Glutamine Sensing by mTORC1

好了！ 摘要 生物体感知细胞外和细胞内的营养物质的有效性，以控制代谢 处理并保持适当的细胞生长。营养感知的中断可能是灾难性的，通常会导致 人类疾病。也许在这一过程中最引人注目的参与者是雷帕霉素的哺乳动物靶标 (MTOR)蛋白激酶，多亚单位蛋白复合体的关键成分，称为mTOR复合体1 (MTORC1)。MTORC1活性增加在包括2型癌症在内的许多人类疾病中很常见 糖尿病、代谢紊乱和神经退行性变。小分子如雷帕霉素和雷帕霉素 抑制mTORC1的类似物(Rapalog)目前在临床上用于治疗疾病，但效果有限。 因此，阐明mtorc1调控的分子机制对临床治疗具有重要意义。 MTORC1驱动的疾病。氨基酸是mTORC1最强大的激活剂，多年来一直是 认为可以通过RAG GTP酶独占地激活mTORC1。我们最近发现了一种新的信号 谷氨酰胺向mTORC1传递信号的途径不依赖于RAG GTP酶，并需要另一个小分子 GTP酶，ADP核糖化因子-1(Arf1)。Arf1鸟嘌呤核苷酸循环是谷氨酰胺促进 MTORC1溶酶体的定位和激活。这一发现的潜在意义在以下方面得到了强调 癌细胞经常对谷氨酰胺上瘾，部分是通过mTORC1，以促进细胞生长和 扩散。我们已经确定了这一途径中涉及的两个新成分，一个已知的Arf1缺口(特异性 目的1)和一种特性不佳的溶质载体(SLC)谷氨酰胺转运体(特异性目标2)。我们建议 研究这两种新成分在谷氨酰胺诱导的mTORC1激活中的作用。此外，我们 将确定这些成分在mTORC1介导的生物学和疾病中的意义(特定目标 3)。因此，这项提议的总体目标是破译分子机制， 谷氨酰胺向mTORC1发出信号。我们预计，拟议的研究将对mTORC1产生新的见解 通过谷氨酰胺的调节，将发现干扰mTORC1介导的疾病的治疗靶点。 好了！

! 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. !