title: Subcellular localization of coagulation factor II receptor-like 1 in neurons governs angiogenesis.
abstract: Neurons have an important role in retinal vascular development. Here we show that the G protein-coupled receptor (GPCR) coagulation factor II receptor-like 1 (F2rl1, previously known as Par2) is abundant in retinal ganglion cells and is associated with new blood vessel formation during retinal development and in ischemic retinopathy. After stimulation, F2rl1 in retinal ganglion cells translocates from the plasma membrane to the cell nucleus using a microtubule-dependent shuttle that requires sorting nexin 11 (Snx11). At the nucleus, F2rl1 facilitates recruitment of the transcription factor Sp1 to trigger Vegfa expression and, in turn, neovascularization. In contrast, classical plasma membrane activation of F2rl1 leads to the expression of distinct genes, including Ang1, that are involved in vessel maturation. Mutant versions of F2rl1 that prevent nuclear relocalization but not plasma membrane activation interfere with Vegfa but not Ang1 expression. Complementary angiogenic factors are therefore regulated by the subcellular localization of a receptor (F2rl1) that governs angiogenesis. These findings may have implications for the selectivity of drug actions based on the subcellular distribution of their targets.
authors.affiliation: 1] Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montréal, Québec, Canada. [2] Department of Ophthalmology, Hôpital Maisonneuve-Rosemont Research Center, Université de Montreal, Montreal, Québec, Canada. [3] Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada. [4] Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada. [5].
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Joyal
authors.affiliation: 1] Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada. [2].
authors.forename: Satra
authors.initials: S
authors.lastname: Nim
authors.affiliation: 1] Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montréal, Québec, Canada. [2].
authors.forename: Tang
authors.initials: T
authors.lastname: Zhu
authors.affiliation: 1] Department of Ophthalmology, Hôpital Maisonneuve-Rosemont Research Center, Université de Montreal, Montreal, Québec, Canada. [2] Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Sitaras
authors.affiliation: 1] Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montréal, Québec, Canada. [2] Department of Ophthalmology, Hôpital Maisonneuve-Rosemont Research Center, Université de Montreal, Montreal, Québec, Canada.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Rivera
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Department of Ophthalmology, Hôpital Maisonneuve-Rosemont Research Center, Université de Montreal, Montreal, Québec, Canada.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
authors.affiliation: Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Hamel
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Melanie
authors.initials: M
authors.lastname: Sanchez
authors.affiliation: Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: Zaniolo
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Manon
authors.initials: M
authors.lastname: St-Louis
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Johanne
authors.initials: J
authors.lastname: Ouellette
authors.affiliation: The Wyss Institute, Harvard University, Boston, Massachusetts, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Montoya-Zavala
authors.affiliation: Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zabeida
authors.affiliation: Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Emilie
authors.initials: E
authors.lastname: Picard
authors.affiliation: Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hardy
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Bhosle
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Daya R
authors.initials: DR
authors.lastname: Varma
authors.affiliation: Department of Pharmacology, Sherbrooke University, Sherbrooke, Quebec, Canada.
authors.forename: Fernand
authors.initials: F
authors.lastname: Gobeil
authors.affiliation: Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Beauséjour
authors.affiliation: Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Christelle
authors.initials: C
authors.lastname: Boileau
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: William
authors.initials: W
authors.lastname: Klein
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Morley
authors.initials: M
authors.lastname: Hollenberg
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ribeiro-da-Silva
authors.affiliation: Department of Cardiology, CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Gregor
authors.initials: G
authors.lastname: Andelfinger
authors.affiliation: 1] Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Université de Montréal, Montréal, Québec, Canada. [2] Department of Ophthalmology, Hôpital Maisonneuve-Rosemont Research Center, Université de Montreal, Montreal, Québec, Canada. [3] Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada. [4] Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D021581:Active Transport, Cell Nucleus; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D044464:Receptor, PAR-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000378:metabolism; D012171:Retinal Vessels / Q000254:growth & development / Q000378:metabolism; D058305:Sorting Nexins / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D050505:Mutant Proteins; D044464:Receptor, PAR-2; D058305:Sorting Nexins; D016329:Sp1 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse