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First published online June 18, 2008
doi: 10.1242/10.1242/jcs.017897

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The role of adherens junctions and VE-cadherin in the control of vascular permeability

¹ FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Italy
² School of Sciences, University of Milan, Milan, Italy
³ Mario Negri Institute for Pharmacological Research, Via La Masa 19, 20156 Milan, Italy

View larger version (43K): [in this window] [in a new window]   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.

View larger version (153K): [in this window] [in a new window]   Fig. 2. Suggested functional modifications of endothelial AJs under in vitro conditions that increase endothelial permeability. (A) Under resting conditions, VE-cadherin clusters at junctions in zipper-like structures; p120, β-catenin (βcat) and plakoglobin (plako) bind directly to VE-cadherin, whereas -catenin (cat) binds indirectly through its association with β-catenin or plakoglobin. (B) Phosphorylation (P) of tyrosine residues of VE-cadherin, β-catenin, plakoglobin and p120 reduces AJ strength. The VE-cadherin complex might become partially disorganized without any evidence of cell retraction. Phosphorylation of VE-cadherin at Ser665 has also been reported. This process is thought to mediate VE-cadherin internalization and increase vascular permeability (see also Fig. 3). (C) Several permeability-increasing agents, or inflammatory conditions or lytic enzymes, can cause intercellular gaps. The phenomenon is mediated by actomyosin, which links to the cadherin complex and induces cell retraction. (D) Antibodies that block VE-cadherin bind to its adhesive domain and inhibit clustering. The effect of such antibodies can last for several hours in vivo and can induce a dramatic increase in permeability.

View larger version (113K): [in this window] [in a new window]   Fig. 3. Phosphorylation of VE-cadherin. The sites of tyrosine (Y) and serine (S) phosphorylation are shown. The interaction of VE-cadherin with individual proteins can be positively (CSK, β-arrestin-2) or negatively (p120, β-catenin) regulated by its phosphorylation at specific amino acid residues. Some pathways that lead to phosphorylation at specific sites have been reported and are shown in the figure. The functional consequences of the phosphorylation events represented in the figure are commented on in the text. References: (1) (Potter et al., 2005); (2) (Gavard and Gutkind, 2006); (3) (Baumeister et al., 2005); (4) A. Galaup, M.G.L., F.O. and E.D., unpublished; (5) (Wallez et al., 2006); (6) (Turowski et al., 2008); (7) (Allingham et al., 2007).

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