The NF2 gene: elucidation of tumor suppressor function

描述（由申请人提供）：2型神经纤维瘤病（NF2）是一种以第八脑神经雪旺细胞瘤为特征的遗传性疾病。NF2基因编码一种与ERM蛋白moesin、ezrin和radixin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至少部分受到Rac/cdc42依赖性磷酸化的调节。最近的数据表明，merlin可能是Rac/cdc42信号通路的负调控因子。该计划的重点是研究merlin的肿瘤抑制特性，以及通过merlin连接细胞外信号与细胞骨架组织和/或细胞增殖状态的信号通路。这项工作涉及两种结合的方法：1)了解merlin如何与Rac/cdc42信号通路相互作用和调节。2) merlin的结构/功能研究，包括将该蛋白的异构体和突变形式引入nf2缺陷细胞。具体地说，影响梅林磷酸化的突变将被检查。拟议的项目将阐明merlin的生长抑制作用以及可能与Rac/cdc42通路的串扰。这将有助于我们更好地了解正常细胞中的merlin功能，以及它在肿瘤发展过程中丧失的后果。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.