title: VE-cadherin signaling induces EB3 phosphorylation to suppress microtubule growth and assemble adherens junctions.
abstract: Vascular endothelial (VE)-cadherin homophilic adhesion controls endothelial barrier permeability through assembly of adherens junctions (AJs). We observed that loss of VE-cadherin-mediated adhesion induced the activation of Src and phospholipase C (PLC)γ2, which mediated Ca(2+) release from endoplasmic reticulum (ER) stores, resulting in activation of calcineurin (CaN), a Ca(2+)-dependent phosphatase. Downregulation of CaN activity induced phosphorylation of serine 162 in end binding (EB) protein 3. This phospho-switch was required to destabilize the EB3 dimer, suppress microtubule (MT) growth, and assemble AJs. The phospho-defective S162A EB3 mutant, in contrast, induced MT growth in confluent endothelial monolayers and disassembled AJs. Thus, VE-cadherin outside-in signaling regulates cytosolic Ca(2+) homeostasis and EB3 phosphorylation, which are required for assembly of AJs. These results identify a pivotal function of VE-cadherin homophilic interaction in modulating endothelial barrier through the tuning of MT dynamics.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA. ykomarov@uic.edu
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Komarova
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.forename: Melissa
authors.initials: M
authors.lastname: Geyer
authors.forename: Nazila
authors.initials: N
authors.lastname: Daneshjou
authors.forename: Alexander
authors.initials: A
authors.lastname: Garcia
authors.forename: Luiza
authors.initials: L
authors.lastname: Idalino
authors.forename: Barry
authors.initials: B
authors.lastname: Kreutz
authors.forename: Dolly
authors.initials: D
authors.lastname: Mehta
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D015820:Cadherins / Q000378:metabolism / Q000502:physiology*; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002147:Calmodulin / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D059008:Time-Lapse Imaging; D019061:src-Family Kinases / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D019703:Calcineurin; D002118:Calcium; D002147:Calmodulin; D008869:Microtubule-Associated Proteins; D051966:Phospholipase C gamma; D019061:src-Family Kinases; D000099152:Cadherin 5; C403664:MAPRE3 protein, human