Taddei Andrea, Giampietro Costanza, Conti Annarita, Orsenigo Fabrizio, Breviario Ferruccio, Pirazzoli Valentina, Potente Michael, Daly Christopher, Dimmeler Stefanie, Dejana Elisabetta
FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
Nat Cell Biol. 2008 Aug;10(8):923-34. doi: 10.1038/ncb1752. Epub 2008 Jul 6.
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.
细胞间连接介导相邻细胞之间的黏附与通讯。尽管紧密连接（TJs）和黏附连接（AJs）由不同分子形成，但它们在功能和结构上相互关联，不过这种相互作用背后的信号通路尚不清楚。在此，我们描述了这两种结构之间相互作用的一种细胞特异性机制。我们发现，AJs处的内皮细胞VE-钙黏蛋白上调编码TJ黏附蛋白claudin-5的基因。这种效应需要解除叉头框因子FoxO1以及Tcf-4-β-连环蛋白转录抑制复合物的抑制活性。血管内皮（VE）-钙黏蛋白通过激活Akt诱导FoxO1磷酸化以及限制β-连环蛋白向细胞核的转位来发挥作用。这些结果为AJs和TJs之间的联系提供了分子基础，并解释了为何抑制VE-钙黏蛋白可能导致通透性显著增加。
