# Eph and Lyn hyper-phosphorylation and CRMP interactions in AD"

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $201,250

## Abstract

Eph receptors make guidance decisions for cell migration in cardiovascular and neuronal development,
disease, and regeneration. Eph receptors are also involved with higher brain functions, memory and
learning. A protein that has been associated with Alzheimer’s, Parkinson’s and other neuronal diseases
and injuries is the Collapsin Response Mediator Protein (CRMP) which interacts with several kinases
and becomes hyper-phosphorylated alongside increased activation of the kinases. The hyper-
phosphorylated CRMP then disrupts the formation of actin and microtubule cytoskeletal structures and it
thought to impede Aβ and tau clearance. Cytosolic Lyn kinase, a close homologue of Fyn kinase, is
known to interact directly with EphA4 and here, for the first time, we show that an EphA family member
and EphB2 directly interacts with CRMP. Analogous to another guidance and cell migration system, the
Fyn-Plexin-CRMP complex, the Lyn-EphA4-CRMP association is likely to form a complex with Cdk5 and
GSK3β kinases, each also involved in Alzheimer’s. The features of the Eph-CRMP and Eph-Lyn
interacting interfaces need to be characterized, as they will be potential biomarkers and targets for
therapeutic intervention. The proposal has two main aims. Aim 1) seeks to establish the in vitro
phosphorylation patters of various kinases on the intracellular domains of EphA4 and –B2 in the
presence and absence of CRMP and to further validate the formation of the complex in cells. Aim 2) The
effect that the corresponding phosphomimetic/phospho-defective mutations have on the level of activity
on these Eph receptor intracellular regions and of the kinases will be studied with purified proteins in
vitro. Eventually, using the knowledge from this project, Antibodies or complex-disrupting-peptides may
drive the future development of early detection diagnostics and/or therapeutics.

## Key facts

- **NIH application ID:** 10886829
- **Project number:** 5R21AG084065-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** MATTHIAS BUCK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $201,250
- **Award type:** 5
- **Project period:** 2023-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886829

## Citation

> US National Institutes of Health, RePORTER application 10886829, Eph and Lyn hyper-phosphorylation and CRMP interactions in AD" (5R21AG084065-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10886829. Licensed CC0.

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