title: The F-BAR protein pacsin2 inhibits asymmetric VE-cadherin internalization from tensile adherens junctions.
abstract: Vascular homoeostasis, development and disease critically depend on the regulation of endothelial cell-cell junctions. Here we uncover a new role for the F-BAR protein pacsin2 in the control of VE-cadherin-based endothelial adhesion. Pacsin2 concentrates at focal adherens junctions (FAJs) that are experiencing unbalanced actomyosin-based pulling. FAJs move in response to differences in local cytoskeletal geometry and pacsin2 is recruited consistently to the trailing end of fast-moving FAJs via a mechanism that requires an intact F-BAR domain. Photoconversion, photobleaching, immunofluorescence and super-resolution microscopy reveal polarized dynamics, and organization of junctional proteins between the front of FAJs and their trailing ends. Interestingly, pacsin2 recruitment inhibits internalization of the VE-cadherin complex from FAJ trailing ends and is important for endothelial monolayer integrity. Together, these findings reveal a novel junction protective mechanism during polarized trafficking of VE-cadherin, which supports barrier maintenance within dynamic endothelial tissue.
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam 1066 CX, The Netherlands.
authors.forename: Yvonne L
authors.initials: YL
authors.lastname: Dorland
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Tsveta S
authors.initials: TS
authors.lastname: Malinova
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam 1066 CX, The Netherlands.
authors.forename: Anne-Marieke D
authors.initials: AM
authors.lastname: van Stalborch
authors.affiliation: Hubrecht Institute and University Medical Center Utrecht, Utrecht 3584 CT, The Netherlands.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Grieve
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam 1066 CX, The Netherlands.
authors.forename: Daphne
authors.initials: D
authors.lastname: van Geemen
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam 1066 CX, The Netherlands.
authors.forename: Nicolette S
authors.initials: NS
authors.lastname: Jansen
authors.affiliation: Department of Medicine, University of California, San Diego, California 92093, USA.
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: de Kreuk
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam 1066 CX, The Netherlands.
authors.forename: Kalim
authors.initials: K
authors.lastname: Nawaz
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam 1081 HV, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Kole
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus University Medical Center, Rotterdam 3015 GE, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Geerts
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam 1081 HV, The Netherlands.
authors.forename: René J P
authors.initials: RJ
authors.lastname: Musters
authors.affiliation: Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands.
authors.forename: Johan
authors.identifier: 0000-0001-6101-7875
authors.initials: J
authors.lastname: de Rooij
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam 1081 HV, The Netherlands.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Hordijk
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam 1066 CX, The Netherlands.|Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Stephan
authors.identifier: 0000-0002-1091-475X
authors.initials: S
authors.lastname: Huveneers
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D022005:Adherens Junctions / Q000378:metabolism*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008856:Microscopy, Fluorescence / Q000379:methods; D000099152:Cadherin 5
chemical_list: D000205:Actomyosin; D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D015820:Cadherins; D000099152:Cadherin 5; C120714:PACSIN2 protein, human