Actinomyosin contraction, phosphorylation of VE-cadherin, and actin remodeling enable melanoma-induced endothelial cell-cell junction disassembly.
Actinomyosin contraction, phosphorylation of VE-cadherin, and actin remodeling enable melanoma-induced endothelial cell-cell junction disassembly.
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DOI：
10.1371/journal.pone.0108092
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Dong C
中科院分区：
文献类型：
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作者：
Weidert E;Pohler SE;Gomez EW;Dong C
在黑色素瘤细胞通过血管内皮外渗期间，黑色素瘤细胞通过分泌细胞因子和通过在相对细胞表面上展示的蛋白质之间的粘附与内皮细胞相互作用。这些肿瘤细胞相关信号如何共同调节内皮细胞内细胞内信号传导途径的动力学，导致内皮细胞-细胞连接破坏，目前还不清楚。在这里，我们使用实验和计算方法的组合来检查血管细胞粘附分子（VCAM）-1，白细胞介素（IL）-8和IL-1β信号通路的激活对血管连接完整性的单独和组合效应。我们的模拟预测了由VCAM-1，IL-8和IL-1β通路的个体激活引起的信号传导的多方面相互作用，与同时打开的所有输入相比，这种相互作用既不是协同的也不是加和的。此外，我们发现，与放线肌球蛋白收缩性和连接拆卸峰值之前，那些相关的肌动蛋白重塑磷酸化蛋白的水平。这项工作的结果提供了深入了解肿瘤介导的内皮连接解体的动力学，并表明，靶向蛋白质下游的几个相互作用途径可能是最有效的治疗方法，以减少黑色素瘤外渗。
During melanoma cell extravasation through the vascular endothelium, melanoma cells interact with endothelial cells through secretion of cytokines and by adhesion between proteins displayed on opposing cell surfaces. How these tumor cell associated signals together regulate the dynamics of intracellular signaling pathways within endothelial cells leading to endothelial cell-cell junction disruption is not well understood. Here, we used a combination of experimental and computational approaches to examine the individual and combined effects of activation of the vascular cell adhesion molecule (VCAM)-1, interleukin (IL)-8, and IL-1β signaling pathways on the integrity of vascular junctions. Our simulations predict a multifaceted interplay of signaling resulting from individual activation of VCAM-1, IL-8 and IL-1β pathways that is neither synergistic nor additive compared to all inputs turned on simultaneously. Furthermore, we show that the levels of phosphorylated proteins associated with actinomyosin contractility and junction disassembly peak prior to those related to actin remodeling. The results of this work provide insight into the dynamics of tumor-mediated endothelial junction disassembly and suggest that targeting proteins downstream of several interaction pathways may be the most effective therapeutic approach to reduce melanoma extravasation.