Induction of apoptosis in cultured endothelial cells by a cadherin antagonist peptide: involvement of fibroblast growth factor receptor-mediated signaling
Induction of apoptosis in cultured endothelial cells by a cadherin antagonist peptide: involvement of fibroblast growth factor receptor-mediated signaling
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DOI：
10.1016/j.yexcr.2003.11.033
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发表时间：
2004-04-01
影响因子：
3.7
通讯作者：
Geiger, B
中科院分区：
文献类型：
--
作者：
Erez, N;Zamir, E;Geiger, B
钙粘蛋白是介导钙依赖性、嗜同性细胞间粘附的跨膜糖蛋白家族。此外，这些分子参与信号传导事件，调节细胞运动、增殖和凋亡等过程。钙粘蛋白亚家族的成员被称为经典钙粘蛋白或1型钙粘蛋白，在其嗜同性结合位点包含由组氨酸-丙氨酸-缬氨酸（HAV）三个氨基酸组成的高度保守序列。以前的研究表明，含有HAV基序的肽抑制钙粘蛋白依赖性事件，如细胞聚集，压实和神经突生长。我们在这里报告，环肽，N-Ac-CHAVC-NH 2可以扰乱钙粘蛋白介导的内皮细胞相互作用，导致进行性凋亡细胞死亡。这种效应取决于细胞密度，因为它仅在用肽处理密集培养物时观察到。粘附连接（AJ）相关的钙粘蛋白和连环蛋白的N-Ac-CHAVC-NH 2治疗的差异影响，判断免疫荧光标记，然后免疫荧光比成像。然而，在加入肽后的最初几个小时内，细胞-细胞粘附大部分保留。还观察到，处理后，肌动蛋白丝部分失去其在AJs的质膜锚定，并向细胞中心移位。有趣的是，向汇合的肽处理的内皮细胞培养物中加入碱性成纤维细胞生长因子完全阻断细胞凋亡，并且抑制肽减少FGF受体靶蛋白FRS 2的磷酸化，表明肽通过抑制钙粘蛋白介导的成纤维细胞生长因子受体信号传导的活化来发挥其作用。我们提出钙粘蛋白介导的信号传导对于维持融合内皮细胞的活力是必不可少的，并且其由N-Ac-CHAVC-NH 2的扰动驱动这些细胞凋亡。(C)2004年爱思唯尔公司All rights reserved.
Cadherins are a family of transmembrane glycoproteins mediating calcium-dependent, homophilic cell-cell adhesion. In addition, these molecules are involved in signaling events, regulating such processes as cell motility, proliferation, and apoptosis. Members of the cadherin subfamily, called either classical or type 1 cadherins, contain a highly conserved sequence at their homophilic binding site consisting of the three amino acids-histidine-alanine-valine (HAV). Previous studies have shown that peptides containing the HAV motif inhibit cadherin-dependent events such as cell aggregation, compaction, and neurite outgrowth. We report here that a cyclic peptide, N-Ac-CHAVC-NH2 can perturb cadherin-mediated endothelial cell interactions, resulting in a progressive apoptotic cell death. This effect depends on cell density, as it is only observed when dense cultures are treated with the peptide. Adherens junction (AJ)-associated cadherin and catenins are differentially affected by the N-Ac-CHAVC-NH2 treatment, as judged by double immunofluorescence labeling followed by immunofluorescence-ratio imaging. However, cell-cell adhesions are largely retained during the first few hours after addition of the peptide. It was also observed that following treatment, actin filaments partially lose their plasma membrane anchorage at AJs and translocate towards the cell center. Interestingly, addition of basic fibroblast growth factor to confluent, peptide-treated, endothelial cell cultures, completely blocks apoptosis and the inhibitory peptide reduce the phosphorylation of the FGF receptor target protein FRS2, suggesting that the peptide exerts its effect by inhibiting cadherin-mediated activation of fibroblast growth factor receptor signaling. We propose that cadherin-mediated signaling is essential for maintaining viability of confluent endothelial cells, and that its perturbation by N-Ac-CHAVC-NH2 drives these cells to apoptosis. (C) 2004 Elsevier Inc. All rights reserved.