We suggest that polarized distribution of a fully functional PMCA4b can generate and maintain a front-to-rear increasing Ca2+ concentration gradient, and induce redistribution of polymerized F-actin and cofilin from the dynamic protrusions to the leading edge, formation of stable stress fibers, increased cell–cell connections, and decreased vinculin expression resulting in a slow motility melanoma cell type. This evidence concerns the gene CFL1 and melanoma.