The NF2 gene: elucidation of tumor suppressor function

描述（由申请人提供）：2型神经纤维瘤病（NF 2）是一种遗传性疾病，其特征为第八脑神经的许旺细胞瘤的发展。NF 2基因编码与ERM蛋白膜突蛋白、埃兹蛋白和根蛋白高度相关的蛋白质，因此被称为merlin。ERM蛋白被认为是细胞膜-细胞骨架连接物。Merlin至少部分受Rac/cdc 42依赖性磷酸化的调节。最近的数据暗示梅林作为一个可能的负调节Rac/cdc 42信号通路。该项目的重点是研究梅林的肿瘤抑制特性，以及通过梅林将细胞外信号与细胞骨架组织和/或细胞增殖状态联系起来的信号通路。这项工作涉及两种结合的方法：1）了解梅林如何与Rac/cdc 42信号通路相互作用和调节。2)Merlin的结构/功能研究，包括将蛋白质的同种型和突变形式引入Nf 2缺陷细胞。具体而言，将检查影响merlin磷酸化的突变。拟议的项目应阐明梅林的生长抑制作用和可能的串扰与Rac/cdc 42途径。这将使我们更好地理解正常细胞中merlin的功能，以及它在肿瘤发展中丧失的后果。这些信息将直接有助于寻找有效的治疗方法。

DESCRIPTION (provided by applicant): Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by development of Schwann cell tumors of the eighth cranial nerve. The NF2 gene codes for a protein highly related to the ERM proteins moesin, ezrin and radixin and was thus termed merlin. The ERM proteins are thought to function as cell membrane-cytoskeleton linkers. Merlin is regulated, at least in part, by Rac/cdc42-dependent phosphorylation. Recent data implicates merlin as a possible negative regulator of the Rac/cdc42 signaling pathway. The proposed project focuses on the study of the tumor suppressive properties of merlin and the signaling pathways connecting extracellular signals to cytoskeletal organization and/or the proliferative state of the cell, via merlin. The work involves two combined approaches: 1) Understanding how merlin might interact with and regulate, the Rac/cdc42 signaling pathway. 2) Structure/function studies of merlin involving introduction of isoforms and mutated forms of the protein into Nf2-deficient cells. Specifically, mutations effecting merlin phosphorylation will be examined. The proposed project should shed light on the growth suppressive effects of merlin and possible cross-talk with the Rac/cdc42 pathway. This should lead to a better understanding of merlin function in normal cells and the consequences of its loss in tumor development. Such information will directly assist in the search for effective therapies.