Scoles D R, Huynh D P, Morcos P A, Coulsell E R, Robinson N G, Tamanoi F, Pulst S M
Division of Neurology, CSMC Burns and Allen Research Institute, Cedars-Sinai Medical Center, University of California School of Medicine at Los Angeles, 90048, USA.
Nat Genet. 1998 Apr;18(4):354-9. doi: 10.1038/ng0498-354.
NF2 is the most commonly mutated gene in benign tumours of the human nervous system. The NF2 protein, called schwannomin or merlin, is absent in virtually all schwannomas, and many meningiomas and ependymomas. Using the yeast two-hybrid system, we identified betaII-spectrin (also known as fodrin) as a schwannomin-binding protein. Interaction occurred between the carboxy-terminal domain of schwannomin isoform 2 and the ankyrin-binding region of betaII-spectrin. Isoform 1 of schwannomin, in contrast, interacted weakly with betaII-spectrin, presumably because of its strong self-interaction. Thus, alternative splicing of NF2 may regulate betaII-spectrin binding. Schwannomin co-immunoprecipitated with betaII-spectrin at physiological concentrations. The two proteins interacted in vitro and co-localized in several target tissues and in STS26T cells. Three naturally occurring NF2 missense mutations showed reduced, but not absent, betaII-spectrin binding, suggesting an explanation for the milder phenotypes seen in patients with missense mutations. STS26T cells treated with NF2 antisense oligonucleotides showed alterations of the actin cytoskeleton. Schwannomin itself lacks the actin binding sites found in ezrin, radixin and moesin, suggesting that signalling to the actin cytoskeleton occurs via actin-binding sites on betaII-spectrin. Thus, schwannomin is a tumour suppressor directly involved in actin-cytoskeleton organization, which suggests that alterations in the cytoskeleton are an early event in the pathogenesis of some tumour types.
NF2是人类神经系统良性肿瘤中最常发生突变的基因。在几乎所有的神经鞘瘤、许多脑膜瘤和室管膜瘤中，都不存在名为施万蛋白或默林的NF2蛋白。利用酵母双杂交系统，我们鉴定出βII-血影蛋白（也称为 fodrin）是一种施万蛋白结合蛋白。施万蛋白同工型2的羧基末端结构域与βII-血影蛋白的锚蛋白结合区域之间发生了相互作用。相比之下，施万蛋白同工型1与βII-血影蛋白的相互作用较弱，推测是因为其强烈的自我相互作用。因此，NF2的可变剪接可能调节βII-血影蛋白的结合。施万蛋白在生理浓度下与βII-血影蛋白进行了共免疫沉淀。这两种蛋白在体外相互作用，并在几个靶组织和STS26T细胞中共定位。三个天然存在的NF2错义突变显示βII-血影蛋白结合减少，但并非完全缺失，这为错义突变患者中出现的较轻表型提供了解释。用NF2反义寡核苷酸处理的STS26T细胞显示肌动蛋白细胞骨架发生了改变。施万蛋白本身缺乏在埃兹蛋白、根蛋白和膜突蛋白中发现的肌动蛋白结合位点，这表明向肌动蛋白细胞骨架的信号传导是通过βII-血影蛋白上的肌动蛋白结合位点发生的。因此，施万蛋白是一种直接参与肌动蛋白细胞骨架组织的肿瘤抑制因子，这表明细胞骨架的改变是某些肿瘤类型发病机制中的早期事件。
