Fiche publication
Date publication
juillet 2016
Journal
Cell discovery
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROUGET Raphaël
Tous les auteurs :
Bhosle VK, Rivera JC, Zhou TE, Omri S, Sanchez M, Hamel D, Zhu T, Rouget R, Rabea AA, Hou X, Lahaie I, Ribeiro-da-Silva A, Chemtob S
Lien Pubmed
Résumé
Platelet-activating factor (PAF) is a pleiotropic phospholipid with proinflammatory, procoagulant and angiogenic actions on the vasculature. We and others have reported the presence of PAF receptor (Ptafr) at intracellular sites such as the nucleus. However, mechanisms of localization and physiologic functions of intracellular Ptafr remain poorly understood. We hereby identify the importance of C-terminal motif of the receptor and uncover novel roles of Rab11a GTPase and importin-5 in nuclear translocation of Ptafr in primary human retinal microvascular endothelial cells. Nuclear localization of Ptafr is independent of exogenous PAF stimulation as well as intracellular PAF biosynthesis. Moreover, nuclear Ptafr is responsible for the upregulation of unique set of growth factors, including vascular endothelial growth factor, in vitro and ex vivo. We further corroborate the intracrine PAF signaling, resulting in angiogenesis in vivo, using Ptafr antagonists with distinct plasma membrane permeability. Collectively, our findings show that nuclear Ptafr translocates in an agonist-independent manner, and distinctive functions of Ptafr based on its cellular localization point to another dimension needed for pharmacologic selectivity of drugs.
Mots clés
Ptafr, angiogenesis, importin, nuclear GPCR, rab GTPase
Référence
Cell Discov. 2016 07 12;2:16017
