# Cadherin Mechanotransduction

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $329,374

## Abstract

This grant builds on our novel discovery that E-cadherin at epithelial cell-cell junctions transduces mechanical
signals, by activating a kinase cascade via the epidermal growth factor receptor (EGFR). E-cadherin is an
essential adhesion protein at epithelial cell-cell junctions, and E-cadherin complexes also transduce force, to
regulate cell shape and epithelial barrier integrity. These new findings suggest that E-cadherin force-
transduction also activates signals that regulate cell proliferation, morphogenesis, and disease. The broad goal
of this program is to identify initial steps in the mechanical activation of EGFR by E-cadherin, and to establish
the broader physiological implications of this mechanism. Our preliminary data also demonstrate that this
force-activated signaling pathway regulates the cytoskeletal reinforcement of stressed cell-cell junctions by
α−catenin in E-cadherin complexes. This unexpected finding supports the hypothesis that EGFR and E-
cadherin are essential components in the core force-transduction machinery at epithelial cell junctions. In this
program, Specific Aim 1 tests the hypothesis that mechanically stimulated E-cadherin activates EGFR
phosphorylation, by triggering the disruption of putative E-cadherin/EGFR complexes. Specific Aim 2 will use
innovative fluorescence-based methodology, developed by collaborator Hristova (Johns Hopkins) to
investigate direct interactions between E-cadherin and EGFR at the plasma membrane. Proposed studies are
based on substantial preliminary data, which reveal direct protein-protein association. Biophysical studies will
establish the molecular requirements for this association, using a subset of E-cadherin and EGFR mutants.
Specific Aim 3 will test the physiological implications of these findings in a three-dimensional, organotypic
model of human mammary epithelial tissue, in collaboration with Weaver (UCSF). Studies will determine
whether E-cadherin/EGFR complexes are indeed central force-sensing units that coordinate with integrins to
tune morphogenesis and malignancy, in response to tissue mechanics. 3D cultures of breast epithelial cells
engineered to express E-cadherin mutants (Aim 2) will determine the impact of E-cadherin/EGFR complex
disruption on proliferation, morphogenesis, and invasion, as a function of matrix rigidity. Integrins are well
known to coordinate with EGFR to regulate breast tissue development and tumor progression. These studies
would potentially establish E-cadherin as an essential component in this force-sensitive network.

## Key facts

- **NIH application ID:** 9976560
- **Project number:** 5R01GM127554-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Deborah E Leckband
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $329,374
- **Award type:** 5
- **Project period:** 2018-09-05 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976560

## Citation

> US National Institutes of Health, RePORTER application 9976560, Cadherin Mechanotransduction (5R01GM127554-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9976560. Licensed CC0.

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