Gα(q/11)-coupled P2Y2 nucleotide receptor inhibits human keratinocyte spreading and migration

Reepithelialization is a critical step in wound healing. It is initiated by keratinocyte migration at the wound edges. After wounding, extracellular nucleotides are released by keratinocytes and other skin cells. Here, we report that activation of P2Y2 nucleotide receptor by ATP/UTP inhibits keratinocyte cell spreading and induces lamellipodium withdrawal. Kymography analysis demonstrates that these effects correlate with a durable decrease of lamellipodium dynamics. P2Y2 receptor activation also induces a dramatic dismantling of the actin network, the loss of α3 integrin expression at the cell periphery, and the dissolution of focal contacts as indicated by the alteration of αv integrins and focal contact protein distribution. In addition, activation of P2Y2R prevents growth factor-induced phosphorylation of Erk1,2 and Akt/PkB. The use of a specific pharmacological inhibitor (YM-254890), the depletion of Gα(q/11) by siRNA, or the expression of a constitutively active Gα(q/11) mutant (Q209L) show that act...