Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5.
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-beta-catenin transcriptional repressor complex. Vascular endothelial (VE)-cadherin acts by inducing the phosphorylation of FoxO1 through Akt activation and by limiting the translocation of beta-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.
Taddei
Andrea
A
FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
Giampietro
Costanza
C
Conti
Annarita
A
Orsenigo
Fabrizio
F
Breviario
Ferruccio
F
Pirazzoli
Valentina
V
Potente
Michael
M
Daly
Christopher
C
Dimmeler
Stefanie
S
Dejana
Elisabetta
E
D022005:Adherens Junctions / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D015820:Cadherins / Q000502:physiology*; D002460:Cell Line; D062507:Claudin-5; D042783:Endothelial Cells; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D019108:Tight Junctions / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D062507:Claudin-5; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D051820:TCF Transcription Factors; D000099152:Cadherin 5; C107466:CLDN5 protein, human; C085126:FOXO1 protein, human