title: Rac1 functions as a reversible tension modulator to stabilize VE-cadherin trans-interaction.
abstract: The role of the RhoGTPase Rac1 in stabilizing mature endothelial adherens junctions (AJs) is not well understood. In this paper, using a photoactivatable probe to control Rac1 activity at AJs, we addressed the relationship between Rac1 and the dynamics of vascular endothelial cadherin (VE-cadherin). We demonstrated that Rac1 activation reduced the rate of VE-cadherin dissociation, leading to increased density of VE-cadherin at AJs. This response was coupled to a reduction in actomyosin-dependent tension across VE-cadherin adhesion sites. We observed that inhibiting myosin II directly or through photo-release of the caged Rho kinase inhibitor also reduced the rate of VE-cadherin dissociation. Thus, Rac1 functions by stabilizing VE-cadherin trans-dimers in mature AJs by counteracting the actomyosin tension. The results suggest a new model of VE-cadherin adhesive interaction mediated by Rac1-induced reduction of mechanical tension at AJs, resulting in the stabilization of VE-cadherin adhesions.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: Nazila
authors.initials: N
authors.lastname: Daneshjou
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: Nathan
authors.initials: N
authors.lastname: Sieracki
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, Vrije University of Amsterdam, 1081 HV Amsterdam, Netherlands.
authors.forename: Geerten P
authors.initials: GP
authors.lastname: van Nieuw Amerongen
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Conway
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Schwartz
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Komarova
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D022005:Adherens Junctions / Q000187:drug effects / Q000201:enzymology*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D008954:Models, Biological; D024462:Myosin Type II / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization; D055550:Protein Stability; D059008:Time-Lapse Imaging; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D000205:Actomyosin; D015703:Antigens, CD; D015820:Cadherins; D024462:Myosin Type II; D047428:Protein Kinase Inhibitors; D020830:rac1 GTP-Binding Protein; D054460:rho-Associated Kinases; D000099152:Cadherin 5; C107953:RAC1 protein, human