# Molecular mechanisms underlying force transduction at cellular adhesion complexes

> **NIH NIH R35** · STANFORD UNIVERSITY · 2022 · $599,214

## Abstract

Our objective is to elucidate the molecular mechanisms by which cellular adhesion complexes form and
remodel in response to mechanical load. Cell-cell and cell-matrix adhesions are a defining feature of metazoan
life and are essential to the physiological function of virtually every tissue in the human body. Despite this central
importance, only a few of the protein-protein interactions that make up adhesion complexes have been
characterized biochemically, and even less is known about the underlying mechanisms by which these structures
respond to mechanical load. This lack of quantitative data presents an unavoidable roadblock in the collective
effort to understand how cells build and remodel multicellular tissues.
 We will use single-molecule biophysical approaches to develop a detailed understanding of how adhesion
complexes templated by E-cadherin sense and transduce mechanical cues. Previously, we demonstrated that a
complex of E-cadherin, β-catenin, and αE-catenin forms a minimal force-sensing unit at intercellular adhesions.
Here, we build on this result to test the hypothesis that this complex lies at the heart of a mechanosensory
assembly that converts small changes in input forces into dramatic alterations in adhesion architecture, size, and
stability.
 In parallel work, we will use biophysical techniques unique to our laboratory to determine how directional
interactions between proteins within adhesion complexes and filamentous (F)-actin may give rise to long-range
organization in the cytoskeleton. Recently, we found that the protein vinculin, which is recruited to both cell-
matrix and intercellular adhesions, forms a directionally asymmetric interaction with F-actin that is stabilized ~10-
fold when load is oriented toward the pointed (-) vs. barbed (+) end of the actin filament. Preliminary data suggest
that force-dependent, asymmetric binding interactions with F-actin are not unique to vinculin, and likely extend
to other adhesion proteins. These observations suggest that asymmetric interactions between F-actin and
proteins within adhesion complexes may play a central and previously unsuspected role in organizing cells and
tissues, a hypothesis that we will test during the next funding period.
 Cell and developmental biological data indicate that αE-catenin plays a central role in organizing epithelial
tissues through its interactions with zonula occludens-1 (ZO-1) and afadin, both of which bind F-actin and recruit
other scaffolding and signaling proteins. We will perform the first detailed biochemical and biophysical
characterization of the interaction of the cadherin-catenin complex with ZO-1 and afadin, and use cutting-edge
imaging techniques to determine how these proteins interact in living cells. These studies will lay the foundation
for a quantitative understanding of how intercellular adhesion complexes function as integrated, multifunctional
force-sensing assemblies.

## Key facts

- **NIH application ID:** 10437720
- **Project number:** 5R35GM130332-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Alexander R Dunn
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $599,214
- **Award type:** 5
- **Project period:** 2019-05-06 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437720

## Citation

> US National Institutes of Health, RePORTER application 10437720, Molecular mechanisms underlying force transduction at cellular adhesion complexes (5R35GM130332-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10437720. Licensed CC0.

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