Journal
CELL DISCOVERY
Volume 2, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/celldisc.2016.17
Keywords
angiogenesis; importin; nuclear GPCR; Ptafr; rab GTPase
Categories
Funding
- Canadian Institutes of Health Research (CIHR) [MOP 11755]
- CIHR Systems Biology studentship award at the McGill University (Montreal, QC, Canada)
- CIHR MD/PhD Program
- Fonds de Suzanne Veronneau-Troutman
- Fonds de recherche en ophtalmologie de l'Universite de Montreal
- CHU Sainte Justine Hospital Research Centre
- Fonds de la Recherche du Quebec-Sante (FRQS)
- Canadian Institutes of Health Research (CIHR)
- March of Dimes Birth Defects Foundation
- FRQS-Quebec Vision Health Network
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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.
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