Signal Transduction by PI3K/Akt/mTOR Pathway

 描述(申请人提供)：由磷脂酰肌醇3-激酶(PI3K)和下游丝氨酸/苏氨酸激酶Akt(也称为蛋白激酶B)调控的信号通路转导由胰岛素和生长因子编码的信号，并调节一些对细胞生理至关重要的过程。除了作为PI3K/Akt途径的关键下游成分外，雷帕霉素的机制靶点(MTOR)还整合了来自氨基酸、应激、氧气和能量水平的信号，影响大多数主要的细胞功能。对于PI3K、Akt和mTOR等调节多种细胞过程的关键节点信号分子，空间区划被认为是获得高信号特异性的重要机制。特别是，越来越多的证据表明，空间区划不仅对提高信号的特异性很重要，而且对PI3K/Akt/mTOR信号通路的功能也是必需的。然而，PI3K/Akt/mTOR信号的空间调控机制还不是很清楚，其潜在的机制也还不是很清楚。我们研究的总体目标是阐明PI3K/Akt/mTOR通路在空间上受到调控的分子和细胞机制。我们对PI3K/Akt/mTOR通路的质膜和核调控进行了一系列的初步研究，从而提出了PI3K/Akt/mTOR通路的信号活性存在于质膜和核室并受到特异性调控的假说。在这个方案中，基于我们的初步发现，我们将使用NIH3T3成纤维细胞、3T3 L1脂肪细胞和原代小鼠脂肪细胞作为细胞模型系统，并将生化和功能表征与生物传感器工程和超分辨荧光显微镜相结合，以解决以下目标：1)研究肌醇磷脂的空间区划；2)研究Akt的细胞调控；3)确定调节亚细胞区段mTORC1活性的机制。异常的PI3K/Akt/mTOR信号转导通路对临床疾病有广泛的意义。在胰岛素反应组织中，PI3K/Akt/mTOR通路在胰岛素效应中起着关键作用，PI3K/Akt/mTOR信号通路受损可能是糖尿病发生的易感因素。对PI3K/Akt/mTOR信号转导机制的了解对于开发针对这些临床疾病的治疗方法至关重要。

 DESCRIPTION (provided by applicant): The signaling pathway regulated by phosphatidylinositol 3-kinase (PI3K) and the downstream serine/threonine kinase Akt (also known as protein kinase B) transduces the signals encoded by insulin and growth factors and regulates a number of processes that are critical to cell physiology. In addition to serving as a critical downstream component in the PI3K/Akt pathway, the mechanistic target of rapamycin (mTOR) also integrates signals from amino acids, stress, oxygen and energy level to impact most major cellular functions. For such key-node signaling molecules as PI3K, Akt and mTOR, which regulate multiple cellular processes, spatial compartmentalization has been suggested to be an important mechanism for achieving high signaling specificity. In particular, accumulating evidence has suggested that spatial compartmentalization is not only important for enhancing signaling specificity, it is also required for the functioning of the PI3K/Akt/mTOR signaling pathway. However, spatial regulation of PI3K/Akt/mTOR signaling is not well defined and the underlying mechanisms remain poorly understood. The overall goal of our research is to elucidate the molecular and cellular mechanisms by which the PI3K/Akt/mTOR pathway is spatially regulated. We have performed a series of preliminary studies that focus on the plasma membrane and nuclear regulation of this pathway, which led to the hypothesis that signaling activities of the PI3K/Akt/mTOR pathway are present and specifically regulated in both plasma membrane and nuclear compartments. In this proposal, building upon our preliminary findings, we will use NIH3T3 fibroblasts, 3T3 L1 adipocytes, and primary mouse adipocytes as cellular model systems, and combine biochemical and functional characterization with biosensor engineering and super-resolution fluorescence microscopy to address the following aims: 1) To investigate spatial compartmentalization of phosphoinositides.; 2) To examine cellular regulation of Akt; 3) To determine the mechanisms that regulate mTORC1 activities in subcellular compartments. Dysregulated PI3K/Akt/mTOR signaling has widespread implications for clinical conditions. In insulin-responsive tissues, the pathway plays a pivotal role for the effects of insulin, and impaired signaling through PI3K/Akt/mTOR may predispose to the development of diabetes. A mechanistic understanding of signal transduction by PI3K/Akt/mTOR is crucial to developing therapeutic approaches for these clinical conditions.