title: Gq-coupled purinergic receptors inhibit insulin-like growth factor-I/phosphoinositide 3-kinase pathway-dependent keratinocyte migration.
abstract: Insulin-like growth factor-I (IGF-I) activation of phosphoinositol 3-kinase (PI3K) is an essential pathway for keratinocyte migration that is required for epidermis wound healing. We have previously reported that activation of Galpha((q/11))-coupled-P2Y(2) purinergic receptors by extracellular nucleotides delays keratinocyte wound closure. Here, we report that activation of P2Y(2) receptors by extracellular UTP inhibits the IGF-I-induced p110alpha-PI3K activation. Using siRNA and pharmacological inhibitors, we demonstrate that the UTP antagonistic effects on PI3K pathway are mediated by Galpha((q/11))-and not G((i/o))-independently of phospholipase Cbeta. Purinergic signaling does not affect the formation of the IGF-I receptor/insulin receptor substrate-I/p85 complex, but blocks the activity of a membrane-targeted active p110alpha mutant, indicating that UTP acts downstream of PI3K membrane recruitment. UTP was also found to efficiently attenuate, within few minutes, the IGF-I-induced PI3K-controlled translocation of the actin-nucleating protein cortactin to the plasma membrane. This supports the UTP ability to alter later migratory events. Indeed, UTP inhibits keratinocyte spreading and migration promoted by either IGF-I or a membrane-targeted active p110alpha mutant, in a Galpha(q/11)-dependent manner both. These findings provide new insight into the signaling cross-talk between receptor tyrosine kinase and Galpha((q/11))-coupled receptors, which mediate opposite effects on p110alpha-PI3K activity and keratinocyte migration.
authors.affiliation: INSERM UMR 911, Centre de Recherche en Oncologie Biologique et en Oncopharmacologie, Université Aix-Marseille, Marseille 13005, France.
authors.forename: Salma
authors.initials: S
authors.lastname: Taboubi
authors.forename: Françoise
authors.initials: F
authors.lastname: Garrouste
authors.forename: Fabrice
authors.initials: F
authors.lastname: Parat
authors.forename: Gilbert
authors.initials: G
authors.lastname: Pommier
authors.forename: Emilie
authors.initials: E
authors.lastname: Faure
authors.forename: Sylvie
authors.initials: S
authors.lastname: Monferran
authors.forename: Hervé
authors.initials: H
authors.lastname: Kovacic
authors.forename: Maxime
authors.initials: M
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D051356:Cortactin / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D010456:Peptides, Cyclic / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D054799:Phospholipase C beta / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2; D015398:Signal Transduction / Q000502:physiology*; D014544:Uridine Triphosphate / Q000378:metabolism
chemical_list: D051356:Cortactin; C546385:P2RY2 protein, human; D010456:Peptides, Cyclic; D021122:Protein Subunits; D034741:RNA, Small Interfering; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; C475455:YM-254890; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D014544:Uridine Triphosphate