Structure, Function and Regulation of Merlin

描述(申请人提供)：Merlin是神经纤维瘤病2型(NF2)基因的产物。在人类中，Merlin的缺失与多种肿瘤的发生有关，包括神经鞘瘤、脑膜瘤、室管膜瘤和间皮瘤。这两个NF2等位基因都必须被灭活才能形成肿瘤，这表明Merlin是一种肿瘤抑制因子。Merlin如何发挥抑制肿瘤生长的作用尚不完全清楚。我们工作的总体目标是了解Merlin的正常功能，并探索分子策略，通过这些策略可以逆转Merlin缺陷神经鞘瘤细胞的异常表型。在上一次授予期间，我们发现Merlin是一种驻留在脂筏上的蛋白质，与其在信号转导中的已知作用一致。我们还鉴定了一些驻留在RAFT上的Merlin结合伙伴，它们与Merlin的相互作用可能在Merlin功能中发挥重要作用。这些结果使我们假设，Merlin在脂筏中的定位是其功能所必需的。在即将到来的赠款期间，我们建议通过实现三个具体目标来检验这一假说。首先，我们将确定Merlin与脂筏结合的功能意义，特别是人类雪旺细胞，这是与2型神经纤维瘤病相关的细胞类型。其次，我们将通过测试基于Merlin和Merlin结合蛋白的PPM1B2去磷酸化的新模型，详细研究新发现的驻留于RAFT的Merlin结合伙伴PPM1B2在Merlin功能中的作用。第三，我们将探索Merlin与脂筏中另一种Merlin结合伙伴--原调节蛋白III之间的相互作用，以及它对细胞生长和运动的潜在影响。我们预计，这些研究将为Merlin介导的肿瘤抑制途径提供新的线索，并可能为Merlin功能丧失引起的肿瘤的治疗策略提供可能的分子靶点。

DESCRIPTION (provided by applicant): Merlin is the product of the neurofibromatosis type 2 (NF2) gene. In humans, loss of merlin is associated with the development of a variety of tumors including schwannomas, meningiomas, ependymomas and mesotheliomas. That both NF2 alleles must be inactivated for tumors to form indicates that merlin is a tumor suppressor. How merlin functions to suppress tumor growth is not fully understood. The overall objective of our work is to understand the normal function of merlin, and to explore molecular strategies by which abnormal phenotypes in merlin-deficient schwannoma cells may be reversed. During the last grant period, we discovered that merlin is a lipid raft-resident protein, consistent with its known role in signal transduction. We also identified a number of raft-resident merlin binding partners, whose interaction with merlin may play important roles in merlin function. These results have led us to hypothesize that the localization of merlin in lipid rafts is essential for its function. In the upcoming grant period, we propose to test this hypothesis by carrying out 3 specific aims. First, we will determine the functional significance of the association of merlin with lipid rafts, with special reference to human Schwann cells, the cell type relevant for the disease of neurofibromatosis type 2. Second, we will study in detail the role of the newly identified, raft-resident, merlin binding partner, PPM1B2, in merlin function by testing a new model of merlin regulation based on PPM1B2 dephosphorylation of merlin and merlin binding proteins. Third, we will explore the interaction between merlin and tropomodulin III, another merlin binding partner in lipid rafts, with reference to its potential impact on cell growth and motility. We anticipate that these studies will shed new light on pathways involved in merlin-mediated tumor suppression, and may suggest possible molecular targets for therapeutic strategies for tumors that arise from loss of merlin function.