Cortical stabilization of β-catenin contributes to NHERF1/EBP50 tumor suppressor function
Cortical stabilization of β-catenin contributes to NHERF1/EBP50 tumor suppressor function
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DOI：
10.1038/sj.onc.1210336
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发表时间：
2007-08-09
期刊：
影响因子：
8
通讯作者：
Georgescu, M-M
中科院分区：
文献类型：
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作者：
Kreimann, E. L.;Morales, F. C.;Georgescu, M-M
锚定非依赖性生长是肿瘤生长的标志，是细胞增殖增强和细胞-细胞及细胞-基质相互作用改变的结果。通过利用基因缺陷的小鼠胚胎成纤维细胞(MEF)，我们首次证明了NHERF1/EBP50(Na/H交换调节因子1/Ezrin-Radioxin-moesin结合磷蛋白50)是一种在生理条件下具有膜定位的适配蛋白，它抑制细胞的运动并抑制锚定非依赖性生长。这两个NHERF1 PDZ结构域都是肿瘤抑制作用所必需的。NHERF1通过PDZ2结构域直接与β-连环素结合，是β-连环素在MEF细胞-细胞连接处定位所必需的。在机制上，NHERF1的缺失选择性地减少了β-连环素与E-钙粘蛋白的相互作用，但不影响与N-钙粘附素的相互作用。随之而来的E-钙粘附素介导的黏附连接的解体以及观察到的β-连环素转录活性的适度增加最有可能导致NHERF1缺陷的MEF的锚定非依赖性生长。在活体中，NHERF1特异性地定位于肠上皮细胞的顶端刷状缘膜，并需要将部分皮质β-连环蛋白维持在这一水平。因此，NHERF1通过维持β-连环蛋白的正确定位和复杂组装，成为上皮组织完整性所必需的辅助因子。
Anchorage-independent growth is a hallmark of tumor growth and results from enhanced proliferation and altered cell-cell and cell-matrix interactions. By using gene-deficient mouse embryonic fibroblasts ( MEFs), we showed for the first time that NHERF1/EBP50 (Na/H exchanger regulator factor 1/ezrin-radixin-moesin binding phosphoprotein 50), an adapter protein with membrane localization under physiological conditions, inhibits cell motility and is required to suppress anchorage-independent growth. Both NHERF1 PDZ domains are necessary for the tumor suppressor effect. NHERF1 associates directly through the PDZ2 domain with beta-catenin and is required for beta-catenin localization at the cell- cell junctions in MEFs. Mechanistically, the absence of NHERF1 selectively decreased the interaction of beta-catenin with E-cadherin, but not with N-cadherin. The ensuing disorganization of E-cadherinmediated adherens junctions as well as the observed moderate increase in beta-catenin transcriptional activity contributed most likely to the anchorage-independent growth of NHERF1-deficient MEFs. In vivo, NHERF1 is specifically localized at the apical brush-border membrane in intestinal epithelial cells and is required to maintain a fraction of the cortical beta-catenin at this level. Thus, NHERF1 emerges as a cofactor essential for the integrity of epithelial tissues by maintaining the proper localization and complex assembly of beta-catenin.