Determining the mechanism of serine sensing by the mTOR pathway

项目摘要/摘要 MTORC1K是细胞生长和代谢的主要调节因子。MTORC1活动为 受上游环境线索的控制，包括生长因子和养分供应；毫不奇怪， MTORC1通路的失调与多种疾病有关，包括癌症， 糖尿病、肥胖症、神经退行性变和衰老过程。为了指导新的治疗方法 对于这些疾病，我们必须了解mTORC1是如何由特定的上游营养输入调节的 在分子水平上。 通过证明mTORC1的活性被急性丝氨酸剥夺所抑制，我们发现了一种 MTORC1途径的新输入。这一结果尤其令人震惊，因为缺乏丝氨酸，一种非 必需氨基酸，可诱导癌细胞代谢重排，扰乱一碳代谢； 此外，外源性丝氨酸在许多肿瘤中是条件必需的。我们的初步数据显示， MTORC1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酶的上游；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mTORC1信号的。阐明mTORC1对丝氨酸的敏感机制 关于这一途径，我们提出了以下具体目标： 1)建立RAG-GTP酶上游信号转导mTORC1丝氨酸充足的途径。 2)确定向mTORC1发出丝氨酸充足信号的代谢产物。 3)确定丝氨酸水平不足时负向调节mTORC1活性的蛋白质。 我们将采用一种多学科的方法，结合代谢物图谱、无偏见的蛋白质组学和 功能基因组学，以确定丝氨酸如何促进mTORC1途径的激活。通过这些 研究表明，我们或许能够在丝氨酸代谢改变和mTORC1依赖之间建立联系 癌细胞的生长和增殖。此外，我们的工作可能会发现新的依赖丝氨酸的代谢。 癌症的脆弱性，并导致在mTORC1途径中发现新的药物靶点。

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.