Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells
Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells
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DOI：
10.1182/blood-2011-09-381012
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发表时间：
2012-03-01
期刊：
影响因子：
20.3
通讯作者：
Dejana, Elisabetta
中科院分区：
文献类型：
--
作者：
Giampietro, Costanza;Taddei, Andrea;Dejana, Elisabetta
内皮细胞（EC）表达钙粘蛋白家族的两个成员，VE和N-钙粘蛋白。尽管VE-钙粘蛋白诱导EC同型粘附，但N-钙粘蛋白在EC中的功能仍然很大程度上未知。EC特异性失活VE或N-钙粘蛋白导致早期胎儿死亡，这表明这些钙粘蛋白在血管发育中起着非冗余的作用。我们在这里报告，VE-钙粘蛋白负控制连接定位和N-钙粘蛋白的表达，限制p120-连环蛋白的可用性和降低β-连环蛋白的转录活性。使用表达VE或N-钙粘蛋白的EC系，我们发现这两种钙粘蛋白都抑制细胞增殖和凋亡。两者均触发磷脂酰肌醇-3-OH-激酶（PI 3 K）-AKT-叉头盒蛋白-O 1（FoxO 1）通路并降低β-连环蛋白转录活性。信号传导的程度与钙粘蛋白的总水平相关，而与表达的钙粘蛋白的类型无关。与此相反，基础和成纤维细胞生长因子（FGF）诱导的细胞运动性的促进N-钙粘蛋白和强烈抑制VE-钙粘蛋白。这种相反的作用部分是由于VE-钙粘蛋白与FGF受体和密度增强型磷酸酶-1（Dep-1）结合的能力，而密度增强型磷酸酶-1反过来又抑制受体信号传导。我们的结论是，VE和N-钙粘蛋白对内皮细胞既有相加作用，也有趋异作用。信号传导的差异部分是由于钙粘蛋白与生长因子受体的结合及其下游信号传导的调节。（血。2012; 119（9）：2159-2170）
Endothelial cells (ECs) express 2 members of the cadherin family, VE and N-cadherin. Although VE-cadherin induces EC homotypic adhesion, N-cadherin function in ECs remains largely unknown. EC-specific inactivation of either VE or N-cadherin leads to early fetal lethality suggesting that these cadherins play a nonredundant role in vascular development. We report here that VE-cadherin negatively controls junctional localization and expression of N-cadherin by limiting p120-catenin availability and reducing beta-catenin transcriptional activity. Using EC lines expressing either VE or N-cadherin we found that both cadherins inhibit cell proliferation and apoptosis. Both trigger the phosphatidylinositol-3-OH- kinase (PI3K)-AKT-Forkhead-box protein-O1 (FoxO1) pathway and reduce beta-catenin transcriptional activity. The extent of signaling correlates with the total level of cadherins regardless of the type of cadherin expressed. In contrast, basal and fibroblast growth factor (FGF)induced cell motility is promoted by N-cadherin and strongly inhibited by VE-cadherin. This opposite effect is partly because of the ability of VE-cadherin to associate with FGF receptor and the density-enhanced phosphatase-1 (Dep-1) which, in turn, inhibits receptor signaling. We conclude that VE and N-cadherin have both additive and divergent effects on ECs. Differences in signaling are due, in part, to cadherin association with growth factor receptors and modulation of their downstream signaling. (Blood. 2012; 119(9):2159-2170)