The P2Y receptor signals through Gα /Ca /PKCα and Gα /ROCK pathways to drive the formation of membrane protrusions and dictate cell migration.

Cell migration is a ubiquitous process necessary to maintain and restore tissue functions. However, in cancer, cell migration leads to metastasis development and thus worsens the prognosis. Although the mechanism of cell migration is well understood, the identification of new targets modulating cell migration and deciphering their signaling events could lead to new therapies to restore tissue functions in diseases, such as inflammatory bowel disease, or to block metastatic development in different forms of cancer. Previous research has identified the G-protein-coupled P2Y receptor as an innovative target that could dictate cell migration under normal and pathological conditions. Surprisingly, there is little information on the cellular events triggered by activated P2Y during cell migration. Here, we demonstrated that P2Y activation stimulated A549 human lung cancer cells and Caco-2 colorectal cancer cell migration. Activated P2Y increased the number of filopodia and focal adhesions; two migratory structures required for cell migration. The generation of these structures involved Gα /calcium/protein kinases C (PKC) and Gα /RHO-associated protein kinase-dependent pathways that dictate the formation of the migratory structures. These pathways led to the stabilization of the actin cytoskeleton through a PKC-dependent phosphorylation of cofilin. These results support the idea that the P2Y receptor represents a target of interest to modulate cell migration and revealed an intricate dialogue between two Gα-protein signaling pathways.