Hazan R B, Norton L
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
J Biol Chem. 1998 Apr 10;273(15):9078-84. doi: 10.1074/jbc.273.15.9078.
Alterations in the expression or function of molecules that affect cellular adhesion and proliferation are thought to be critical events for tumor progression. Loss of expression of the cell adhesion molecule E-cadherin and increased expression of the epidermal growth factor receptor are two prominent molecular events that are associated with tumorigenesis. The regulation of E-cadherin-dependent cell adhesion by epidermal growth factor (EGF) was therefore examined in the human breast cancer cell line, MDA-MB-468. In this study, changes were observed in the subcellular distribution of components that mediate the cytoplasmic connection between E-cadherin and the actin-based cytoskeleton in response to activation of the EGF receptor. Serum withdrawal activated E-cadherin-dependent cell-cell aggregation in MDA-MB-468 cells, and this treatment stimulated the interaction of actin, alpha-actinin, and vinculin with E-cadherin complexes, despite the absence of alpha-catenin in these cells. By contrast, the co-precipitation of actin with E-cadherin was not detected in several alpha-catenin positive epithelial cell lines. Treatment with EGF inhibited cellular aggregation but did not affect either the levels of E-cadherin or catenin expression nor the association of catenins (beta-catenin, plakoglobin/gamma-catenin, or p120(cas)) with E-cadherin. However, EGF treatment of the MDA-MB-468 cell line dissociated actin, alpha-actinin, and vinculin from the E-cadherin-catenin complex, and this coincided with a robust phosphorylation of beta-catenin, plakoglobin/gamma-catenin, and p120(cas) on tyrosine residues. Furthermore, inactivation of the EGF receptor in serum-treated MDA-MB-468 cells with either a function-blocking antibody or EGF receptor kinase inhibitors mimicked the effects of serum starvation by stimulating both cellular aggregation and assembly of E-cadherin complexes with vinculin and actin. These results demonstrate that the EGF receptor directly regulates cell-cell adhesion through modulation of the interaction of E-cadherin with the actin cytoskeleton and thus substantiates the coordinate role of both of these molecules in tumor progression and metastasis.
影响细胞黏附和增殖的分子表达或功能改变被认为是肿瘤进展的关键事件。细胞黏附分子E-钙黏蛋白表达缺失和表皮生长因子受体表达增加是与肿瘤发生相关的两个突出分子事件。因此，在人乳腺癌细胞系MDA-MB-468中研究了表皮生长因子（EGF）对E-钙黏蛋白依赖性细胞黏附的调节作用。在本研究中，观察到在EGF受体激活后，介导E-钙黏蛋白与肌动蛋白细胞骨架之间细胞质连接的成分亚细胞分布发生了变化。血清饥饿激活了MDA-MB-468细胞中E-钙黏蛋白依赖性细胞间聚集，并且这种处理刺激了肌动蛋白、α-辅肌动蛋白和纽蛋白与E-钙黏蛋白复合物的相互作用，尽管这些细胞中不存在α-连环蛋白。相比之下，在几种α-连环蛋白阳性上皮细胞系中未检测到肌动蛋白与E-钙黏蛋白的共沉淀。用EGF处理可抑制细胞聚集，但不影响E-钙黏蛋白或连环蛋白的表达水平，也不影响连环蛋白（β-连环蛋白、桥粒斑蛋白/γ-连环蛋白或p120（cas））与E-钙黏蛋白的结合。然而，用EGF处理MDA-MB-468细胞系会使肌动蛋白、α-辅肌动蛋白和纽蛋白从E-钙黏蛋白-连环蛋白复合物中解离，这与β-连环蛋白、桥粒斑蛋白/γ-连环蛋白和p120（cas）酪氨酸残基的强烈磷酸化同时发生。此外，用功能阻断抗体或EGF受体激酶抑制剂使血清处理的MDA-MB-468细胞中的EGF受体失活，通过刺激细胞聚集以及E-钙黏蛋白复合物与纽蛋白和肌动蛋白的组装，模拟了血清饥饿的作用。这些结果表明，EGF受体通过调节E-钙黏蛋白与肌动蛋白细胞骨架的相互作用直接调节细胞间黏附，从而证实了这两种分子在肿瘤进展和转移中的协同作用。
