IGF-I receptor-induced cell-cell adhesion of MCF-7 breast cancer cells requires the expression of junction protein ZO-1
IGF-I receptor-induced cell-cell adhesion of MCF-7 breast cancer cells requires the expression of junction protein ZO-1
复制标题
DOI：
10.1074/jbc.m106673200
复制
发表时间：
2001-10-26
影响因子：
4.8
通讯作者：
Surmacz, E
中科院分区：
文献类型：
--
作者：
Mauro, L;Bartucci, M;Surmacz, E
胰岛素样生长因子I受体（IGF-IR）的过度活化有助于原发性乳腺癌的发展，但IGF-IR在肿瘤转移中的作用尚不清楚。在这里，我们研究了IGF-IR对主要上皮粘附蛋白E-钙粘蛋白（E-ead）介导的细胞间连接的影响。我们发现IGF-IR过表达显著刺激E-cad阳性MCF-7乳腺癌细胞的聚集，但不刺激E-ead阴性MDA-MB-231细胞。然而，当IGF-IR和E-ead在MDA-MB-231细胞中共表达时，细胞-细胞粘附显著增加。MCF-7细胞的IGF-IR依赖性细胞间粘附与E-cad或α-、β-或γ-连环蛋白的表达改变无关，但与E-cad复合物的另一个元件闭合小带-1（ZO-1）的上调一致。ZO-1的表达（mRNA和蛋白质）诱导IGF-I和被阻断在MCF-7细胞与酪氨酸激酶缺陷型IGF-IR突变体。通过免疫共沉淀，我们发现ZO-1与E-cad复合物和IGF-IR结合。高水平的ZO-1与IGF-IR/α-catenin/ZO-1结合的增加和ZO-1/肌动蛋白结合的改善相一致，而通过表达抗ZO-1 RNA下调ZO-1抑制IGF-IR依赖的细胞-细胞粘附。结果表明，激活的IGF-IR调节E-cad介导的细胞-细胞粘附的机制之一是ZO-1的过表达和E-cad复合物与肌动蛋白细胞骨架之间更强的连接。我们推测，在E-cad阳性细胞中，IGF-IR可能产生抗转移作用。
Hyperactivation of the insulin-like growth factor I receptor (IGF-IR) contributes to primary breast cancer development, but the role of the IGF-IR in tumor metastasis is unclear. Here we studied the effects of the IGF-IR on intercellular connections mediated by the major epithelial adhesion protein, E-cadherin (E-ead). We found that IGF-IR overexpression markedly stimulated aggregation in E-cad-positive MCF-7 breast cancer cells, but not in E-ead-negative MDA-MB-231 cells. However, when the IGF-IR and E-ead were co-expressed in MDA-MB-231 cells, cell-cell adhesion was substantially increased. The IGF-IR-dependent cell-cell adhesion of MCF-7 cells was not related to altered expression of E-cad or alpha-, beta-, or gamma -catenins but coincided with the up-regulation of another element of the E-cad complex, zonula occludens-1 (ZO-1). ZO-1 expression (mRNA and protein) was induced by IGF-l and was blocked in MCF-7 cells with a tyrosine kinase-defective IGF-IR mutant. By co-immunoprecipitation, we found that ZO-1 associates with the E-cad complex and the IGF-IR. High levels of ZO-1 coincided with an increased IGF-IR/alpha -catenin/ZO-1-binding and improved ZO-1/actin association, whereas down-regulation of ZO-1 by the expression of an anti-ZO-1 RNA inhibited IGF-IR-dependent cell-cell adhesion. The results suggested that one of the mechanisms by which the activated IGF-IR regulates E-cad-mediated cell-cell adhesion is overexpression of ZO-1 and the resulting stronger connections between the E-cad complex and the actin cytoskeleton. We hypothesize that in E-cad-positive cells, the IGF-IR may produce antimetastatic effects.