Molecular Function of the Nf2 Tumor Suppressor, Merlin

描述（申请人提供）：NF 2肿瘤抑制基因突变是2型神经纤维瘤病（NF 2）的基础，NF 2是一种家族性癌症综合征，以中枢神经系统肿瘤的发展为特征。NF 2编码的蛋白Merlin与ERM（Ezrin、Radixin和Moesin）蛋白密切相关，其被认为促进膜：肌动蛋白细胞骨架复合物的组装。然而，Merlin控制细胞增殖的机制尚不清楚。为了创建Nf 2相关肿瘤发生的动物模型并开发用于定义Merlin分子功能的工具，我们产生了Nf 2突变小鼠品系，并发现Nf 2突变使小鼠易患各种高转移性癌症。考虑到人类NF 2患者中良性肿瘤的有限谱，这是令人惊讶的，并且表明Nf 2失活可能在癌症发展和进展中起未被认识的作用。我们的广泛目标是使用Nf 2突变小鼠和细胞来描述Merlin及其家族成员在癌症发展和进展中的功能。我们最近发现，在几种类型的原代细胞的NF 2-缺陷的签名是接触依赖性抑制增殖和缺乏正常的钙粘蛋白介导的细胞：细胞通信的损失。我们发现Merlin定位于野生型细胞中含钙粘蛋白的粘附连接（AJs），并且是建立最终肌动蛋白细胞骨架相关AJs结构所必需的。我们还发现，沉默的表皮生长因子受体（EGFR）在高细胞密度，这是已知的AJ建立介导的，是有缺陷的梅林的情况下。本提案的目的是确定AJ建立和EGFR沉默的控制是否是Merlin作为肿瘤和转移抑制剂的细胞机制，并描述Merlin在AJ建立中的功能机制。这项研究的结果将产生重要的洞察梅林作为一种肿瘤抑制剂的功能机制，并确定新的治疗干预NF 2的目标。

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.