# Decoding mechanotransduction mechanisms of cell-surface receptors

> **NIH NIH R35** · UNIVERSITY OF MINNESOTA · 2020 · $445,431

## Abstract

Project Summary
An explosion of recent studies has indicated that altered mechanical forces in the microenvironment of cells, or
its “mechano-some”, is a potentially targetable and quantifiable factor in disease, much like changes in the ge-
nome or proteome. Valuable insights into the mechanical microenvironment at the cell and tissue level have
been achieved by measuring forces that cells exert on deformable surfaces or their macroscopic stiffness, but
have largely ignored how cells sense and respond to force at the molecular level. Changes in macroscopic
stiffness in disease are accompanied by a wealth of molecular changes in a cell's tensional homeostasis where
“mechanotransduction” signaling pathways are aberrantly activated. At the epicenter of tension sensing are
transmembrane cell-surface receptors, which are uniquely positioned to sense and integrate all cellular me-
chanical cues from outside, inside, and within the membrane of the cell. Our overall hypothesis is that studying
how cell-surface receptors change conformation to sense and respond to force will lead to a critical under-
standing of the mechanical microenvironment of cells at a molecular level thus leading to novel therapeutics
and diagnostic tools for many diseases. While advanced single molecule spectroscopy tools exist to probe
force-induced conformational changes at a molecular level, decoding mechanotransduction mechanisms has
been crippled by a lack of tools to measure how cells sense and respond to force at a molecular level and re-
quires synergy between “cellular-biophysics” and “structure-function” approaches within the NIGMS mission.
To tackle the challenge of measuring molecular-level forces that cells sense in order to identify cell-surface
mechanosensors, define magnitudes of physiologic forces, and measure how force changes during disease
progression, new hybrid fluorescent molecular tension sensors will be devised that marry advantages of cur-
rent genetically-encoded and immobilized DNA-based sensors using a new fusion-tag technology that allows
covalent attachment of DNA nanostructures to genetically-encoded proteins in cells. To tackle the challenge of
measuring downstream cellular effects of applying force to specific cell-surface receptors, an improved version
of a high-throughput magnetic tweezers assay developed to study mechanotransduction of Notch receptors will
be used, which applies piconewton forces to magnetic beads tethered to specific receptors, and measures
downstream responses using imaging and cell-lysate based readouts such as transcription, localization of
adaptor proteins, cytoskeleton dynamics, and relevant kinase and GTPase activity. To tackle the challenge of
decoding mechanisms that receptors use to sense and respond to force, x-ray crystallography and an im-
proved single molecule proteolysis assay will be used to test the hypothesis that force-induced proteolysis is a
general mechanosensing mechanism, as was recently discovered for ...

## Key facts

- **NIH application ID:** 9962443
- **Project number:** 5R35GM119483-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** WENDY RYAN GORDON
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $445,431
- **Award type:** 5
- **Project period:** 2016-07-20 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962443

## Citation

> US National Institutes of Health, RePORTER application 9962443, Decoding mechanotransduction mechanisms of cell-surface receptors (5R35GM119483-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9962443. Licensed CC0.

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