# Cytoskeletal force-sensing mechanisms

> **NIH GM R35** · ROCKEFELLER UNIVERSITY · 2026 · $395,499

## Abstract

Cells perceive mechanical cues in their local environments, which must be converted into intracellular
biochemical signals to modulate cellular physiology and control gene expression. This process of mechanical
signal transduction (“mechanotransduction”) is critical for development and frequently dysfunctions in disease
states such as cancer. Despite increasing appreciation of its importance for human physiology, the molecular
mechanisms of mechanotransduction remain poorly understood, hampering efforts to define mechanistically
distinct mechanical signaling pathways, delineate their specific biological functions, and target them
therapeutically. The actin cytoskeleton, a network of dynamic actin filaments (F-actin), myosin motor proteins,
and hundreds of associated factors, enables cells to mechanically interface with their surroundings. While the
cytoskeleton is classically understood as a force generation and transmission apparatus that indirectly facilitates
mechanotransduction, our research has provided evidence that actin filaments can also serve as direct molecular
force transducers. By developing innovative cryo-electron microscopy (cryo-EM) sample preparation and
machine-learning based computational analysis approaches, we have uncovered multiple classes of force-
dependent structural transitions in F-actin (elicited by fluid flow and myosin molecular motor forces) that can be
discriminated by force-sensitive actin-binding proteins. This work has provided a first direct glimpse at how forces
alter protein structure to regulate function. Using biophysical reconstitution and cell biology studies, we have also
shown how force-activated F-actin binding by proteins from the LIM (LIN-11, Isl-1 & Mec-3) domain superfamily
can coordinate downstream mechanotransduction processes, including repair of physical damage to actin-
myosin cables mediated by zyxin and extracellular matrix stiffness-dependent nuclear localization of Four-and-
a-Half LIM domains (FHL) transcr

## Key facts

- **NIH application ID:** 11259182
- **Project number:** 1R35GM161251-01
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** GREGORY M ALUSHIN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** GM
- **Fiscal year:** 2026
- **Award amount:** $395,499
- **Award type:** 1
- **Project period:** 2026-04-01T00:00:00 → 2031-02-28T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11259182

## Citation

> US National Institutes of Health, RePORTER application 11259182, Cytoskeletal force-sensing mechanisms (1R35GM161251-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11259182. Licensed CC0.

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