title: Cdc42 regulates adherens junction stability and endothelial permeability by inducing alpha-catenin interaction with the vascular endothelial cadherin complex.
abstract: The endothelial adherens junctions (AJs) consist of trans-oligomers of membrane spanning vascular endothelial (VE)-cadherin proteins, which bind beta-catenin through their cytoplasmic domain. beta-Catenin in turn binds alpha-catenin and connects the AJ complex with the actin cytoskeleton. We addressed the in vivo effects of loss of VE-cadherin interactions on lung vascular endothelial permeability and the role of specific Rho GTPase effectors in regulating the increase in permeability induced by AJ destabilization. We used cationic liposomes encapsulating the mutant of VE-cadherin lacking the extracellular domain (DeltaEXD) to interfere with AJ assembly in mouse lung endothelial cells. We observed that lung vascular permeability (quantified as microvessel filtration coefficient [K(f,c)]) was increased 5-fold in lungs expressing DeltaEXD. This did not occur to the same degree on expression of the VE-cadherin mutant, DeltaEXDDeltabeta, lacking the beta-catenin-binding site. The increased vascular permeability was the result of destabilization of VE-cadherin homotypic interaction induced by a shift in the binding of beta-catenin from wild-type VE-cadherin to the expressed DeltaEXD mutant. Because DeltaEXD expression in endothelial cells activated the Rho GTPase Cdc42, we addressed its role in the mechanism of increased endothelial permeability induced by AJ destabilization. Coexpression of dominant-negative Cdc42 (N17Cdc42) prevented the increase in K(f,c) induced by DeltaEXD. This was attributed to inhibition of the association of alpha-catenin with the DeltaEXD-beta-catenin complex. The results demonstrate that Cdc42 regulates AJ permeability by controlling the binding of alpha-catenin with beta-catenin and the consequent interaction of the VE-cadherin/catenin complex with the actin cytoskeleton.
authors.affiliation: Department of Pharmacology, Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Broman
authors.forename: Panos
authors.initials: P
authors.lastname: Kouklis
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Gao
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Ramchandran
authors.forename: Radu F
authors.initials: RF
authors.lastname: Neamu
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D002199:Capillary Permeability; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D051178:alpha Catenin / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D051178:alpha Catenin; D020764:cdc42 GTP-Binding Protein; D000099152:Cadherin 5