# Analysis of Desmoglein 2-mediated control of cell spreading and migration by cellular impedance.

> **NIH NIH R15** · FURMAN UNIVERSITY · 2024 · $99,130

## Abstract

PROJECT SUMMARY
The desmosome cell-cell adhesion complex plays an important role in the maintenance of tissue structure
and integrity in response to mechanical stress. In addition to this central adhesive role, desmosomal
proteins also coordinate multiple processes such as proliferation, apoptosis, differentiation and cell
migration. Prior studies show that desmosomal cadherins, the proteins responsible for mediating the
extracellular attachment between cells, can have both pro- and anti-migratory functions, indicating that their
influence on migration is more complex than a simple consequence of defective cell-cell attachment. Our
recent work has shown that loss of the cadherin Desmoglein-2 (DSG2) triggers increased activation of the
Rap1 GTPase, leading to enhanced cell spreading on extracellular matrix (ECM) proteins (such as
fibronectin and collagen). As these experiments were performed on singly spreading cells, we have
identified a novel cell-autonomous, cell-cell adhesion independent role for DSG2 in the regulation of cell
spreading. Nevertheless, the signaling mechanisms via which DSG2 regulates Rap1 activity remain
unknown. Our preliminary data also shows that localization of the Rap1 activator PDZ-GEF2 is dramatically
altered in DSG2 knockout cells, and that knockdown of the desmosomal protein Desmoplakin (DSP) can
rescue both the enhanced spreading and mis-localization of PDZ-GEF2 seen in these cells. Further, we
have obtained evidence that loss of DSG2 increases ECM gene expression via deregulated Src and NF-kB
signaling. In this proposal, we will test the central hypothesis that DSG2 orchestrates cell-matrix
adhesion and spreading through control of both inside-out signaling (via Rap1 GEFs) and outside-in
signaling (via ECM gene expression). In Aim 1, we will investigate whether binding of PDZ-GEF2 to
DSG2 or DSP reduces its activity, thereby inducing inside-out control of cell spreading via inhibition of Rap1
signaling. In Aim 2, we will explore a role for NF-kB and Src signaling in DSG2-dependent ECM gene
expression, and whether this promotes outside-in control of cell-matrix spreading and migration. Finally, in
Aim 3, we will explore the hypothesis that the ability of DSG2 to regulate cell migration is independent of its
extracellular domains and/or localization to the cell membrane. The scientific impact of these data will be
to produce a comprehensive picture of the molecular mechanisms by which the desmosomal cadherin
DSG2 coordinates both inside-out and outside-in signaling to control cell-matrix adhesion, spreading and
migration, functions critical for biological processes such as tissue morphogenesis, wound healing and re-
epithelialization. The training impact of these data will be to provide undergraduate students at Furman
University (a primarily undergraduate institution) with foundational skills in the scientific method, foster their
desire to tackle important biological problems and pursue a career in the biomedical sc...

## Key facts

- **NIH application ID:** 11037061
- **Project number:** 3R15GM150080-01S1
- **Recipient organization:** FURMAN UNIVERSITY
- **Principal Investigator:** Adi D Dubash
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $99,130
- **Award type:** 3
- **Project period:** 2024-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11037061

## Citation

> US National Institutes of Health, RePORTER application 11037061, Analysis of Desmoglein 2-mediated control of cell spreading and migration by cellular impedance. (3R15GM150080-01S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11037061. Licensed CC0.

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