Indispensable role of STIL in the regulation of cancer cell motility through the lamellipodial accumulation of ARHGEF7-PAK1 complex
Indispensable role of STIL in the regulation of cancer cell motility through the lamellipodial accumulation of ARHGEF7-PAK1 complex
复制标题
DOI：
10.1038/s41388-019-1115-9
复制
发表时间：
2020-02-01
期刊：
影响因子：
8
通讯作者：
Kasai, Kenji
中科院分区：
文献类型：
--
作者：
Ito, Hideaki;Tsunoda, Takumi;Kasai, Kenji
细胞运动是一种受到严格调控的现象，它支持器官结构在发育和动态平衡过程中的准确形成，包括伤口愈合和炎症。与此同时，癌细胞表现出运动异常，导致扩散和侵袭。DBL家族RhogeFARHGEF7/beta-PIX及其结合伙伴p21激活的激酶PAK1在多种癌症中过表达，并已被证明与癌细胞迁移有关。运动的一个关键步骤是ARHGEF7-PAK1复合体在细胞内的运输到细胞的迁移前沿，在那里有效地发生板状脂体突起和细胞骨架重塑。然而，该复合体在细胞内转运的分子机制尚不完全清楚。在此，我们揭示了SCL/TAL1-interrupting Locus(STIL)对于癌细胞的有效迁移是不可或缺的。STIL与ARHGEF7和PAK1形成三元复合体，并与这些蛋白聚集在运动细胞的片层突起处。STIL的敲除阻止了ARHGEF7-PAK1复合体在膜褶皱中的积累，并减弱了PAK1底物的磷酸化和迁移前沿的皮质肌动蛋白重塑。有趣的是，ARHGEF7基因敲除也减少了STIL和PAK1在膜皱纹中的积累。STIL或ARHGEF7基因敲除都会阻碍细胞迁移和细胞迁移前沿的rac1活性。这些结果表明，STIL通过在片状脂膜中积累ARHGEF7-PAK1复合体，参与了ARHGEF7介导的细胞骨架重构的正反馈激活。我们得出结论，它的参与对于rac1介导的前沿的极化形成至关重要，这支持了癌细胞的有效迁移。
Cell motility is a tightly regulated phenomenon that supports the accurate formation of organ structure during development and homeostasis, including wound healing and inflammation. Meanwhile, cancer cells exhibit dysregulated motility, which causes spreading and invasion. The Dbl family RhoGEF ARHGEF7/beta-PIX and its binding partner p21-activated kinase PAK1 are overexpressed in a variety of cancers and have been shown to be responsible for cancer cell migration. A key step in motility is the intracellular transport of ARHGEF7-PAK1 complex to the migrating front of cells, where lamellipodia protrusion and cytoskeletal remodeling efficiently occur. However, the molecular mechanisms of the intracellular transport of this complex are not fully understood. Here we revealed that SCL/TAL1-interrupting locus (STIL) is indispensable for the efficient migration of cancer cells. STIL forms a ternary complex with ARHGEF7 and PAK1 and accumulates with those proteins at the lamellipodia protrusion of motile cells. Knockdown of STIL impedes the accumulation of ARHGEF7-PAK1 complex within membrane ruffles and attenuates the phosphorylation of PAK1 substrates and cortical actin remodeling at the migrating front. Intriguingly, ARHGEF7 knockdown also diminishes STIL and PAK1 accumulation in membrane ruffles. Either STIL or ARHGEF7 knockdown impedes cell migration and Rac1 activity at the migrating front of cells. These results indicate that STIL is involved in the ARHGEF7-mediated positive-feedback activation of cytoskeletal remodeling through accumulating the ARHGEF7-PAK1 complex in lamellipodia. We conclude that its involvement is crucial for the polarized formation of Rac1-mediated leading edge, which supports the efficient migration of cancer cells.