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Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5

Abstract

Intercellular junctions mediate adhesion and communication between adjoining cells. Although formed by different molecules, tight junctions (TJs) and adherens junctions (AJs) are functionally and structurally linked, but the signalling pathways behind this interaction are unknown. Here we describe a cell-specific mechanism of crosstalk between these two types of structure. We show that endothelial VE-cadherin at AJs upregulates the gene encoding the TJ adhesive protein claudin-5. This effect requires the release of the inhibitory activity of forkhead box factor FoxO1 and the Tcf-4–β-catenin transcriptional repressor complex. Vascular endothelial (VE)-cadherin acts by inducing the phosphorylation of FoxO1 through Akt activation and by limiting the translocation of β-catenin to the nucleus. These results offer a molecular basis for the link between AJs and TJs and explain why VE-cadherin inhibition may cause a marked increase in permeability.

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Figure 1: Claudin-5 is upregulated by VE-cadherin expression and clustering.
Figure 2: Claudin-5 upregulation by VE-cadherin in mouse allantoises and its role in the control of endothelial permeability.
Figure 3: VE-cadherin activates the PI(3)K–Akt pathway and induces FoxO1 phosphorylation.
Figure 4: FoxO1 is a repressor of claudin-5 expression.
Figure 5: VEC-null cells present higher nuclear β-catenin localization, signalling and association with FoxO1.
Figure 6: β-Catenin association enhances FoxO1 repressor activity on claudin-5 expression.
Figure 7: FoxO1 and β-catenin bind to claudin-5 promoter region.
Figure 8: Suggested model for the regulation of claudin-5 expression by VE-cadherin.

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Acknowledgements

We thank Barbara Felice for help in the transcription-factor-binding-site analysis. This work was supported by the Associazione Italiana per la Ricerca sul Cancro, Association for International Cancer Research, the European Community (Integrated Project Contract No LSHG-CT-2004-503573; NoE MAIN 502935; NoE EVGN 503254; EUSTROKE and OPTISTEM Networks), Istituto Superiore di Sanita', Italian Ministry of Health, MIUR (COFIN prot: 2006058482_002), Fondation Leducq Transatlantic Network of Excellence. C.G. is supported by an AIRC-SISAL fellowship.

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E.D. and A.T. planned the experimental design. E.D., A.T. and C.G. analysed data and conducted the scientific writing. A.T. and C.G. performed the experimental work. A.C. analysed the Affymetrix data. F.O. and F.B. provided molecular biology support. V.P. performed the TOP/FOP assay. M.P., C.D. and S.D. provided scientific input and reagents.

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Correspondence to Elisabetta Dejana.

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The authors declare no competing financial interests.

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Supplementary Figures S1, S2, S3, S4, S5, S6, S7 and Supplementary Methods (PDF 1417 kb)

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Taddei, A., Giampietro, C., Conti, A. et al. Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nat Cell Biol 10, 923–934 (2008). https://doi.org/10.1038/ncb1752

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