CDC42 switches IRSp53 from inhibition of actin growth to elongation by clustering of VASP
CDC42 switches IRSp53 from inhibition of actin growth to elongation by clustering of VASP
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DOI：
10.1038/emboj.2013.208
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发表时间：
2013-10-16
期刊：
影响因子：
11.4
通讯作者：
Scita, Giorgio
中科院分区：
文献类型：
--
作者：
Disanza, Andrea;Bisi, Sara;Scita, Giorgio
丝状伪足探索环境，在定向运动和组织形态发生过程中感知可溶性和机械性线索。丝状伪足是如何起始并在空间上局限于质膜上的特定位点的尚不清楚。在这里，我们表明，膜变形和曲率传感IRSp53（53 kDa的胰岛素受体底物）蛋白减缓肌动蛋白丝倒刺末端的生长。这种抑制作用被CDC42缓解，并被VASP抵消，VASP也与IRSp53结合。VASP：IRSp53相互作用受活化的CDC42调节，并促进VASP的高密度聚集，这是进行性肌动蛋白丝伸长所必需的。这种相互作用还介导VASP向脂质体的募集。在细胞中，IRSp53和VASP在前缘的离散病灶处积累，其中丝状伪足起始。IRSp53的遗传去除损害VASP病灶、丝状伪足和趋化运动的形成，而IRSp53缺失小鼠显示有缺陷的伤口愈合。因此，IRSp53抑制倒刺末端生长。CDC42激活抑制这种活性，并促进IRSp53依赖性募集和聚集VASP驱动肌动蛋白组装。这些事件导致在细胞迁移、侵袭和组织修复过程中VASP细丝伸长以启动丝状伪足的空间限制。
Filopodia explore the environment, sensing soluble and mechanical cues during directional motility and tissue morphogenesis. How filopodia are initiated and spatially restricted to specific sites on the plasma membrane is still unclear. Here, we show that the membrane deforming and curvature sensing IRSp53 (Insulin Receptor Substrate of 53 kDa) protein slows down actin filament barbed end growth. This inhibition is relieved by CDC42 and counteracted by VASP, which also binds to IRSp53. The VASP: IRSp53 interaction is regulated by activated CDC42 and promotes high-density clustering of VASP, which is required for processive actin filament elongation. The interaction also mediates VASP recruitment to liposomes. In cells, IRSp53 and VASP accumulate at discrete foci at the leading edge, where filopodia are initiated. Genetic removal of IRSp53 impairs the formation of VASP foci, filopodia and chemotactic motility, while IRSp53 null mice display defective wound healing. Thus, IRSp53 dampens barbed end growth. CDC42 activation inhibits this activity and promotes IRSp53-dependent recruitment and clustering of VASP to drive actin assembly. These events result in spatial restriction of VASP filament elongation for initiation of filopodia during cell migration, invasion, and tissue repair.