Structure, Function and Regulation of Merlin

描述（由申请方提供）：Merlin是2型神经纤维瘤病（NF 2）基因的产物。在人类中，梅林蛋白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NF 2等位基因必须失活才能形成肿瘤，这表明梅林是一种肿瘤抑制因子。梅林如何抑制肿瘤生长的功能还没有完全了解。我们的工作的总体目标是了解梅林的正常功能，并探索分子策略，梅林缺陷神经鞘瘤细胞的异常表型可能被逆转。在上一个资助期间，我们发现merlin是一种脂筏驻留蛋白，这与其在信号转导中的已知作用一致。我们还确定了一些筏居民梅林结合伙伴，其相互作用与梅林梅林可能发挥重要作用梅林功能。这些结果使我们推测，定位的梅林在脂筏是必不可少的，它的功能。在即将到来的赠款期间，我们建议通过执行3个具体目标来测试这一假设。首先，我们将确定梅林与脂筏的关联的功能意义，特别是人类雪旺细胞，与神经纤维瘤病2型疾病相关的细胞类型。第二，我们将详细研究新发现的，筏居民，梅林结合伙伴，PPM1B2，梅林功能的作用，通过测试一个新的模型，梅林调节的基础上PPM1B2梅林和梅林结合蛋白的去磷酸化。第三，我们将探讨梅林和tropomodulin III，另一个梅林在脂筏结合伙伴之间的相互作用，参考其对细胞生长和运动的潜在影响。我们预计，这些研究将揭示梅林介导的肿瘤抑制途径的新的光，并可能建议可能的分子靶点的治疗策略所产生的梅林功能丧失的肿瘤。

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.