LaJeunesse D R, McCartney B M, Fehon R G
Developmental, Cell and Molecular Biology Group, Department of Zoology, Duke University, Durham, North Carolina 27708-1000, USA.
J Cell Biol. 1998 Jun 29;141(7):1589-99. doi: 10.1083/jcb.141.7.1589.
Merlin, the product of the Neurofibromatosis type 2 (NF2) tumor-suppressor gene, is a member of the protein 4.1 superfamily that is most closely related to ezrin, radixin, and moesin (ERM). NF2 is a dominantly inherited disease characterized by the formation of bilateral acoustic schwannomas and other benign tumors associated with the central nervous system. To understand its cellular functions, we are studying a Merlin homologue in Drosophila. As is the case for NF2 tumors, Drosophila cells lacking Merlin function overproliferate relative to their neighbors. Using in vitro mutagenesis, we define functional domains within Merlin required for proper subcellular localization and for genetic rescue of lethal Merlin alleles. Remarkably, the results of these experiments demonstrate that all essential genetic functions reside in the plasma membrane- associated NH2-terminal 350 amino acids of Merlin. Removal of a seven-amino acid conserved sequence within this domain results in a dominant-negative form of Merlin that is stably associated with the plasma membrane and causes overproliferation when expressed ectopically in the wing. In addition, we provide evidence that the COOH-terminal region of Merlin has a negative regulatory role, as has been shown for ERM proteins. These results provide insights into the functions and functional organization of a novel tumor suppressor gene.
Merlin是2型神经纤维瘤病（NF2）肿瘤抑制基因的产物，属于蛋白质4.1超家族成员，与埃兹蛋白、根蛋白和膜突蛋白（ERM）关系最为密切。NF2是一种常染色体显性遗传病，其特征是双侧听神经鞘瘤以及与中枢神经系统相关的其他良性肿瘤的形成。为了解其细胞功能，我们正在研究果蝇中的一种Merlin同源物。与NF2肿瘤情况相同，缺乏Merlin功能的果蝇细胞相对于其相邻细胞过度增殖。利用体外诱变技术，我们确定了Merlin中对于正确亚细胞定位以及挽救致死性Merlin等位基因的遗传功能所必需的功能结构域。值得注意的是，这些实验结果表明，所有重要的遗传功能都存在于与质膜相关的Merlin氨基末端350个氨基酸中。去除该结构域内一个七氨基酸保守序列会产生一种显性负性形式的Merlin，它与质膜稳定结合，并在翅中异位表达时导致过度增殖。此外，我们提供证据表明，Merlin的羧基末端区域具有负调控作用，这与ERM蛋白的情况相同。这些结果为一种新型肿瘤抑制基因的功能及功能组织提供了深入见解。
