Determining the mechanism of aspartate sensing by the mTOR pathway

项目摘要/摘要 MTORC1激酶复合体是细胞生长和新陈代谢的主要调节因子，在 人类常见的疾病，如糖尿病和癌症。因此，理解正常的规则， MTORC1对指导这些疾病的治疗具有重要意义。我们发现了一种新的投入到 涉及天冬氨酸感应的mTOR通路。有趣的是，天冬氨酸的生物合成需要完整的 线粒体电子传输链功能提示天冬氨酸提供了一种先前未知的 线粒体功能与mTOR途径之间的联系。就像对mTOR途径中其他氨基酸的感知一样 我们发现天冬氨酸位于RAG-GTP酶的上游。然而，天冬氨酸传感器的身份 天冬氨酸充足是如何向RAG发出信号的，目前还完全不清楚。这个项目的目标是 通过mTOR通路确定天冬氨酸敏感的机制。为此，我们建议 以下目标： 1.确定RAG-GTP酶上游的哪条途径发出门冬氨酸氨基转移酶对mTORC1的信号。 2.确定与向mTORC1发出天冬氨酸充足信号有关的蛋白质。 3.确定AIM 2中鉴定的蛋白质是否为直接天冬氨酸感受器。 通过采用假设驱动和无偏见的方法，我们提议的工作将描述一种新的输入到 MTOR途径。我们的结果也可能提供一种新的机制来解释药物之间的联系 靶向电子传输链，如二甲双胍和mTOR途径。

Project Summary/Abstract The mTORC1 kinase complex is a major regulator of cell growth and metabolism and is deregulated in common human diseases such as diabetes and cancer. Therefore, understanding the normal regulation of mTORC1 is of great importance to guide therapies for these diseases. We have discovered a novel input into the mTOR pathway that involves aspartate sensing. Interestingly, aspartate biosynthesis requires intact mitochondrial electron transport chain function suggesting that aspartate provides a previously unrecognized link from mitochondrial function to the mTOR pathway. Like sensing of other amino acids in the mTOR pathway we find that aspartate is sensed upstream of the Rag-GTPases. However, the identity of an aspartate sensor and how aspartate sufficiency signals to the Rags remains entirely unknown. The goal of this project is to determine the mechanism of aspartate sensing by the mTOR pathway. To that end, we propose the following aims: 1. Establish which pathway upstream of the Rag-GTPases signals aspartate sufficiency to mTORC1. 2. Identify proteins involved in signaling aspartate sufficiency to mTORC1. 3. Determine whether proteins identified in aim 2 are direct aspartate sensors. By taking both hypothesis driven and unbiased approaches, our proposed work will describe a new input into the mTOR pathway. Our results may also provide a new mechanism that explains the link between drugs that target the electron transport chain, such as metformin, and the mTOR pathway.