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

Taddei, A. et al., Nat. Cell Biol. 10: 923-934 (2008)

Speaker: Shiao-Chi Chang (張筱琦)             Time: 13:00-14:00, Nov. 5, 2008

Commentator: Dr. Li-Wha Wu (吳梨華博士)      Place: Room 601

Abstract

Endothelial cell-cell junctions control adhesion between adjacent cells and function as signaling structures (1).  Adherens junctions (AJs) and tight junctions (TJs) are interconnected.  Blocking AJs inhibits the correct organization of TJs in some cell systems.  However, the molecular mechanism of AJ and TJ crosstalk is still unclear.  In this seminar paper, the authors found that the expression and clustering of VE-cadherin (VEC) upregulated a TJ adhesive protein claudin-5.  Claudin-5 was determined to play a central role in controlling endothelial permeability.  VEC clustering in confluent cells activated Akt pathway, which in turn phosphorylated FoxO1 and inhibited its transcriptional activity.  In a microarray gene expression screening, claudin-5 was found to be downregulated by FoxO1 (2).  Inhibition of PI(3)K-Akt pathway resulted in FoxO1 activation and claudin-5 downregulation.   Ectopic expression of constitutively active FoxO1 suppressed claudin-5 expression, suggesting that FoxO1 might be a transcriptional repressor of the claudin-5 gene.  b-catenin, a central component of Wnt signaling, has been reported to interact with FoxO1 and enhance its activity (3).  Increased association of b-catenin with FoxO1 in the nucleus was observed in VEC-null cells, and this association enhanced FoxO1 repressor activity on claudin-5.  Chromatin immunoprecipitation experiments showed that FoxO1/Tcf/b-catenin complexes bound toclaudin-5 promoter.  Abolishment of b-catenin association attenuated FoxO1 binding to DNA.  Taken together, VEC clustering upregulates the claudin-5 expression by inhibiting FoxO1 activity through Akt pathway and by preventing b-catenin nuclear translocation, suggesting a molecular link between AJs and TJs.

References

1.          Dejana, E. Endothelial cell–cell junctions: happy together. Nat. Rev. Mol. Cell Biol. 5: 261-270 (2004)

2.          Daly, C. et al. Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes Dev. 18: 1060-1071 (2004)

3.          Essers, M. A. et al. Functional interaction between β-catenin and FOXO in oxidative stress signaling. Science 308: 1181-1184 (2005)