Glutamine Sensing by mTORC1

! 摘要 细胞外和细胞内的养分可利用性被生物体感知以控制代谢 处理并维持细胞正常生长。营养感测的中断可能是灾难性的，通常会导致 人类疾病也许在这个过程中最值得注意的球员是雷帕霉素的哺乳动物目标 （mTOR）蛋白激酶，称为mTOR复合物1的多亚基蛋白复合物中的关键组分 （mTORC 1）。mTORC 1活化增加在许多人类疾病中是常见的，包括癌症、2型 糖尿病、代谢紊乱和神经变性。小分子如雷帕霉素和雷帕霉素 抑制mTORC 1的类似物（雷帕霉素类似物）目前在临床上用于治疗疾病，但成功有限。 因此，阐明mTORC 1调节的分子机制对于治疗肿瘤具有重要意义。 mTORC 1驱动的疾病。氨基酸是mTORC 1最强有力的激活剂，多年来， 被认为仅通过Rag GTP酶激活mTORC 1。我们最近发现了一种新的信号 途径，其中谷氨酰胺信号mTORC 1独立的Rag GTP酶，并需要另一个小的 GTP酶，ADP核糖基化因子-1（Arf 1）。Arf 1鸟嘌呤核苷酸循环是谷氨酰胺促进 mTORC 1溶酶体定位和活化。这一发现的潜在意义被强调为 事实上，癌细胞往往是“上瘾”谷氨酰胺，部分通过mTORC 1，以燃料电池的生长， 增殖我们已经确定了两个新的组件参与这一途径，一个已知的Arf 1 GAP（特异性 目的1）和一个表征不佳的溶质载体（SLC）谷氨酰胺转运蛋白（特定目的2）。我们建议 研究这两种新组分在谷氨酰胺诱导的mTORC 1活化中的作用。而且我们 将确定这些组分在mTORC 1介导的生物学和疾病中的重要性（特异性目的 3）。因此，本提案的总体目标是破译分子机制， 谷氨酰胺向mTORC 1发出信号。我们预计，拟议的研究将产生新的见解mTORC 1 通过谷氨酰胺的调节，并将揭示干扰mTORC 1介导的疾病的治疗靶点。 !

! Abstract Extracellular and intracellular nutrient availability is sensed by organisms in order to control metabolic processes and maintain proper cell growth. Disruption in nutrient sensing can be disastrous, often leading to human disease. Perhaps the most notable player in this process is the mammalian target of rapamycin (mTOR) protein kinase, a key component in the multi-subunit protein complex called mTOR complex 1 (mTORC1). Increased mTORC1 activation is common in many human diseases including cancer, type 2 diabetes, metabolic disorders, and neurodegeneration. Small molecules such as rapamycin and rapamycin analogs (rapalogs) that inhibit mTORC1, are currently used in the clinic to treat disease with limited success. Therefore, elucidating the molecular mechanisms of mTORC1 regulation is of great interest in order to treat mTORC1 driven disease. Amino acids are the most powerful activator of mTORC1 and for several years were thought to activate mTORC1 exclusively through the Rag GTPases. We recently discovered a novel signaling pathway whereby glutamine signals to mTORC1 independent of the Rag GTPases, and requires another small GTPase, ADP ribosylation factor-1 (Arf1). Arf1 guanine nucleotide cycling is required for glutamine to promote mTORC1 lysosomal localization and activation. The potential significance of this discovery is underscored by the fact that cancer cells are often “addicted” to glutamine, in part through mTORC1, to fuel cell growth and proliferation. We have identified two new components involved in this pathway, a known Arf1 GAP (Specific Aim 1) and a poorly characterized solute carrier (SLC) glutamine transporter (Specific Aim 2). We propose to investigate the role of these two new components in glutamine-induced mTORC1 activation. Furthermore, we will determine the significance of these components in mTORC1-mediated biology and disease (Specific Aim 3). Thus, the overall objective of this proposal is to decipher the molecular mechanisms by which glutamine signals to mTORC1. We anticipate that the proposed studies will yield new insights into mTORC1 regulation by glutamine and will uncover therapeutic targets to perturb mTORC1-mediated disease. !