# Alpha-catenin function in cardiomyocyte adhesion and cytoskeletal organization

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $383,789

## Abstract

Project Summary
With every heartbeat, the junctional complexes that couple cardiomyocytes must transmit the mechanical
forces of contraction while maintaining adhesive homeostasis. Cardiomyocytes are linked end-to-end by the
intercalated disc (ICD), a specialized junction that coordinates cell signaling, electrical and mechanical
operations. The ICD comprises adherens junctions (AJs) and desmosomes that connect the actin and
intermediate filament cytoskeletons, respectively, of adjoining cells. ICD function requires multiple adhesion
and cytoskeletal proteins and mutations in these proteins are linked to cardiomyopathies. However, relatively
little is known about how adhesion complexes are regulated to establish and maintain heart tissue integrity.
The core of the adherens junction is the cadherin-catenin complex, which is connected to the actin
cytoskeleton through a-catenin. a-Catenin is a multifunctional, mechanoresponsive actin-binding protein that
localizes to the cardiomyocyte ICD. However, a-catenin functions in cell-cell adhesion in cardiomyocytes are
poorly understood. Our objective in this application is to determine how mechanical and molecular inputs are
transduced through the two a-catenins expressed in the human heart – aE(Epithelial)-catenin and aT(Testes)-
catenin – to regulate cardiomyocyte adhesion. Our rationale is that defining the individual and collective roles
of a-catenin at cardiomyocyte AJs will provide fundamental insight into how cardiomyocyte AJs balance
mechanical and signaling functions. We hypothesize that aE-catenin and aT-catenin form unique cadherin-
catenin complexes in response to cellular cues to function as mechanical checkpoints for ICD assembly and
cardiomyocyte organization. In this proposal, we seek to: 1) define the allosteric mechanisms that regulate a-
catenin ligand binding at the cardiomyocyte AJ; 2) determine how ligand recruitment to a-catenin promotes AJ
assembly and cytoskeletal attachment; and 3) identify how external mechanical cues regulate AJ organization.
Knowledge to be gained through our studies include a detailed, mechanistic understanding of how a-catenin
molecular properties are tuned for adhesion in cardiomyocytes; how unique molecular complexes are built
along the cardiomyocyte AJ to establish and maintain adhesion; and how external mechanical cues feed into
the cardiomyocyte AJ to drive organization. This comprehensive, multiscale analysis will develop new tools
and acquire new knowledge about the molecular mechanisms of cell adhesion in cardiomyocytes.
Understanding the fundamental mechanisms of cell adhesion in cardiomyocytes is necessary for determining
how mutations in ICD proteins lead to heart disease and inform the development of new strategies for the
treatment of cardiomyopathies.

## Key facts

- **NIH application ID:** 10885149
- **Project number:** 5R01HL127711-09
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Adam Vincent Kwiatkowski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $383,789
- **Award type:** 5
- **Project period:** 2016-04-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885149

## Citation

> US National Institutes of Health, RePORTER application 10885149, Alpha-catenin function in cardiomyocyte adhesion and cytoskeletal organization (5R01HL127711-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10885149. Licensed CC0.

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