VE-Cadherin and VEGF R2 are transmembrane glycoproteins that are expressed in the adherens junctions between vascular endothelial cells (EC). VE-Cadherin interacts homophilically between neighboring cells to provide strength to the endothelium. VE-Cadherin adhesion is reduced during angiogenesis and leukocyte extravasation, two processes that require decreased EC attachment. It is well established that adherens junction integrity is regulated by VE-Cadherin phosphorylation and internalization in response to VEGF stimulation.1, 2 Several recent publications provide additional details about the molecular mechanism directing this process.
In adherens junctions between quiescent vascular EC, VEGF R2 is maintained in an inactive state by protein tyrosine phosphatases.2 VEGF binding activates the tyrosine kinase domain of VEGF R2, initiating the sequential activation of the Src-Vav2-Rac1-PAK pathway, which results in the phosphorylation of VE-Cadherin at Ser665 by PAK.2 The subsequent binding of beta-arrestin2 to serine-phosphorylated VE-Cadherin promotes the internalization of VE-Cadherin into clathrin-coated pits.3 This disrupts the architecture of endothelial junctions and allows for the passage of molecules and cells. In addition, phosphorylation of the VE-Cadherin complexes by Src at Tyr685 may contribute to the disassembly of adherens junctions.4
It was recently reported that VEGF R2 signaling is enhanced by endocytosis. Interestingly, VE-Cadherin was shown to play an inhibitory role in this process. By binding to VEGF R2, VE-Cadherin prevents VEGF R2 endocytosis. This favors inactivation by a junction-associated, transmembrane tyrosine phosphatase, called DEP-1.5 When clathrin-dependent internalization transports phosphorylated VEGF R2 to endosomal vesicles, uninterrupted VEGF R2 signaling is made possible by phosphorylated Tyr1175 inaccessible to cell surface DEP-1.5 Phosphorylated Tyr1175 is required for the binding and activation of PLCgamma, a primary mediator of VEGF R2-promoted cell proliferation.6 Notably, cell surface VEGF R2-mediated clathrin-dependent internalization delivers VE-Cadherin to compartments distinct from intracellular VEGF R2 compartments.3
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|Figure 1. Homophilic interactions between VE-cadherin molecules at adherens junctions in adjacent endothelial cells help maintain the endothelial barrier. Upon VEGF exposure, activation of VEGF R2 triggers a phosphorylation cascade that targets VE-cadherin. VEGF R2 continues to signal after internalization, while sequestration of VE-cadherin in endosomes disrupts adhesion. This process promotes loss of cell-cell contacts, increased vascular permeability, and endothelial cell migration. (Figure adapted from those contained within references 2 & 3)|
Other molecules influence these processes as well, although specifically how they are integrated into the above pathways is not clear. The scaffolding protein IQGAP1, which is bound to VE-Cadherin both at the adherens junction and after internalization, is necessary for VE-Cadherin localization at cell-cell contacts.7 It potentially mediates the interaction of VE-Cadherin and VEGF R2, and also tethers VE-Cadherin to the cytoskeleton.1,7 In addition, VEGF stimulation of quiescent microvascular EC induces the transport of intracellular JAM-C to adherens junctions, where it disrupts VE-Cadherin adhesion.8 TNF-alpha also promotes vascular permeability by inducing Fyn-dependent tyrosine phosphorylation of VE-Cadherin.9 Lastly, exposure of endothelium to oxidized LDL promotes VE-Cadherin internalization and increased monocyte transendothelial migration.10
These advances in the understanding of the interactions between VE-Cadherin and VEGF R2 clarify how the adherens junction is regulated in response to VEGF stimulation. Prolonged VEGF R2 signaling enables the continued proliferation and migration of vascular EC during angiogenesis. Internalization of VE-Cadherin weakens adherens junction adhesion, permitting increased EC mobility, vascular permeability, and leukocyte extravasation.
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