Function of Merlin, a Drosophila NF2 gene homologue

描述（申请人提供）：2型神经纤维瘤病（NF 2）是一种显性遗传性疾病，由蛋白质4.1超家族成员Merlin（Schwannomin）突变引起。NF 2的症状通常在成年早期出现，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然未知。鉴定Merlin相互作用的特定蛋白质和信号转导途径尤其重要，因为这些伴侣可能作为NF 2疾病表型的遗传修饰剂，并为治疗剂提供潜在靶点。常见的果蝇，果蝇，已被证明是一个有用的模型系统，了解基因功能的背景下，发展中的有机体。因此，本提案的总体目标是研究果蝇中Merlin和密切相关的ERM蛋白Moesin的细胞功能，特别是与细胞增殖，细胞极性和上皮身份调节的控制有关。 在下一个资助期内，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。具体而言，拟议的实验将： 1)检查Merlin调节细胞增殖的机制。具体来说，我们将测试梅林功能负调节EGF受体途径的假设。 2)检查密切相关的ERM蛋白调节Rho通路活性的机制，以及这与顶端/基底极性和上皮完整性的关系。 3)探索Merlin和ERM蛋白之间的功能关系，测试它们之间的协同或拮抗相互作用。 这些实验有望为Merlin和ERM蛋白的功能提供深入了解。因此，他们将有助于我们了解人类NF 2，肿瘤抑制一般，和致癌作用。此外，拟议的实验应该导致更好地了解细胞过程，建立专门的上皮细胞和神经元的膜域。最后，这些研究应该有助于研究细胞相互作用在发育过程中控制细胞生长和决定细胞命运的机制

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