Gelsolin-induced epithelial cell invasion is dependent on Ras-Rac signaling
Gelsolin-induced epithelial cell invasion is dependent on Ras-Rac signaling
复制标题
DOI：
10.1093/emboj/cdf680
复制
发表时间：
2002-12-16
期刊：
影响因子：
11.4
通讯作者：
Gettemans, J
中科院分区：
文献类型：
--
作者：
De Corte, V;Bruyneel, E;Gettemans, J
凝溶胶蛋白是一种广泛分布的肌动蛋白结合蛋白，参与控制细胞形态、运动、信号传导和凋亡。然而，凝溶胶蛋白在肿瘤进展中的作用仍然知之甚少。在这里，我们表明，绿色荧光蛋白（GFP）标记的凝溶胶蛋白在MDCK-AZ，MDCKtsSrc或HEK 293 T细胞中的表达促进了对I型胶原的侵袭。在器官培养试验中，表达凝溶胶蛋白-GFP的MDCK细胞侵入预培养的鸡心脏碎片。凝溶胶蛋白表达抑制E-钙粘蛋白介导的细胞聚集，但不破坏E-钙粘蛋白-连环蛋白复合物。显性负Rac 1 N17，但不是RhoAN 19或Cdc 42 N17的共表达，抵消凝溶胶蛋白诱导的入侵，表明Rac 1活性的要求。ARF 6、PLD或PIP 5 K 1 α活性的增加抵消了凝溶胶蛋白诱导的侵袭。此外，我们发现凝溶胶蛋白诱导的侵袭依赖于Ras活性，通过Ras鸟嘌呤核苷酸交换因子Sos-1通过PI 3 K-Rac途径起作用。这些发现建立了凝溶胶蛋白和Ras致癌信号通路之间的联系。
Gelsolin is a widely distributed actin binding protein involved in controlling cell morphology, motility, signaling and apoptosis. The role of gelsolin in tumor progression, however, remains poorly understood. Here we show that expression of green fluorescent pro tein (GFP)-tagged gelsolin in MDCK-AZ, MDCKtsSrc or HEK293T cells promotes invasion into collagen type I. In organ culture assays, MDCK cells expressing gelsolin-GFP invaded pre-cultured chick heart fragments. Gelsolin expression inhibited E-cadherin-mediated cell aggregation but did not disrupt the E-cadherin-catenin complex. Co-expression of dominant-negative Rac1N17, but not RhoAN19 or Cdc42N17, counteracted gelsolin-induced invasion, suggesting a requirement for Rac1 activity. Increased ARF6, PLD or PIP5K 1alpha activity canceled out gelsolin-induced invasion. Furthermore, we found that invasion induced by gelsolin is dependent on Ras activity, acting through the PI3K-Rac pathway via the Ras guanine nucleotide exchange factor Sos-1. These findings establish a connection between gelsolin and the Ras oncogenic signaling pathway.