A Rho GTPase-effector ensemble governs cell migration behavior

Heeyoung Lee, Sangkyu Lee, Yeji Seo, Dongsan Kim, Yohan Oh, Juae Jin, Bobae Hyeon, Younghyun Han, Hyunjun Kim, Yong Jin Lee, Ho Min Kim, Gabsang Lee (), Kwang-Hyun Cho () and Won Heo ()
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Heeyoung Lee: Korea Advanced Institute of Science and Technology (KAIST)
Sangkyu Lee: Institute for Basic Science
Yeji Seo: Hulux
Dongsan Kim: Korea Advanced Institute of Science and Technology (KAIST)
Yohan Oh: Hanyang University
Juae Jin: Korea Advanced Institute of Science and Technology (KAIST)
Bobae Hyeon: Korea Advanced Institute of Science and Technology (KAIST)
Younghyun Han: Korea Advanced Institute of Science and Technology (KAIST)
Hyunjun Kim: Johns Hopkins University
Yong Jin Lee: Hulux
Ho Min Kim: Korea Advanced Institute of Science and Technology (KAIST)
Gabsang Lee: Johns Hopkins University School of Medicine
Kwang-Hyun Cho: Korea Advanced Institute of Science and Technology (KAIST)
Won Heo: Korea Advanced Institute of Science and Technology (KAIST)

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract How can a cell navigate its environment without any external cues? Since such cues are not always present in the environment, cells rely on internal machinery to explore their surroundings. Although Rho GTPases are known for orchestrating cell motility, the intrinsic Rho GTPase-effector mechanisms governing spontaneous migration remain incompletely understood. Here we show an imaging-based method that profiles protein-protein interactions (PPIs) through phase-separated condensates. By applying this method to hundreds of interaction profiles between Rho small GTPases and their effector proteins, we uncovered two intrinsic mechanisms governing cell migration. Formin-like protein (FMNL) determines the front of the cell by restricting Cdc42 activity, establishing front-rear polarity. In contrast, Rac1-ROCK-interaction-mediated arc stress fiber formation at the front inherently enables spontaneous directional changes and enhances cellular responses to external cues. Our findings elucidate the intricate roles of the Rho GTPase-effector ensemble that governs cell migration behavior, revealing an intrinsic program for efficient motility strategies.

Date: 2025
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DOI: 10.1038/s41467-025-64635-0

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