Actin-rich protrusions and nonlocalized GTPase activation in Merlin-deficient schwannornas
Actin-rich protrusions and nonlocalized GTPase activation in Merlin-deficient schwannornas
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DOI：
10.1097/nen.0b013e318093e555
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发表时间：
2007-07-01
影响因子：
3.2
通讯作者：
Hanemann, Clemens Oliver
中科院分区：
文献类型：
--
作者：
Flaiz, Christine;Kaempchen, Katherine;Hanemann, Clemens Oliver
神经鞘瘤缺乏肿瘤抑制因子 Merlin（一种细胞骨架-膜连接子）的两个等位基因。先前的结果显示神经鞘瘤细胞的细胞扩散增加，但对其潜在机制知之甚少。电子显微镜显示神经鞘瘤细胞不仅显示出更多的片状伪足/褶边，而且还显示出多个丝状伪足。我们发现在丝状伪足形成中重要的 Cdc42 被激活。 Racl 和 Cdc42 均存在于细胞外周周围，并与人类神经鞘瘤细胞中的效应器磷酸-p21 激活激酶共定位。因此，我们声称 Racl 和 Cdc42 以非局部方式激活，这解释了片状伪足/褶边和丝状伪足的分散分布。使用活细胞成像，我们进一步证明了神经鞘瘤细胞中许多富含肌动蛋白的突起的连续重塑。这些结构的底层细胞骨架很薄且分支广泛。肌动蛋白相关蛋白 2/3 复合物是肌动蛋白分支的主要调节因子，在人类原代神经鞘瘤细胞的许多片状伪足和皱褶中富集。我们认为，人原代神经鞘瘤细胞中的 Merlin 缺陷会导致 Rac1 和 Cdc42 的随机、非局部激活，从而诱导许多富含肌动蛋白的突出区域，不仅在前缘，而且在细胞周围。它们的非定向发生与连续且高度动态的肌动蛋白重塑一起导致这些肿瘤细胞的去分化。
Schwannomas lack both alleles for the tumor suppressor Merlin, a cytoskeleton-membrane linker. Previous results showed increased cell spreading of schwannoma cells, but little is known about the underlying mechanisms. Electron microscopy reveals that schwannoma cells not only show more lamellipodia/ruffles but also multiple filopodia. We show that Cdc42, important in filopodia formation, is activated. Both Racl and Cdc42 are found all around the cell periphery and in colocalization with their effector phospho-p21 activated kinase in human schwannoma cells. We therefore claim that Racl and Cdc42 are activated in a nonlocalized manner, which explains the disperse distribution of lamellipodia/ruffles and filopodia. Using live cell imaging, we further demonstrate continuous remodeling of the many actin-rich protrusions in schwannoma cells. The underlying cytoskeleton of these structures is thin and extensively branched. The actin-related protein 2/3 complex, a major regulator of actin branching, is enriched in the many lamellipodia and ruffles of human primary schwannoma cells. We suggest that the Merlin deficiency in human primary schwannoma cells leads to a random, nonlocalized activation of Rac1 and Cdc42, inducing many actin-rich protrusion zones, not only at the leading edge but also all around the cell periphery. Their nondirectional occurrence together with the continuous and highly dynamic actin remodeling results in the dedifferentiation of these tumor cells.