Calcium influx mediated by a mechano-gated ion channel TRPV4 controls actin architecture in lamellipodia to promote cell migration.

Cell migration is crucial for various physiological processes, enabling cells to navigate through complex environments during development and immune surveillance. Dysregulated cell migration leads to severe pathologies, highlighting the necessity to understand its regulation. Although Ca2+ signaling has long been recognized to regulate cell migration, its specific role in coordinating cell protrusion, often the first event of migration, remains elusive. Here, we identify a Ca2+ signaling axis involving the mechano-gated channel TRPV4, which regulates lamellipodia protrusions across various cell types. Using Ca2+ and FRET imaging, we demonstrate that TRPV4-mediated Ca2+ influx is essential for local activation of RhoA, which densifies lamellipodial F-actin through formins. Mechanistically, we identify CaMKII and TEM4 as key mediators relaying the Ca2+ signal from TRPV4 to RhoA. This localized Ca2+ signaling axis, comprising TRPV4, CaMKII, TEM4, and RhoA, is essential for organizing the actin machinery and promoting cell migration in diverse biological contexts.