Spatiotemporal coupling of caveolae mechanosensing and RhoA-GEFs regulates cell polarity and directional migration

Migrating cells dynamically adapt their morphogenetic programs in response to microenvironmental changes, requiring coordinated spatiotemporal integration of mechanical and biochemical signals. The plasma membrane, through membrane tension and actin dynamics modulation, is essential for cell motility. Caveolae, small plasma membrane invaginations, act as mechanosensors to buffer tension changes under mechanical stress. Recent evidence suggests a role for caveolae in cell migration. Here, we demonstrate that breast cancer cells exhibit a front-rear asymmetry in caveolae and caveolin-1 scaffolds, which is regulated by membrane tension and is crucial for persistent migration and cell directionality. RhoA-driven cell contraction relies on the spatiotemporally coordinated assembly of caveolae and recruitment of RhoA-GEFs at the cell rear. These results are supported by a physical model establishing a feedback loop between local membrane tension and contractility, through caveolae formation and disruption. Our findings underscore the importance of caveolae mechanosensing in regulating RhoA activation and guiding cell migration. This study reveals that caveolae and caveolin-1 form a front-rear asymmetry in migrating cells, coupling membrane tension to RhoA-GEF recruitment and activation. This mechanosensing feedback regulates cell polarity and promotes persistent migration.