Mechanical forces as long-range organizers of cellular physiology

In migrating cells, the GTPase Rac organizes a protrusive front, whereas Rho organizes a contractile back, yet how these GTPases segregate remains unclear. We leverage optogenetics, mechanical perturbations, and modeling to reveal a mechanochemical long-range mutual activation between front and back polarity programs that complements their known local mutual inhibition. Rac-driven protrusions increase membrane tension, triggering mTORC2-dependent Rho activation at the opposite side of the cell. Conversely, Rho-mediated contractility induces cortical-flow regulation of phosphoinositide signaling, promoting distal Rac activation. Our findings demonstrate how the actin cortex and plasma membrane interact as an integrated mechanochemical system for long-range Rac-Rho patterning. Efficient migration also requires polarized organization of the cell interior, with organelle positioning increasingly recognized as a key determinant of cell movement. Yet how this organization is established remains unclear. Building on our mechanochemical framework, we now investigate how actin-generated forces position organelles during migration and how disruption of this intracellular organization contributes to disease.

Website of the De Belly lab: https://cri.utsw.edu/faculty/henry-de-belly/

This is part of the Physics of Living Systems monthly symposium: https://pols.epfl.ch/physics-of-living-systems-seminars/monthly-symposium/