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The plasma membrane is a key actor of cell migration. For instance, its tension controls persistent cell migration and cell surface caveolae integrity. Then, caveolae constituents like caveolin-1 can initiate a mechano-tranduction loop that involves actin-and focal adhesions- dependent control of the mechanosensor YAP to finely tune cell migration. Tetraspanin CD82 (also named KAI-1) is an integral membrane protein and a metastasis suppressor. Its expression is lost in many cancers including breast cancer. It is a strong inhibitor of cell migration by a not well-known mechanism. We demonstrated here that CD82 controls persistent 2D migration of EGF-induced single cell, stress fibers and focal adhesion sizes and dynamics. In addition, CD82 regulates cell mechanics e.g. membrane tension, cell surface caveolae abundance and YAP nuclear translocation in a caveolin-1 dependent manner. Altogether, our data strongly suggest that CD82 controls 2D cell migration using a membrane-driven mechanical loop involving caveolin and the YAP pathway.