Structure, Function and Regulation of Merlin

描述（由申请人提供）：Merlin 是 2 型神经纤维瘤病 (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。两个 NF2 等位基因必须失活才能形成肿瘤，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，并探索可逆转 merlin 缺陷神经鞘瘤细胞异常表型的分子策略。在上一次资助期间，我们发现 merlin 是一种脂筏驻留蛋白，与其已知的信号转导作用一致。我们还鉴定了许多驻留在筏上的 merlin 结合伴侣，它们与 merlin 的相互作用可能在 merlin 功能中发挥重要作用。这些结果使我们推测 merlin 在脂筏中的定位对其功能至关重要。在即将到来的资助期内，我们建议通过实现 3 个具体目标来检验这一假设。首先，我们将确定 merlin 与脂筏关联的功能意义，特别是人类雪旺细胞（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 merlin 调节模型，详细研究新鉴定的脂筏驻留性 merlin 结合伴侣 PPM1B2 在 merlin 功能中的作用。第三，我们将探讨 merlin 和原调节蛋白 III（脂筏中另一种 merlin 结合伙伴）之间的相互作用，并参考其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出可能的分子靶点。

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.