The role of Folliculin, tumor suppressor mutated in BHD, in mTOR nutrient sensing

描述（由申请方提供）：雷帕霉素复合物1（mTORC 1）蛋白激酶的机制靶点是生长的主要调节因子。它整合了一系列不同的信号，包括营养物质的可用性，能量水平，生长因子和细胞应激，以调节细胞内稳态过程，如核糖体生物合成，蛋白质翻译和自噬。毫不奇怪，这种途径在常见的人类疾病如癌症、糖尿病和神经退行性疾病中失调。 虽然控制生长因子、能量水平和细胞应激感测的机制已被很好地表征，但营养感测仍然相对知之甚少。营养素是激酶活性所必需的，并利用独立于其他输入的机制来调节mTORC 1通路。阐明控制营养传感的分子机制对于开发靶向mTORC 1通路的疗法具有更高的疗效，同时最大限度地减少副作用。 我们已经使用蛋白质组学方法来确定滤泡素（FLCN），在家族性癌症综合征Birt-Hogg-Dube（BHD）中突变的肿瘤抑制因子和mTORC 1途径的营养感应轴之间的新联系。尽管FLCN与人类疾病有因果关系，但其功能仍不清楚。初步证据表明，FLCN易位到溶酶体，以响应氨基酸饥饿，与Rag GTP酶和Ragulator复合物相互作用，这是mTORC 1营养反应的关键调节因子。本项目的目标是表征FLCN和FLCN相互作用蛋白1和2（FNIP）在营养感应mTORC 1途径中的功能。我们提出以下目标：1）表征在不同营养条件下FLCN与Rags和Ragulator复合物的相互作用和定位。2)确定FLCN/FNIPs敲低和过表达对不同营养条件下mTORC 1活性和定位的影响。3)研究FLCN/FNIP调节Rag GTP酶和Ragulator复合物活性的机制。通过假设驱动和无偏的方法，我们提出的工作将阐明肿瘤抑制因子FLCN如何在人类癌症中常见的mTORC 1通路中发挥作用。这些见解将揭示BHD的发病机制，并可能导致合理开发新的癌症治疗方法。

DESCRIPTION (provided by applicant): The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master regulator of growth. It integrates a diverse set of signals, including nutrient availability, energy levels, growth factors, and cellular stresses, to regulate ey homeostatic processes such as ribosome biogenesis, protein translation, and autophagy. Not surprisingly, this pathway is deregulated in common human diseases such as cancer, diabetes, and neurodegeneration. While the mechanisms governing the sensing of growth factors, energy levels, and cellular stresses are well characterized, nutrient sensing remains relatively poorly understood. Nutrients are absolutely required for kinase activity and utilize an independent mechanism from other inputs to regulate the mTORC1 pathway. Elucidation of the molecular mechanisms that control nutrient sensing is fundamental for the development of therapies that target the mTORC1 pathway with more efficacy, while minimizing side effects. We have used a proteomic approach to identify a new link between folliculin (FLCN), the tumor suppressor mutated in the familial cancer syndrome Birt-Hogg-Dube (BHD), and the nutrient sensing axis of the mTORC1 pathway. Despite its causative link to a human disease, the function of FLCN remains unclear. Preliminary evidence suggests that FLCN translocates to the lysosome in response to amino acid starvation to interact with the Rag GTPases and the Ragulator complex, key regulators of the mTORC1 nutrient response. The goal of this project is to characterize the functions of FLCN and FLCN interacting protein 1 and 2 (FNIPs) in the nutrient sensing mTORC1 pathway. We propose the following aims: 1) Characterize the FLCN interaction and localization with the Rags and Ragulator complex under different nutrient conditions. 2) Determine the effects of FLCN/FNIPs knockdown and overexpression on mTORC1 activity and localization under different nutrient conditions. 3) Investigate the mechanism through which FLCN/FNIPs modulate the activity of the Rag GTPases and the Ragulator complex. Through hypothesis driven and unbiased approaches, our proposed work will clarify how the tumor suppressor FLCN functions in the mTORC1 pathway commonly deregulated in human cancers. These insights will shed light on the pathogenesis of BHD and may lead to the rational development of novel therapies for cancer.