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Indispensable role of STIL in the regulation of cancer cell motility through the lamellipodial accumulation of ARHGEF7-PAK1 complex.
Oncogene ( IF 6.9 ) Pub Date : 2019-11-21 , DOI: 10.1038/s41388-019-1115-9 Hideaki Ito 1 , Takumi Tsunoda 1 , Miho Riku 1 , Shingo Inaguma 1 , Akihito Inoko 1 , Hideki Murakami 1 , Hiroshi Ikeda 1 , Michiyuki Matsuda 2 , Kenji Kasai 1
Oncogene ( IF 6.9 ) Pub Date : 2019-11-21 , DOI: 10.1038/s41388-019-1115-9 Hideaki Ito 1 , Takumi Tsunoda 1 , Miho Riku 1 , Shingo Inaguma 1 , Akihito Inoko 1 , Hideki Murakami 1 , Hiroshi Ikeda 1 , Michiyuki Matsuda 2 , Kenji Kasai 1
Affiliation
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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/β-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.
中文翻译：
STIL 在通过 ARHGEF7-PAK1 复合物的片状积累调节癌细胞运动中的不可或缺的作用。
细胞运动是一种受严格调控的现象，它支持器官结构在发育和体内平衡过程中的准确形成，包括伤口愈合和炎症。同时，癌细胞表现出运动失调，导致扩散和侵袭。Dbl 家族 RhoGEF ARHGEF7/β-PIX 及其结合伴侣 p21 激活激酶 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将 ARHGEF7-PAK1 复合物在细胞内转运到细胞的迁移前沿，在此处有效地发生板状伪足突出和细胞骨架重塑。然而，这种复合物的细胞内转运的分子机制尚不完全清楚。在这里，我们揭示了 SCL/TAL1 中断基因座 (STIL) 对于癌细胞的有效迁移是必不可少的。STIL 与 ARHGEF7 和 PAK1 形成三元复合物，并与这些蛋白质在运动细胞的片状伪足突起处积累。敲除 STIL 会阻碍 ARHGEF7-PAK1 复合物在膜褶皱内的积累，并减弱 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 敲低也减少了膜褶皱中的 STIL 和 PAK1 积累。STIL 或 ARHGEF7 敲低会阻碍细胞迁移前部的细胞迁移和 Rac1 活性。这些结果表明，STIL 通过在板状伪足中积累 ARHGEF7-PAK1 复合物参与 ARHGEF7 介导的细胞骨架重塑的正反馈激活。
更新日期：2019-11-22
中文翻译：
STIL 在通过 ARHGEF7-PAK1 复合物的片状积累调节癌细胞运动中的不可或缺的作用。
细胞运动是一种受严格调控的现象，它支持器官结构在发育和体内平衡过程中的准确形成，包括伤口愈合和炎症。同时，癌细胞表现出运动失调，导致扩散和侵袭。Dbl 家族 RhoGEF ARHGEF7/β-PIX 及其结合伴侣 p21 激活激酶 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将 ARHGEF7-PAK1 复合物在细胞内转运到细胞的迁移前沿，在此处有效地发生板状伪足突出和细胞骨架重塑。然而，这种复合物的细胞内转运的分子机制尚不完全清楚。在这里，我们揭示了 SCL/TAL1 中断基因座 (STIL) 对于癌细胞的有效迁移是必不可少的。STIL 与 ARHGEF7 和 PAK1 形成三元复合物，并与这些蛋白质在运动细胞的片状伪足突起处积累。敲除 STIL 会阻碍 ARHGEF7-PAK1 复合物在膜褶皱内的积累，并减弱 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 敲低也减少了膜褶皱中的 STIL 和 PAK1 积累。STIL 或 ARHGEF7 敲低会阻碍细胞迁移前部的细胞迁移和 Rac1 活性。这些结果表明，STIL 通过在板状伪足中积累 ARHGEF7-PAK1 复合物参与 ARHGEF7 介导的细胞骨架重塑的正反馈激活。
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