# Converting cytoskeletal forces into biochemical signals

> **NIH GM R01** · ROCKEFELLER UNIVERSITY · 2026 · $339,000

## Abstract

PROJECT SUMMARY
 Cells perceive mechanical cues in their local environments, which must be converted into intracellular
biochemical signals to modulate cellular physiology and control gene expression. There is increasing
appreciation for mechanical signal transduction’s (“mechanotransduction”) critical role in development and its
dysfunction in disease states such as cancer. However, in contrast to canonical signal transduction, cellular force
sensing is poorly understood, hampering efforts to define mechanistically distinct mechanotransduction
pathways, delineate their specific biological functions, and target them therapeutically.
 The actin cytoskeleton, a network of dynamic actin filaments, myosin motor proteins, and hundreds of
associated factors, enables cells to mechanically interface with their surroundings. The cytoskeleton is classically
understood to serve as a force generation and transmission apparatus that indirectly facilitates mechano-
transduction through its physical linkages to membrane-anchored sites which mediate force signal conversion
(e.g. cell-cell and cell-matrix adhesions). However, we and others have recently reported direct binding of soluble
cytosolic proteins containing tandem arrays of LIM (LIN-11, Isl-1 & Mec-3) domains to tensed actin filaments,
suggesting that the cytoskeleton itself may have the capacity to transduce forces into biochemical signals. Here
I propose to test the hypothesis that force-activated actin binding by distinct LIM proteins is upstream of
functionally discrete downstream mechanotransduction pathways. Through cellular assays and biophysical
reconstitution, we will investigate how the representative force-activated actin binding LIM proteins zyxin (Aim 1)
and FHL1/2 (Four-and-a-Half LIM domains 1/2, Aim 2) mediate distinct downstream functions in cytoplasmic
cytoskeletal damage repair and nuclear gene expression regulation, respectively. We will then innovatively
interface these approaches with cryo-electron mi

## Key facts

- **NIH application ID:** 11254904
- **Project number:** 5R01GM146880-04
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** GREGORY M ALUSHIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** GM
- **Fiscal year:** 2026
- **Award amount:** $339,000
- **Award type:** 5
- **Project period:** 2023-03-15T00:00:00 → 2027-01-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11254904

## Citation

> US National Institutes of Health, RePORTER application 11254904, Converting cytoskeletal forces into biochemical signals (5R01GM146880-04). Retrieved via AI Analytics 2026-07-10 from https://api.ai-analytics.org/grant/nih/11254904. Licensed CC0.

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