Abstract
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 ependymomas1-3. Using the yeast two-hybrid system, we identified βII-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 βII-spectrin. Isoform 1 of schwannomin, in contrast, interacted weakly with βII-spectrin, presumably because of its strong self-interaction. Thus, alternative splicing of NF2 may regulate βII-spectrin binding. Schwannomin co-immunoprecipitated with βII-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, βII-spectrin binding, suggesting an explanation for the milder phenotypes seen in patients with missense mutations. STS26T cells treated with NF2 anti-sense oligonucleotides showed alterations of the actin cyto-skeleton. 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 βII-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.
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Scoles, D., Huynh, D., Morcos, P. et al. Neurofibromatosis 2 tumour suppressor schwannomin interacts with βII-spectrin. Nat Genet 18, 354–359 (1998). https://doi.org/10.1038/ng0498-354
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DOI: https://doi.org/10.1038/ng0498-354
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