Signal Transduction by PI3K/Akt/mTOR Pathway

 描述（由申请人提供）：由磷脂酰肌醇3-激酶（PI 3 K）和下游丝氨酸/苏氨酸激酶Akt（也称为蛋白激酶B）调节的信号传导途径转导由胰岛素和生长因子编码的信号，并调节对细胞生理学至关重要的许多过程。除了作为PI 3 K/Akt通路中的关键下游组分外，雷帕霉素的机制靶标（mTOR）还整合来自氨基酸、应激、氧和能量水平的信号以影响大多数主要细胞功能。对于调节多个细胞过程的关键节点信号分子如PI 3 K、Akt和mTOR，空间区室化已被认为是实现高信号特异性的重要机制。特别是，越来越多的证据表明，空间区室化不仅对增强信号特异性很重要，而且对PI 3 K/Akt/mTOR信号通路的功能也是必需的。然而，PI 3 K/Akt/mTOR信号传导的空间调节尚未被很好地定义，并且其潜在机制仍然知之甚少。本研究的总体目标是阐明PI 3 K/Akt/mTOR通路空间调控的分子和细胞机制。 我们已经进行了一系列的初步研究，重点是质膜和核调节这一途径，这导致的假设，PI 3 K/Akt/mTOR途径的信号转导活动的存在，并在质膜和核隔室的具体调节。在本研究中，我们将以NIH 3 T3成纤维细胞、3 T3 L1脂肪细胞和原代小鼠脂肪细胞为细胞模型系统，联合收割机生物传感器工程和超分辨率荧光显微镜技术，研究磷酸肌醇的空间区室化。2)研究Akt的细胞调节; 3）确定亚细胞区室中调节mTORC 1活性的机制。 PI 3 K/Akt/mTOR信号转导失调对临床病症具有广泛的影响。在胰岛素应答组织中，该通路对胰岛素的作用起关键作用，并且通过PI 3 K/Akt/mTOR的信号传导受损可能易患糖尿病。通过PI 3 K/Akt/mTOR的信号转导的机制理解对于开发这些临床病症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.