VE-cadherin 通过调节 Kaiso 依赖性基因表达促进血管生成拟态。
VE-cadherin promotes vasculogenic mimicry by modulating kaiso-dependent gene expression.
机构信息
Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
出版信息
Cell Death Differ. 2019 Jan;26(2):348-361. doi: 10.1038/s41418-018-0125-4. Epub 2018 May 21.
Aberrant extra-vascular expression of VE-cadherin (VEC) has been observed in metastasis associated with vasculogenic mimicry (VM); however, the ultimate reason why non-endothelial VEC favors the acquisition of this phenotype is not established. In this study, we show that human malignant melanoma cells have a constitutively high expression of phoshoVEC (pVEC) at Y658; pVEC is a target of focal adhesion kinase (FAK) and forms a complex with p120-catenin and the transcriptional repressor kaiso in the nucleus. FAK inhibition enabled kaiso to suppress the expression of its target genes and enhanced kaiso recruitment to KBS-containing promoters. Finally we have found that ablation of kaiso-repressed genes WNT11 and CCDN1 abolished VM. Thus, identification of pVEC as a component of the kaiso transcriptional complex establishes a molecular paradigm that links FAK-dependent phosphorylation of VEC as a major mechanism by which ectopical VEC expression exerts its function in VM.
已经观察到血管生成拟态（VM）相关转移中血管内皮钙黏蛋白（VE-cadherin，VEC）的异常血管外表达；然而，非内皮细胞 VEC 倾向于获得这种表型的最终原因尚未确定。在这项研究中，我们表明，人恶性黑素瘤细胞在 Y658 处具有磷酸化 VEC（pVEC）的组成性高表达；pVEC 是粘着斑激酶（FAK）的靶标，并在核内与 p120-连环蛋白和转录抑制因子 Kaiso 形成复合物。FAK 抑制使 Kaiso 能够抑制其靶基因的表达，并增强 Kaiso 募集到含有 KBS 的启动子。最后，我们发现，剔除 Kaiso 受抑制基因 WNT11 和 CCDN1 可消除 VM。因此，鉴定 pVEC 作为 Kaiso 转录复合物的一个组成部分，确立了一个分子范例，即 FAK 依赖性 VEC 磷酸化作为异位 VEC 表达在 VM 中发挥功能的主要机制。
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