transferring information across membranes. One such mechanism is the
oligomerization, or clustering, of membrane-spanning receptor proteins, wherein the receipt of a signal on one
side of the membrane is converted into a biochemical response on the other side. The mechanisms and
regulation of oligomeric transitions remain poorly understood for most families of receptor proteins due to the
inherent experimental difficulty of detecting and probing these subtle transitions. My lab is interested in
harnessing the latest developments in optogenetics, single-molecule microscopy, genome editing, and high-
throughput sequencing to dissect the receptor clustering events that allow cells to “talk” to each other in a
systematic and quantitative way. The proposed research program will tackle the activation and regulation of Eph
receptors in human cells. Eph receptors constitute the largest known family of receptor tyrosine kinases (RTK’s)
and are linked to a broad range of biological processes in both health and disease, ranging from tissue patterning
and embryonic development to neurodegeneration and cancer. The mechanistic details behind Eph receptor
activation remain obscure, in large part because of the large number of receptor types that are often expressed
in a single cell and their apparent ability to from both homo- and hetero-oligomers of varying stoichiometries.
Over the next five years, we will develop a combined approach for precisely manipulating and detecting homo-
and hetero-oligomerization of Eph receptors, allowing us to directly determine the effects of cluster size and
composition on the downstream signaling outcomes. This approach will also allow us to reveal the cryptic roles
of heterodimers between Eph receptors of different types, including the two catalytically inactive members of the
family. Light-inducible optogenetic clustering in living cells will be cross-validated with in vitro enzymology and
direct observation of clustering in single-molecule tracking experiments, ensuring that we are faithfully
recapitulating the biologically relevant oligomeric transitions. In addition to its immediate significance to the Eph
receptor field, the proposed work will develop a biophysical framework for analyzing the signaling of other
receptor families at the cell-cell interface. Finally, the spatially defined and non-invasive nature of light means
that development of optically controlled receptors will serve as a powerful tool for the study of cell-cell signaling
at the organoid or organismal level.

## Key facts

- **NIH application ID:** 10938787
- **Project number:** 1R35GM154813-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Vladislav Belyy
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $297,513
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938787

## Citation

> US National Institutes of Health, RePORTER application 10938787, Molecular mechanisms of Eph receptor signaling (1R35GM154813-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10938787. Licensed CC0.

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