# Mechanoregulation of E-cadherin Adhesion

> **NIH NIH R15** · OLD DOMINION UNIVERSITY · 2024 · $468,958

## Abstract

Project Summary
E-cadherin is the primary mediator of strong cell-cell adhesion between epithelial cells and plays an
essential role in the morphogenesis and maintenance of epithelial tissues. E-cadherin is also a known
mechanosensor that actively responds to the levels of inter-cellular forces and resides in a
microenvironment formed by adjoining epithelial cells. The long-term goal of the project is to understand
how the mechanical regulation of E-cadherin adhesion leads to a cohesive yet dynamic multi-cellular
architecture in epithelial tissues. The goal of the proposed project is to delineate the mechanism by which
forces are transmitted via E-cadherin adhesions and to uncover how epithelial cells sense cell-like stiffness
laterally via E-cadherin adhesions. The E-cadherin-β-catenin-α-catenin complex directly and indirectly
couples to actin to transmit cell-generated forces. Firstly, while the α-catenin-vinculin link, which plays a role
in force sensing is thought to be the primary force transmission pathway, we recently found that,
surprisingly, α-catenin is not essential for force transmission. Therefore, we will test the hypothesis that the
less studied β-catenin-vinculin link is an alternate significant mechanism of force transmission at E-cadherin
adhesions. We will test this by using mutant versions of vinculin and α-catenin deficient in binding β-catenin
and vinculin, respectively, and corresponding knockout cell lines. We will use traction force microscopy with
E-cadherin-coated soft substrates to avoid the confounding factor of vinculin’s mechanical role in cell-matrix
contacts. We will also use magnetic pulling cytometry with E-cadherin-coated beads and biaxial stretching
of cell islands to assess the adhesion strength at multiple scales. Secondly, while E-cadherin has been
shown to sense the stiffness of E-cadherin-coated soft substrates, it is still unclear if epithelial cells sense
cell-like stiffness laterally via E-cadherin adhesions. To test this, we will devise a biomimetic model of E-
cadherin in a physiologically relevant geometry, in which cells interface laterally with an E-cadherin-coated,
stiffness tunable, soft surface. We will test the hypothesis that lateral sensing of cell-like stiffness modulates
E-cadherin density, cell dynamics, Rho and YAP levels. We will also test whether this lateral stiffness
sensing is dependent on the α-catenin-vinculin mechanotransduction axis. We will use biomimetic soft
substrate fabrication, mutant version of α-catenin deficient in binding vinculin in α-catenin knockout cells,
sensors/indicators of Rho and YAP, and perform live-cell imaging and immunofluorescence to accomplish
this. Knowledge gained on cell-to-cell force transmission and epithelial cell sensing of neighboring cell
mechanical properties will be crucial in understanding the context-dependent biophysical control of E-
cadherin adhesion. This will be essential to better understand the functional basis of the role of E-cadhe...

## Key facts

- **NIH application ID:** 10974558
- **Project number:** 2R15GM116082-03
- **Recipient organization:** OLD DOMINION UNIVERSITY
- **Principal Investigator:** Venkat Maruthamuthu
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $468,958
- **Award type:** 2
- **Project period:** 2015-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10974558

## Citation

> US National Institutes of Health, RePORTER application 10974558, Mechanoregulation of E-cadherin Adhesion (2R15GM116082-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10974558. Licensed CC0.

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