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Long range mutual activation establishes Rho and Rac polarity during cell migration.

Henry De Belly1,2, Andreu Fernandez Gallen3, Evelyn Strickland1,2

  • 1Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.

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|April 16, 2025
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Summary
This summary is machine-generated.

Cell migration relies on Rac and Rho GTPases. This study reveals long-range activation between their polarity programs, complementing local inhibition, to ensure proper cell positioning and migration.

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Area of Science:

  • Cell Biology
  • Biophysics
  • Mechanobiology

Background:

  • Cell migration involves distinct front (Rac-driven protrusion) and back (Rho-driven contraction) domains.
  • The precise mechanisms governing the spatial organization of Rac and Rho at opposite cell poles remain poorly understood.

Purpose of the Study:

  • To elucidate the mechanisms underlying the long-range spatial partitioning of Rac and Rho GTPases in migrating cells.
  • To investigate the interplay between local inhibition and long-range activation of polarity pathways.

Main Methods:

  • Utilized optogenetics and cell mechanics manipulation.
  • Developed and employed a minimal unifying mechanochemical model.
  • Validated findings in primary human lymphocytes during chemotaxis.

Main Results:

  • Discovered a long-range mutual activation mechanism between front (Rac) and back (Rho) polarity programs.
  • Identified two distinct modes of mechanochemical crosstalk: membrane tension-mediated Rac-to-Rho activation and cortical flow-mediated Rho-to-Rac activation.
  • Demonstrated that this long-range facilitation is crucial for robust Rho and Rac partitioning and cell migration.

Conclusions:

  • The actin cortex and plasma membrane act as an integrated mechanochemical system for long-range Rac and Rho partitioning.
  • This mechanism is essential for directed cell migration, particularly in response to chemoattractants.
  • Findings have implications for understanding cell polarity in various biological contexts.