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Regulation by mTORC1 of the lysosomal efflux of essential amino acids

mTORC1 对必需氨基酸溶酶体流出的调节

基本信息

批准号：
10534130
负责人：
Jibril Kedir
金额：
$ 3.46万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534130
关键词：
Affect Amino Acid Transporter Amino Acids Arginine Autophagocytosis Binding Biological Assay Biological Process CDK6-associated protein p18 Carrier Proteins Catabolic Process Cells Cellular Metabolic Process Cellular Stress Complex Data Diabetes Mellitus Disease Epilepsy Essential Amino Acids Event FDA approved FRAP1 gene Growth Growth Factor Guanosine Triphosphate Phosphohydrolases Homeostasis Immunoprecipitation In Vitro Knowledge Leucine Liposomes Lysosomes Malignant Neoplasms Mammalian Cell Mass Spectrum Analysis Mediating Membrane Methods Modeling Molecular Mutate Nerve Degeneration Nucleotides Nutrient Nutrient availability Nutritional Organ Transplantation Pathway interactions Phosphorylation Phosphorylation Site Phosphotransferases Play Protein Family Protein-Serine-Threonine Kinases Proteins Proteomics Regulation Research Role Serine Signal Transduction Sirolimus Surface Testing Therapeutic Agents candidate identification cell growth detection of nutrient genetic regulatory protein human disease inhibitor insight interest lysosomal proteins mTOR Inhibitor metabolomics mutant new therapeutic target novel novel therapeutics prevent protein complex recruit response sensor tool tumor

项目摘要

Project Summary/Abstract The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine kinase which coordinates cell growth and metabolism by balancing anabolic and catabolic processes in response to nutrients, growth factor signaling, and energy levels 1,2. Deregulated signaling in this pathway has been implicated in many human diseases including neurodegeneration, diabetes, and cancer3. As such, the mechanisms involved in mTORC1 activation and the biological processes under the control of mTORC1 are of significant interest. Lysosomes play a crucial role in the signal transduction of the nutrient sensing branch of the mTORC1 pathway9. While developing a novel tool for the rapid isolation of pure lysosomes, we made the surprising discovery that mTORC1 regulates the lysosomal concentration of a distinct set of non-polar, mostly essential amino acids. Using the same method, we noticed that loss of SLC38A9, a largely unstudied amino acid transporter that senses lysosomal arginine, results in the accumulation of the same set of non-polar, mostly essential amino acids. Despite this knowledge, the mechanism by which mTORC1 regulates the lysosomal abundance of essential amino acids through SLC38A9 is not known. Elucidation of this mechanism will give key insights into how mammalian cells respond to nutrient availability and may also provide novel therapeutic targets for the treatment of tumors. Preliminary evidence suggests the Rag-Ragulator complex, which interacts with SLC38A9 and conveys the availability of nutrients to mTORC1, is necessary for mTORC1 to regulate the efflux of essential amino acids from lysosomes. To characterize the molecular mechanism by which mTORC1 regulates SLC38A9 transport function, we propose the following aims: . 1. Determine the role of mTORC1 in controlling the interaction between SLC38A9 and Rag- Ragulator. 2. Understand the role of Rag-Ragulator phosphorylation on the regulation of the transport function of SLC38A9. 3. Identification of lysosomal proteins that regulate SLC38A9.

项目总结/文摘