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:
    10308469
  • 负责人:
  • 金额:
    $ 5.18万
  • 依托单位:
  • 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 2023-12-31
  • 项目状态:
    已结题

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/摘要 雷帕霉素复合物1(mTORC 1)的机制靶点是丝氨酸/苏氨酸激酶, 通过平衡合成代谢和分解代谢过程来协调细胞生长和代谢, 营养素、生长因子信号和能量水平1,2.在这条通路中的信号失调已经被 与许多人类疾病有关,包括神经变性、糖尿病和癌症3。因此, 参与mTORC 1激活的机制和mTORC 1控制下的生物学过程如下: 重大利益。 溶酶体在mTORC 1营养感测分支的信号传导中发挥关键作用 途径9.在开发一种快速分离纯溶酶体的新工具时,我们令人惊讶地发现, 发现mTORC 1调节一组独特的非极性,主要是必需的溶酶体浓度 个氨基酸使用同样的方法,我们注意到SLC 38 A9的缺失,一种很大程度上未研究的氨基酸, 一种感觉溶酶体精氨酸的转运蛋白,导致同一组非极性精氨酸的积累,主要是 必需氨基酸尽管有这些知识,mTORC 1调节溶酶体的机制, 通过SLC 38 A9的必需氨基酸的丰度是未知的。阐明这一机制将使 了解哺乳动物细胞如何对营养物质的可用性做出反应的关键见解,也可能提供新的治疗方法。 治疗肿瘤的靶点。 初步证据表明,Rag-Ragulator复合物与SLC 38 A9相互作用,并传递 mTORC 1对营养物质的利用率是mTORC 1调节必需氨基酸流出所必需的 来自溶酶体的酸。表征mTORC 1调节SLC 38 A9的分子机制 运输功能,我们提出以下目标: . 1.确定mTORC 1在控制SLC 38 A9和Rag之间相互作用中的作用。 拉古勒。 2.了解Rag-Ragulator磷酸化在转运调节中的作用 SLC 38 A9的功能 3.鉴定调节SLC 38 A9的溶酶体蛋白。

项目成果

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Jibril Kedir其他文献

Jibril Kedir的其他文献

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{{ truncateString('Jibril Kedir', 18)}}的其他基金

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
  • 批准号:
    10534130
  • 财政年份:
    2019
  • 资助金额:
    $ 5.18万
  • 项目类别:
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
  • 批准号:
    10454518
  • 财政年份:
    2019
  • 资助金额:
    $ 5.18万
  • 项目类别:

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