BAG3 regulates motility and adhesion of epithelial cancer cells
BAG3 regulates motility and adhesion of epithelial cancer cells
复制标题
DOI：
10.1158/0008-5472.can-07-0618
复制
发表时间：
2007-11-01
期刊：
影响因子：
11.2
通讯作者：
Takayama, Shinichi
中科院分区：
文献类型：
--
作者：
Iwasaki, Masahiro;Homma, Sachiko;Takayama, Shinichi
BAG3蛋白结合并调节Hsp70分子伴侣活性。BAG3蛋白含有WW结构域和富含脯氨酸的区域，该区域具有SH3结合基序，这表明它可能与信号转导相关的蛋白质相互作用，将Hsp70募集到信号复合物中并改变细胞反应。已经在人类癌症中观察到BAG3过表达。我们在这里表明，纯合子BAG3缺陷小鼠胚胎成纤维细胞（MEF）表现出延迟形成的丝状伪足和粘着斑复合物时，新鲜铺板。BAG3缺陷型MEF在培养物中显示降低的细胞运动性。我们观察到内源性BAG3蛋白在许多人上皮癌细胞系，特别是腺癌中高度表达。基因转移介导的BAG3过表达增加了Cos7细胞和几种人癌细胞系的运动性，包括乳腺癌MCF 7和前列腺癌DU 145和ALVA 31细胞系。相反，通过RNA干扰（RNAi）减少BAG3蛋白降低了测试的四种上皮肿瘤系中的四种的细胞运动性。我们观察到BAG3对培养物中细胞粘附的影响。在Cos7肾上皮细胞中，BAG3蛋白在迁移细胞的前缘与肌动蛋白部分共定位，其中发生活性肌动蛋白聚合和成核。RNAi介导的BAG3表达减少与Rac1活性降低相关，表明BAG3在调节这种参与肌动蛋白细胞骨架动力学的小GT3中的作用。在小鼠中，RNAi介导的人肿瘤异种移植物中BAG3的减少抑制了体内侵袭和转移。因此，在一些上皮癌细胞系中观察到的高水平的BAG3蛋白可能与肿瘤侵袭和转移的机制有关。
BAG3 protein binds to and regulates Hsp70 chaperone activity. The BAG3 protein contains a WW domain and a proline-rich region with SH3-binding motifs, suggesting that it may interact with proteins relevant to signal transduction, recruiting Hsp70 to signaling complexes and altering cell responses. BAG3 overexpression has been observed in human cancers. We show here that homozygous BAG3-deficient mouse embryonic fibroblasts (MEF) exhibit delayed formation of filopodia and focal adhesion complexes when freshly plated. BAG3-deficient MEFs show reduced cell motility in culture. We observed that endogenous BAG3 protein is highly expressed in many human epithelial cancer cell lines, especially adenocarcinomas. Gene transfer-mediated overexpression of BAG3 increased motility of Cos7 cell and several human cancer cell lines, including breast cancer MCF7 and prostate cancer DU145 and ALVA31 cell lines. Conversely, reduction of BAG3 protein by RNA interference (RNAi) decreased cell motility in four of four epithelial tumor lines tested. We observed an influence of BAG3 on cell adhesion in culture. In Cos7 kidney epithelial cells, BAG3 protein partially colocalizes with actin at the leading edge of migrating cells, wherein active actin polymerization and nucleation occur. RNAi-mediated reductions in BAG3 expression were associated with decreased Rac1 activity, suggesting a role for BAG3 in regulating this small GTPase involved in actin-cytoskeleton dynamics. In mice, RNAi-mediated reductions in BAG3 in a human tumor xenograft suppressed invasion and metastasis in vivo. Thus, the high levels of BAG3 protein seen in some epithelial cancer cell lines may be relevant to mechanisms of tumor invasion and metastasis.