Rapamycin-Insensitive Signaling by Rictor-mTOR

描述（由申请人提供）：质量积累（细胞生长）的过程是细胞、器官和身体大小的重要调节因子，在癌症和糖尿病等多种疾病中可以解除调节。我们的实验室正在研究哺乳动物TOR（mTOR）通路，这是一种信号网络，可以调节生长因子，压力，营养和代谢的生长。mTOR通路在医学上很重要，因为它是FDA批准的免疫抑制剂雷帕霉素的靶点，雷帕霉素也可以预防血管成形术后的血管再狭窄，并具有作为抗癌剂的潜力。此外，最近的工作表明，在癌症易感遗传综合征结节性硬化症中，mTOR通路变得过度活跃和失调。 在过去的几年里，我们一直在研究人类组织培养细胞中mTOR通路的生物化学，并发现了两种不同的含mTOR的蛋白质复合物。第一个包含mTOR和两种新蛋白，raptor和GbL，并介导mTOR的雷帕霉素敏感作用（如S6K1磷酸化）。第二个复合物也包含mTOR和GbetaL，但不是raptor，而是另一种我们命名为rictor的新蛋白质。我们提出的工作重点是了解rictor蛋白的生化，细胞和有机体功能，rictor蛋白是雷帕霉素不敏感mTOR通路的核心成分。虽然我们对这一途径知之甚少相比，雷帕霉素敏感的分支，我们的初步结果表明，rictor起着关键作用，在控制细胞的存活和增殖，通过调节这些过程中的已知效应物的活动。我们意外发现mTOR具有雷帕霉素不敏感的功能，这表明mTOR激酶活性的直接抑制剂可能具有与雷帕霉素不同的药理作用和临床应用。因此，我们提出的工作将导致我们对调节细胞生长和存活的分子机制的理解取得重要进展，并可用于解决这些过程失调的疾病。

DESCRIPTION (provided by applicant): The process of mass accumulation (cell growth) is an important regulator of cell, organ, and body size and can be deregulated in diverse diseases such as cancer and diabetes. Our lab is studying the mammalian TOR (mTOR) pathway, a signaling network that regulates growth in response to growth factors, stress, nutrients, and metabolism. The mTOR pathway is medically important, as it is the target of the FDA-approved immunosuppressant rapamycin that also prevents vessel restenosis after angioplasty and has potential as an anti-cancer agent. Moreover, recent work suggests that in the cancer-prone genetic syndrome tuberous sclerosis complex the mTOR pathway becomes hyperactive and deregulated. Over the last few years we have been studying the biochemistry of the mTOR pathway in human tissue culture cells and have discovered two distinct mTOR-containing protein complexes. The first contains mTOR and two novel proteins, raptor and GbL, and mediates the rapamycin-sensitive roles of mTOR (like S6K1 phosphorylation). The second complex also contains mTOR and GbetaL but, instead of raptor, another novel protein that we named rictor. Our proposed work focuses on understanding the biochemical, cellular and organismal functions of the rictor protein, the central component of the rapamycin-insensitive mTOR pathway. Although we know little about this pathway compared to the rapamycin-sensitive branch, our preliminary results suggest that rictor plays critical roles in the control of cell survival and proliferation by regulating the activity of known effectors of these processes. Our unexpected discovery that mTOR has rapamycin-insensitive functions suggests that direct inhibitors of the mTOR kinase activity will likely have different pharmacological effects and clinical applications than rapamycin. Therefore, our proposed work will lead to an important advance in our understanding of the molecular mechanisms that regulate cell growth and survival and that may be exploited to tackle diseases in which these processes are deregulated.