Journal
FASEB JOURNAL
Volume 21, Issue 14, Pages 4047-4058Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.06-7476com
Keywords
GPCR; wound healing; PI3K/Akt; MAPK; UTP
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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 P2Y(2) 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 alpha 3 integrin expression at the cell periphery, and the dissolution of focal contacts as indicated by the alteration of alpha v integrins and focal contact protein distribution. In addition, activation of P2Y(2)R prevents growth factor-induced phosphorylation of Erk(1,2) and Akt/ PkB. The use of a specific pharmacological inhibitor (YM-254890), the depletion of G alpha((q/ 11)) by siRNA, or the expression of a constitutively active G alpha(( q/ 11)) mutant (Q209L) show that activation of G alpha((q/ 11)) is responsible for these ATP/UTP-induced effects. Finally, we report that ATP delays growth factor-induced wound healing of keratinocyte monolayers. Collectively, these findings provide evidence for a unique and important role for extracellular nucleotides as efficient autocrine/paracrine regulators of keratinocyte shape and migration during wound healing. -Taboubi, S., Milanini, J., Delamarre, E., Parat, F., Garrouste, F., Pommier, G., Takasaki, J., Hubaud, J-C., Kovacic, H., Lehmann, M. G alpha((q/ 11))coupled P2Y2 Nucleotide Receptor Inhibits Human Keratinocyte Spreading and Migration.
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