Function of Merlin, a Drosophila NF2 gene homologue

描述(申请人提供)：神经纤维瘤病2型(NF2)是一种主要遗传的疾病，由蛋白4.1超家族成员Merlin(Schwannomin)突变引起。NF2的症状通常出现在成年早期，由双侧前庭神经鞘瘤(导致耳聋)和其他良性肿瘤的形成引起。Merlin的细胞功能及其在肿瘤抑制中的作用在很大程度上仍不清楚。确定Merlin与之相互作用的特定蛋白质和信号转导途径尤其重要，因为这些伙伴可能作为NF2疾病表型的遗传修饰物，并为治疗药物提供潜在的靶点。常见的果蝇，果蝇，已被证明是一个有用的模型系统，以了解在发育中的有机体背景下的基因功能。因此，这项建议的总体目标是研究Merlin和密切相关的ERM蛋白Moesin在果蝇中的细胞功能，特别是与控制细胞增殖、细胞极性和调节上皮特性有关的功能。 在下一个资助阶段，我们计划继续研究Merlin在发育中的生物体和单个细胞中的功能。具体地说，拟议的实验将： 1)研究Merlin调控细胞增殖的机制。具体地说，我们将测试Merlin功能负调控EGF受体途径的假设。 2)研究密切相关的ERM蛋白调节Rho通路活性的机制，以及这与顶端/基底端的极性和上皮完整性的关系。 3)探讨Merlin与ERM蛋白的功能关系，检测它们之间的协同或拮抗作用。 这些实验有望对Merlin和ERM蛋白的功能提供深入的了解。因此，它们将有助于我们理解人类NF2、肿瘤抑制和癌症发生。此外，拟议的实验应该有助于更好地理解在上皮细胞和神经元中建立专门的膜域的细胞过程。最后，这些研究应该有助于研究细胞相互作用控制细胞生长和决定发育过程中细胞命运的机制。

DESCRIPTION (provided by applicant): Neurofibromatosis type 2 (NF2), a dominantly inherited disease, is caused by mutations in Merlin (Schwannomin), a member of the Protein 4.1 superfamily. Symptoms of NF2, which usually appear by early adult life, are caused by the formation of bilateral vestibular Schwannomas (resulting in deafness) and other benign tumors. The cellular functions of Merlin and its role in tumor suppression are still largely unknown. Identifying specific proteins and signal transduction pathways with which Merlin interacts is especially important because these partners may act as genetic modifiers of NF2 disease phenotypes and provide potential targets for therapeutic agents. The common fruit fly, Drosophila, has proven to be a useful model system for understanding gene function in the context of a developing organism. The overall goal of this proposal is therefore to examine the cellular functions of Merlin and the closely related ERM protein Moesin in Drosophila, particularly in relation to the control of cell proliferation, cell polarity, and the regulation of epithelial identity. In the next funding period, we plan to continue our studies of Merlin function in developing organisms and in individual cells. Specifically, the proposed experiments will: 1) Examine the mechanisms by which Merlin regulates cell proliferation. Specifically, we will test the hypothesis that Merlin functions to negatively regulate the EGF receptor pathway. 2) Examine the mechanism by which the closely related ERM proteins function to regulate Rho pathway activity, and how this relates to apical/basal polarity and epithelial integrity. 3) Explore the functional relationship between Merlin and the ERM proteins, testing for synergistic or antagonistic interactions between them. These experiments are expected to provide insights into the functions of Merlin and the ERM proteins. Thus they will contribute to our understanding of human NF2, tumor suppression in general, and carcinogenesis. In addition, the proposed experiments should lead to a better understanding of the cellular processes that establish specialized membrane domains in epithelial cells and neurons. Finally, these studies should contribute to work on the mechanisms by which cellular interactions function to control cell growth and determine cell fate during development