Structural analysis of Drosophila merlin reveals functional domains important for growth control and subcellular localization.
Structural analysis of Drosophila merlin reveals functional domains important for growth control and subcellular localization.
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DOI：
10.1083/jcb.141.7.1589
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发表时间：
1998-06-29
期刊：
影响因子：
--
通讯作者：
Fehon RG
中科院分区：
文献类型：
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作者：
LaJeunesse DR;McCartney BM;Fehon RG
Merlin是2型神经纤维瘤病（NF 2）肿瘤抑制基因的产物，是蛋白质4.1超家族的成员，与ezrin，radixin和moesin（ERM）关系最密切。NF 2是一种显性遗传性疾病，其特征在于形成双侧听神经鞘瘤和其他与中枢神经系统相关的良性肿瘤。为了了解它的细胞功能，我们正在研究果蝇中的Merlin同源物。与NF 2肿瘤的情况一样，缺乏Merlin功能的果蝇细胞相对于它们的邻居过度增殖。使用体外诱变，我们定义梅林内的功能域需要适当的亚细胞定位和致命的梅林等位基因的遗传拯救。值得注意的是，这些实验的结果表明，所有必需的遗传功能都存在于Merlin的质膜相关的NH 2末端350个氨基酸中。去除该结构域内的7个氨基酸保守序列导致显性阴性形式的梅林，其与质膜稳定相关，并且当在翼中异位表达时引起过度增殖。此外，我们提供的证据表明，COOH-末端区域的梅林具有负调控作用，已被证明为ERM蛋白。这些结果提供了一个新的肿瘤抑制基因的功能和功能组织的见解。
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.