Fig. 1. Molecular organization of endothelial AJs. VE-cadherin is represented as a dimer, which is the minimal functional unit of cadherins; see Gumbiner (Gumbiner, 2005), in which various models of the intercellular association of cadherin dimers are discussed. EC1-EC5 are the five homologous extracellular domains of VE-cadherin. Clustering of VE-cadherin at cell-cell contacts promotes the formation of multimolecular complexes that comprise signaling, regulatory and scaffold proteins. Proteins that are well known to interact with VE-cadherin include the catenin proteins p120, β-catenin (βcat) and plakoglobin (plako). β-catenin and plakoglobin associate directly with VE-cadherin and -catenin (cat). Other AJ proteins are listed in Table 1. Some VE-cadherin-interacting proteins have enzymatic activity (tyrosine or serine kinases, tyrosine phosphatases and GTPases). Others have a scaffolding function, which might allow the organization of very complex molecular clusters. The interaction of such proteins with VE-cadherin can be either direct or indirect. The proteins shown in the figure and in Table 1 assemble into AJs – multimeric complexes that can modulate endothelial-barrier function by regulating the activity of VE-cadherin and transducing intracellular signals. There is likely to be local specificity of the molecular composition of such complexes, depending on the type and the state of activation of the vessels.