Determining the mechanism of serine sensing by the mTOR pathway

项目总结/摘要 mTORC 1激酶是细胞生长和代谢的主要调节因子。mTORC 1活性是 受上游环境因素的控制，包括生长因子和营养物质的可用性;毫不奇怪， mTORC 1途径的失调与多种疾病有关，包括癌症， 糖尿病、肥胖症、神经退化和衰老过程。为了指导新的治疗方法 对于这些疾病，我们必须了解mTORC 1是如何被特定的上游营养输入所调节的 在分子水平上。 通过证明mTORC 1活性被急性丝氨酸剥夺抑制，我们已经确定了一种新的抑制剂。 mTORC 1通路的新输入。这一结果特别引人注目，因为缺乏丝氨酸，一种非- 必需氨基酸，可以诱导癌细胞中的代谢重新布线并破坏一碳代谢; 此外，外源性丝氨酸在许多肿瘤中是条件必需的。初步数据显示， mTORC 1通过营养感应途径检测丝氨酸或丝氨酸衍生代谢物的存在 Rag-GTP酶上游;然而，我们不知道丝氨酸传感器的身份，也不知道 它是如何调节mTORC 1信号的阐明mTORC 1的丝氨酸传感机制 为此，我们提出以下具体目标： 1)建立Rag-GTP酶上游的通路，其向mTORC 1发出丝氨酸充足的信号。 2)确定向mTORC 1发出丝氨酸充足信号的代谢物。 3)确定丝氨酸水平不足时负调节mTORC 1活性的蛋白质。 我们将采用多学科的方法，包括代谢物分析，无偏见的蛋白质组学， 功能基因组学，以确定丝氨酸如何促进mTORC 1通路的激活。通过这些 研究，我们可能能够建立丝氨酸代谢改变和mTORC 1依赖性 癌细胞的生长和增殖。此外，我们的工作可能揭示新的丝氨酸依赖性代谢， 癌症中的脆弱性，并导致在mTORC 1途径中识别新的药物靶标。

Project Summary/Abstract The mTORC1 kinase is a master regulator of cellular growth and metabolism. mTORC1 activity is controlled by upstream environmental cues, including growth factors and nutrient availability; not surprisingly, dysregulation of the mTORC1 pathway has been implicated in a diverse set of diseases, including cancers, diabetes, obesity, neurodegeneration, and the aging process. In order to guide new therapeutic approaches toward these diseases, we must understand how mTORC1 is regulated by specific upstream nutritional inputs on a molecular level. By demonstrating that mTORC1 activity is inhibited by acute serine deprivation, we have identified a new input into the mTORC1 pathway. This result is especially striking because deprivation of serine, a non- essential amino acid, can induce metabolic rewiring in cancer cells and disrupt one-carbon metabolism; moreover, exogenous serine is conditionally essential in many tumors. Our preliminary data show that mTORC1 detects the presence of serine, or a serine-derived metabolite, through the nutrient-sensing pathway upstream of the Rag-GTPases; however, we do not know the identity of the serine sensor, nor do we know how it regulates mTORC1 signaling. To elucidate the mechanism of serine sensing by the mTORC1 pathway, we propose the following specific aims: 1) Establish the pathway upstream of the Rag-GTPases which signals serine sufficiency to mTORC1. 2) Determine the metabolite that signals serine sufficiency to mTORC1. 3) Identify the protein that negatively regulates mTORC1 activity when serine levels are insufficient. We will employ a multidisciplinary approach that incorporates metabolite profiling, unbiased proteomics, and functional genomics to determine how serine promotes activation of the mTORC1 pathway. Through these studies, we may be able to establish a link between altered serine metabolism and mTORC1-dependent growth and proliferation in cancer cells. In addition, our work may uncover new serine-dependent metabolic vulnerabilities in cancers and lead to the identification of novel drug targets in the mTORC1 pathway.