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SUMMARY

Cell migration is crucial for development and tissue homeostasis, while its dysregulation leads to severe pathologies. Cell migration is driven by the extension of actin-based lamellipodia protrusions, powered by actin polymerization, which is tightly regulated by signaling pathways, including Rho GTPases and Ca ²⁺ signaling. While the importance of Ca ²⁺ signaling in lamellipodia protrusions has been established, the molecular mechanisms linking Ca ²⁺ to lamellipodia assembly are unknown. Here, we identify a novel Ca ²⁺ signaling axis involving the mechano-gated channel TRPV4, which regulates lamellipodia protrusions in various cell types. Using Ca ²⁺ and FRET imaging, we demonstrate that TRPV4-mediated Ca ²⁺ influx upregulates RhoA activity within lamellipodia, which then facilitates formin-mediated actin assembly. Mechanistically, we identify CaMKII and TEM4 as key mediators relaying the TRPV4-mediated Ca ²⁺ signal to RhoA. These data define a molecular pathway by which Ca ²⁺ influx regulates small GTPase activity within a specific cellular domain – lamellipodia - and demonstrate the critical role in organizing the actin machinery and promoting cell migration in diverse biological contexts.