Molecular Function of the Nf2 Tumor Suppressor, Merlin

描述(由申请人提供)：NF2肿瘤抑制基因突变是2型神经纤维瘤病(NF2)的基础，NF2是一种以中枢神经系统肿瘤发展为特征的家族性癌症综合征。NF2编码的蛋白Merlin与ERM(Ezrin、Radioxin和Moesin)蛋白关系密切，这些蛋白被认为有助于膜：肌动蛋白细胞骨架复合体的组装。然而，Merlin控制细胞增殖的机制尚不清楚。为了建立Nf2相关肿瘤发生的动物模型，并开发定义Merlin分子功能的工具，我们产生了Nf2突变的小鼠品系，并发现Nf2突变使小鼠易患各种高转移性癌症。考虑到人类NF2患者良性肿瘤的有限频谱，这是令人惊讶的，并表明NF2失活可能在癌症的发展和进展中发挥未被认识的作用。我们的广泛目标是使用Nf2突变的小鼠和细胞来描述Merlin及其家族成员在癌症发生和发展中的功能。我们最近发现，在几种类型的原代细胞中，NF2缺乏的一个特征是失去了接触依赖性的增殖抑制，缺乏正常的钙粘附素介导的细胞间通讯。我们发现，在野生型细胞中，Merlin定位于含钙粘附素的黏附连接(AJ)，并且是建立最终的肌动蛋白细胞骨架相关AJ结构所必需的。我们还发现，在缺乏Merlin的情况下，表皮生长因子受体(EGFR)在高细胞密度下的沉默是有缺陷的，这种沉默是由AJ的建立介导的。该方案的目的是确定控制AJ建立和EGFR沉默是否是Merlin作为肿瘤和转移抑制因子的细胞机制，并描述Merlin在AJ建立中的作用机制。这项研究的结果将对Merlin作为肿瘤抑制因子的作用机制产生重要的见解，并为NF2的治疗干预寻找新的靶点。

DESCRIPTION (provided by applicant): Mutations in the NF2 tumor suppressor gene underlie Neurofibromatosis type 2 (NF2), a familial cancer syndrome featuring the development of central nervous system tumors. The NF2-encoded protein, Merlin, is closely related to the ERM (Ezrin, Radixin and Moesin) proteins, which are thought to facilitate the assembly of membrane:actin cytoskeleton complexes. However, the mechanism whereby Merlin controls cell proliferation is not known. To create an animal model for Nf2-associated tumorigenesis and develop tools for defining the molecular function of Merlin, we generated an Nf2-mutant strain of mice and found that Nf2 mutation predisposes mice to a variety of highly metastatic cancers. This is surprising given the limited spectrum of benign tumors in human NF2 patients and suggests that Nf2 inactivation may play an unrecognized role in cancer development and progression. Our broad objective is to use Nf2-mutant mice and cells to delineate the function of Merlin and its family members in cancer development and progression. We have recently found that a signature of Nf2-deficiency across several types of primary cells is loss of contact-dependent inhibition of proliferation and lack of normal cadherin-mediated cell:cell communication. We discovered that Merlin localizes to cadherin-containing adherens junctions (AJs) in wild-type cells and is required for the establishment of the final actin cytoskeleton associated AJ structure. We also found that silencing of the epidermal growth factor receptor (EGFR) at high cell density, which is known to be mediated by AJ establishment, is defective in the absence of Merlin. The goals of this proposal are to determine whether control of AJ establishment and EGFR silencing is the cellular mechanism whereby Merlin acts as a tumor and metastasis suppressor and to delineate the mechanism of Merlin function in AJ establishment. The results of this study will yield important insight into the mechanism of Merlin function as a tumor suppressor and identify novel targets for therapeutic intervention of NF2.