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的丧失与多种肿瘤的发展有关，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是如何抑制肿瘤生长的还不完全清楚。我们工作的总体目标是了解梅林蛋白的正常功能，并探索在梅林蛋白缺陷的神经鞘瘤细胞中异常表型可能被逆转的分子策略。在上一个资助期间，我们发现merlin是一种脂质筏驻留蛋白，与它在信号转导中的已知作用一致。我们还发现了一些居住在木筏上的梅林结合伙伴，它们与梅林的相互作用可能在梅林的功能中起重要作用。这些结果使我们假设梅林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，我们建议通过实施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，特别参考人类雪旺细胞，这种细胞类型与2型神经纤维瘤病相关。其次，我们将通过测试基于PPM1B2对merlin和merlin结合蛋白去磷酸化的merlin调控新模型，详细研究新发现的筏驻留的merlin结合伙伴PPM1B2在merlin功能中的作用。第三，我们将探讨梅林与脂筏中的另一种梅林结合伙伴原调蛋白III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梅林蛋白介导的肿瘤抑制途径提供新的线索，并可能为梅林蛋白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.