Determining the mechanism of aspartate sensing by the mTOR pathway

通过 mTOR 途径确定天冬氨酸传感机制

• 批准号: 9337243
• 负责人: Jose Miguel Orozco
• 金额: $ 4.9万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9337243
• 关键词: 5' -AMP-activated protein kinase; Affect; Amino Acid Transporter; Amino Acids; Anabolism; Arginine; Aspartate; Biguanides; Binding; Biochemical; CRISPR/Cas technology; Cell Line; Cells; Cellular Metabolic Process; Clinical; Complex; Cytoplasm; Data; Diabetes Mellitus; Disease; Drug Targeting; Electron Transport; Enzymes; FRAP1 gene; Foundations; GTPase-Activating Proteins; Genetic; Goals; Growth Factor; Guanine; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; In Vitro; Label; Leucine; Link; Liposomes; Lysosomes; Malignant Neoplasms; Metformin; Mitochondria; N-terminal; Nature; Nutrient; Output; Pathway interactions; Phosphotransferases; Proteins; Proteomics; Recombinant Proteins; Regulation; Signal Transduction; Stress; Testing; Therapeutic; Work; base; cancer therapy; cell growth; design; experimental study; gain of function; genetic approach; genetic manipulation; genetic regulatory protein; human disease; inhibitor/antagonist; novel; overexpression; protein complex; reconstitution; scaffold; sensor

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.

项目总结/摘要 mTORC 1激酶复合物是细胞生长和代谢的主要调节因子， 常见的人类疾病，如糖尿病和癌症。因此，了解正常的调节 mTORC 1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输入方法 涉及天冬氨酸感知的mTOR通路。有趣的是，天冬氨酸的生物合成需要完整的 线粒体电子传递链功能表明天冬氨酸提供了一种以前未被认识到的 从线粒体功能到mTOR通路的联系。类似于mTOR通路中其他氨基酸的传感 我们发现天冬氨酸在Rag-GTP酶的上游被感知。然而，天冬氨酸传感器的身份 天冬氨酸的充足性是如何向拉格人发出信号的，这一点仍然完全未知。该项目的目标是 确定mTOR通路的天冬氨酸感知机制。为此，我们建议 以下目标： 1.确定Rag-GTP酶上游的哪条通路向mTORC 1发出天冬氨酸充足信号。 2.鉴定参与向mTORC 1发出天冬氨酸充足信号的蛋白质。 3.确定目标2中鉴定的蛋白质是否是直接天冬氨酸传感器。 通过采取假设驱动和无偏的方法，我们提出的工作将描述一个新的输入， mTOR通路。我们的研究结果还可能提供一种新的机制，解释药物之间的联系， 靶向电子传递链，如二甲双胍和mTOR通路。