Cortactin Promotes Migration and Platelet-derived Growth Factor-induced Actin Reorganization by Signaling to Rho-GTPases
Cortactin Promotes Migration and Platelet-derived Growth Factor-induced Actin Reorganization by Signaling to Rho-GTPases
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DOI：
10.1091/mbc.e08-12-1180
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发表时间：
2009-07-15
影响因子：
3.3
通讯作者：
Rottner, Klemens
中科院分区：
文献类型：
--
作者：
Lai, Frank P. L.;Szczodrak, Malgorzata;Rottner, Klemens
动态肌动蛋白重排由肌动蛋白丝成核剂（包括 Arp2/3 复合体）启动和维持。这种蛋白质组装在体外被不同的成核促进因子（例如 Wiskott-Aldrich 综合征蛋白/Scar 家族蛋白或 Cortactin）激活，但它们各自的相对体内功能仍然存在争议。在这里，我们报告了小鼠皮质蛋白的条件性遗传破坏，该破坏先前与驱动片状足突出和内吞作用的动态肌动蛋白重组有关。出乎意料的是，皮质素缺陷的细胞在整体细胞形态和生长方面几乎没有变化。超微结构分析和活细胞成像研究揭示了未受损的片状伪足结构、Rac 诱导的突出和肌动蛋白网络周转，尽管片状伪足中的肌动蛋白组装率略有增加。相反，在皮质蛋白缺失细胞中，血小板衍生生长因子诱导的肌动蛋白重组和 Rac 激活受到损害。此外，cortactin 缺乏导致 Cdc42 活性降低以及随机和定向细胞迁移缺陷。活性 Rac 和 Cdc42 变体可以至少部分恢复皮质蛋白无效细胞迁移的减少。最后，皮质蛋白的去除并不影响受体介导的内吞作用的效率。总之，我们得出结论，在板状伪足突出或网格蛋白凹坑内吞作用期间，cortactin 对于 Arp2/3 复合物的激活是完全可有可无的。此外，我们提出 Cortactin 通过促进选定的 Rho-GTP 酶的激活来间接促进细胞迁移。
Dynamic actin rearrangements are initiated and maintained by actin filament nucleators, including the Arp2/3-complex. This protein assembly is activated in vitro by distinct nucleation-promoting factors such as Wiskott-Aldrich syndrome protein/Scar family proteins or cortactin, but the relative in vivo functions of each of them remain controversial. Here, we report the conditional genetic disruption of murine cortactin, implicated previously in dynamic actin reorganizations driving lamellipodium protrusion and endocytosis. Unexpectedly, cortactin-deficient cells showed little changes in overall cell morphology and growth. Ultrastructural analyses and live-cell imaging studies revealed unimpaired lamellipodial architecture, Rac-induced protrusion, and actin network turnover, although actin assembly rates in the lamellipodium were modestly increased. In contrast, platelet-derived growth factor-induced actin reorganization and Rac activation were impaired in cortactin null cells. In addition, cortactin deficiency caused reduction of Cdc42 activity and defects in random and directed cell migration. Reduced migration of cortactin null cells could be restored, at least in part, by active Rac and Cdc42 variants. Finally, cortactin removal did not affect the efficiency of receptor-mediated endocytosis. Together, we conclude that cortactin is fully dispensable for Arp2/3-complex activation during lamellipodia protrusion or clathrin pit endocytosis. Furthermore, we propose that cortactin promotes cell migration indirectly, through contributing to activation of selected Rho-GTPases.