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

Area of Science:

• Cell Biology
• Mechanobiology
• Biophysics

Background:

• Cell migration requires spatial organization of GTPases Rac and Rho.
• Rac typically drives cell protrusion at the front, while Rho mediates contraction at the back.
• The mechanisms positioning these GTPases at opposite cell poles are not fully understood.

Purpose of the Study:

• To elucidate the long-range communication mechanisms governing Rac and Rho GTPase localization.
• To understand how these GTPases establish and maintain cell polarity during migration.
• To investigate the interplay between mechanical forces and biochemical signaling in cell patterning.

Main Methods:

• Optogenetics to control GTPase activity.
• Mechanical perturbations to probe cellular responses.
• Mathematical modeling to simulate and explain observed phenomena.
• Analysis of phosphoinositide signaling and membrane tension.

Main Results:

• A novel long-range mutual activation mechanism between Rac and Rho polarity programs was discovered.
• Rac-driven protrusions increase membrane tension, activating Rho at the cell rear via mTORC2.
• Rho-mediated contractility triggers Rac activation at the front through cortical flow and phosphoinositide signaling.
• A minimal model demonstrated how long-range facilitation and local inhibition ensure robust Rho-Rac partitioning.

Conclusions:

• The actin cortex and plasma membrane form an integrated mechanochemical system for long-range Rac-Rho patterning.
• This regulatory circuit is essential for efficient cell polarity and migration in human T cells.
• The identified mechanism is conserved across different cell types, including epithelial cells, suggesting broad biological relevance.