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Cadherin & Claudin Cadherin & Claudin: It takes two to tango Julie Gavard1 and J. Silvio Gutkind2 1 Institut Cochin, CNRS, UMR8104, INSERM, U567, Université Paris Descartes, 22 rue Méchain, 75014, Paris, FRANCE 2 Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Branch, National Institutes of Health, Bldg 30, Room 211, Bethesda MD20892, USA The endothelial barrier function requires the adhesive activity of VE-cadherin and claudin- 5, two key components of adherens and tight endothelial junctions, respectively. Emerging evidence that VE-cadherin controls claudin-5 expression by preventing the nuclear accumulation of FoxO1 and β-catenin, which repress the claudin-5 promoter, provides a crosstalk between these endothelial junctional structures. The formation of adhesive structures tight junctions are intermingled throughout between adjacent cells, including adherens cell-cell contact areas3. The formation, and tight junctions, contribute to the maintenance, and remodelling of the establishment of cell polarity, differentiation intercellular contacts requires a functional and survival, and is ultimately required for interaction between these two adhesive the maintenance of the tissue integrity. structures. For example, the barrier function Cadherins, the main constituent of the of the endothelium requires the adhesive adherens junctions, belong to a conserved activity of VE-cadherin and claudin-5, family of adhesion molecules that provide a which are key components of the adherens molecular bond between cells and link the and tight endothelial junctions, respectively. plasma membrane with the intracellular Surprisingly, this functional relationship actin cytoskeleton through catenin family involves also the direct control of the proteins1. Tight junctions form a dense ultra- expression of claudin-5 by VE-cadherin. structure organization, observable by Indeed, as shown on page xxx of this issue electron microscopy, which involves by Taddei et al, VE-cadherin-mediated numerous adhesive molecules, including adhesion enables claudin-5 expression in occludin, junctional adhesion molecules endothelial cells by preventing the nuclear (JAMs), and the claudin family of tetraspan accumulation of two transcriptional transmembrane proteins, as well as and regulators, FoxO1 and β-catenin, which intracellular adapters, such as ZO-1 and ZO- repress claudin-5 expression when VE- 22. Whereas in epithelial cells, tight cadherin is absent or non-functional (Fig. 1). junctions are often located apically with These findings clearly place VE-cadherin respect to adherens junctions, in other cells, upstream of claudin-5 in the establishment, such as in endothelial cells, the adherens and maturation and maintenance of endothelial cell-cell junctions and further suggest that recently described in neuronal cells, in any changes in VE-cadherin adhesive which Slit stimulation of its receptor, Robo, properties will impact at multiple levels on triggers the rapid loss of N-cadherin the endothelial barrier function. dependent adhesion, which leads to the At the molecular level, Taddei et al. release of β-catenin from adhesion observed that VE-cadherin adhesion triggers complexes and its nuclear accumulation and a sustained activation of the PI-3 activation of β-catenin/TCF target genes5. In kinase/AKT pathway, and the subsequent light of these studies, it will be intriguing to phosphorylation of FoxO1, a forkhead determine whether FoxO1 might also repressor transcription factor, which results participate in the Slit/Robo long-term in its cytosolic localization, thus preventing remodelling of cell adhesion in axon FoxO1 binding to its DNA targets within the guidance, and how the partition of β-catenin nuclear compartment. In the absence of VE- between FoxO and TCF is integrated in cadherin at the cell surface, non- response to canonical Wnt signalling. In this phosphorylated FoxO1 constitutively regard, β-catenin’s interaction with FoxO accumulates within the nucleus thereby has been proposed to compete with TCF/β- repressing the claudin-5 promoter by acting catenin-dependent activation of canonical directly on two FoxO1 response elements Wnt-target genes6, while Taddei et al. (Fig. 1). Strikingly, β-catenin is required for suggest that TCF is required for β- FoxO1 repression of claudin-5 gene catenin/FoxO1 stabilization on the claudin-5 expression, most likely through the promoter. This raises the question as to stabilization of FoxO1 interactions to its whether Wnt-regulated target genes are also DNA recognition sites. This depends on the affected by VE-cadherin adhesion, either T-cell factor (TCF), which is constitutively directly by β-catenin trapping, and/or by associated to the claudin-5 promoter. Further FoxO competition. While VE-cadherin can work is still required to understand fully be considered as a multifunctional adhesion how FoxO1 phosphorylation modulates its receptor modulating endothelial biology, the localization, interactions with β-catenin and emerging picture is that VE-cadherin may TCF, and its transcriptional repressive also dictate endothelial cell fate through the activity. regulation of intracellular signalling The role of cadherins in the control of circuitries controlling gene transcription via gene expression has been often associated to multiple DNA-binding proteins including, at their negative effect on the canonical Wnt- least, β-catenin, TCF and FoxO1. initiated pathway, by a mechanism that The nature of the adhesion molecules, involves the retention of β-catenin at the such as VE-cadherin and claudin-5, plasma membrane upon binding to clustered distinguish endothelial junctions, as their cadherins, which therefore limits the pool of pattern of expression is highly restricted to free β-catenin available for nuclear the endothelial lineage and their shuttling4. The mechanism identified here in organization is quite distinct from more endothelial cells is quite reminiscent to that common junctions, such as those found in epithelial cells3. Their functions are non- In addition to angiogenesis, there is a redundant since, for instance, claudin-5 is plethora of physiological and pathological the major claudin identified in normal conditions where the endothelial barrier endothelial cells while multiple claudins can integrity is compromised. Hierarchically, be found at the surface of epithelial cells. VE-cadherin is major in controlling the Interestingly, while claudin-5 knockout mice endothelial barrier function. For example, develop normally but have a defective blood VE-cadherin endocytosis and uncoupling brain barrier function and die shortly after from catenin-associated proteins have been birth7, VE-cadherin knockout mice are proposed to collectively contribute to the embryonic lethal and exhibit multiple severe disruption of endothelial cell-cell junctions defects during developmental angiogenesis in response to VEGF10, 11. In light of the 8, suggesting that VE-cadherin function may study published in page xxx of this issue, go far beyond promoting cell-cell adhesion. inhibition of VE-cadherin expression level, For example, VE-cadherin can modulate its adhesive ability, or its plasma membrane VEGF receptor signalling, which transduces availability might provoke β-catenin and the pro-angiogenic and pro-permeability FoxO1 nuclear accumulation, and therefore effects of VEGF8. Indeed, many of the the repression of claudin-5 transcription biological responses attributed to VE- (Fig. 1). Thus, while the acute VEGF cadherin appear intimately linked to VEGF stimulation could induce an increase in signalling9. The work by Taddei et al. vascular permeability by a reversible identifies a unique mechanism by which disruption of VE-cadherin adhesion and the VE-cadherin can control claudin-5 subsequent disorganization of the tight expression, independently of VEGF/VEGF junctions10, the chronic exposure to VEGF receptor downstream signalling, as blocking or other pro-permeability factors might either VEGF or the activity of its receptor affect severely the endothelial barrier, as the does not alter VE-cadherin control over turnover and the expression of claudin-5 claudin-5 gene expression. The molecular could be compromised in the absence of mechanism reported here supports a functional VE-cadherin adhesion. The permissive role for VE-cadherin clustering regulation of claudin-5 expression by VE- on claudin-5 expression, and one can cadherin points to an intimate crosstalk envision that VE-cadherin might act as key between tight and adherens junctions. regulator of endothelial cell lineage, as However, this crosstalk is bidirectional since ultimately claudin-5 expression is restricted tight junctional molecules, such as JAMs to VE-cadherin expressing cells. However, may regulate cadherin-mediated adhesion in more studies are required now to fully endothelial cells12. understand whether VE-cadherin can Beside VEGF, reactive oxygen species orchestrate the activation of an endothelial can increase vascular permeability through a maturation program and/or the repression of Rac-dependent mechanism, associated with a non-endothelial phenotype. a loss of endothelial cell-cell junctions13. Interestingly, recent work in C. elegans suggests that oxygen stress signalling with neural cell damage caused by the depends on a functional interaction between breakdown of the blood brain barrier, and FoxO and β-catenin14. The novel findings the subsequent exudation of plasma reported on page xxx allow us to speculate components and oedema. In
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