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–-catenin transcriptional repressor complex. Vascular endothelial (VE)-cadherin acts by inducing the phosphorylation of FoxO1 through Akt activation and by limiting the translocation of -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.

1. FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
2. Mario Negri Institute for Pharmacological Research, 20156 Milan, Italy.
3. Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, 60590 Frankfurt am Main, Germany.
4. Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591, USA.
5. Department of Biomolecular Sciences and Biotechnologies, School of Sciences, University of Milan, 20133 Milan, Italy.

Correspondence to: Elisabetta Dejana^1,2,5 e-mail: elisabetta.dejana@ifom-ieo-campus.it.

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