Department of Neuroscience, Neuroscience Graduate Program, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Nature. 2010 Feb 11;463(7282):823-7. doi: 10.1038/nature08724.
How instructive cues present on the cell surface have their precise effects on the actin cytoskeleton is poorly understood. Semaphorins are one of the largest families of these instructive cues and are widely studied for their effects on cell movement, navigation, angiogenesis, immunology and cancer. Semaphorins/collapsins were characterized in part on the basis of their ability to drastically alter actin cytoskeletal dynamics in neuronal processes, but despite considerable progress in the identification of semaphorin receptors and their signalling pathways, the molecules linking them to the precise control of cytoskeletal elements remain unknown. Recently, highly unusual proteins of the Mical family of enzymes have been found to associate with the cytoplasmic portion of plexins, which are large cell-surface semaphorin receptors, and to mediate axon guidance, synaptogenesis, dendritic pruning and other cell morphological changes. Mical enzymes perform reduction-oxidation (redox) enzymatic reactions and also contain domains found in proteins that regulate cell morphology. However, nothing is known of the role of Mical or its redox activity in mediating morphological changes. Here we report that Mical directly links semaphorins and their plexin receptors to the precise control of actin filament (F-actin) dynamics. We found that Mical is both necessary and sufficient for semaphorin-plexin-mediated F-actin reorganization in vivo. Likewise, we purified Mical protein and found that it directly binds F-actin and disassembles both individual and bundled actin filaments. We also found that Mical utilizes its redox activity to alter F-actin dynamics in vivo and in vitro, indicating a previously unknown role for specific redox signalling events in actin cytoskeletal regulation. Mical therefore is a novel F-actin-disassembly factor that provides a molecular conduit through which actin reorganization-a hallmark of cell morphological changes including axon navigation-can be precisely achieved spatiotemporally in response to semaphorins.
细胞表面上的指导线索如何精确地影响肌动蛋白细胞骨架尚不清楚。信号蛋白是这些指导线索中最大的家族之一，它们在细胞运动、导航、血管生成、免疫学和癌症方面的作用被广泛研究。信号蛋白/崩溃蛋白的特征部分基于它们在神经元过程中剧烈改变肌动蛋白细胞骨架动力学的能力，但尽管在鉴定信号蛋白受体及其信号通路方面取得了相当大的进展，但将它们与细胞骨架元件的精确控制联系起来的分子仍然未知。最近，发现了非常特殊的 Mical 酶家族的酶与大的细胞表面信号蛋白受体plexin 的细胞质部分相关联，并介导轴突导向、突触发生、树突修剪和其他细胞形态变化。Mical 酶进行氧化还原（redox）酶反应，并且还包含在调节细胞形态的蛋白质中发现的结构域。然而，Mical 或其氧化还原活性在介导形态变化中的作用尚不清楚。在这里，我们报告 Mical 直接将信号蛋白及其 plexin 受体与肌动蛋白丝（F-actin）动力学的精确控制联系起来。我们发现 Mical 是体内信号蛋白- plexin 介导的 F-actin 重排所必需和充分的。同样，我们纯化了 Mical 蛋白，发现它直接结合 F-actin 并解聚单个和束状肌动蛋白丝。我们还发现 Mical 利用其氧化还原活性在体内和体外改变 F-actin 动力学，表明特定氧化还原信号事件在肌动蛋白细胞骨架调节中的一个以前未知的作用。因此，Mical 是一种新型的 F-actin 解聚因子，它提供了一个分子通道，通过该通道，肌动蛋白重排——包括轴突导航在内的细胞形态变化的标志——可以在空间和时间上精确地响应信号蛋白而发生。
