Signal Transduction to P70 S6 Kinase 1

描述(由申请人提供)：mTOR蛋白激酶复合体1(MTORC1)的信号在正常的分化和发育以及调节正常的细胞内稳态中发挥着重要作用。当调控不当时，这种信号系统与多种与新陈代谢改变相关的疾病有关，如衰老、糖尿病、肥胖、免疫紊乱、神经退行性变、肌肉生理学疾病、良性肿瘤综合征和恶性肿瘤。上一个资助期的总体目标是开始在分子和生化水平上定义mTOR信号如何通过调节蛋白质合成来控制细胞生长，开始努力定义信号格局(mTORC1磷酸化蛋白质组)和mTORC1下游调控的生物过程，并开发高通量、基于RNAi的筛选，以广泛评估mTORC1如何受到生长因子、癌基因、肿瘤抑制因子、营养物质、压力和细胞能量状态的调控。我们在各方面的持续成功为目前的提议奠定了基础。从我们的创新方法和拟议的研究中，我们将阐明C3G和各种GEF在mTORC1激活中的未知角色(目标1)；定义AA如何以及为什么调节RAG和/或mTORC1的核进入(目标2)；并确定mTORC1如何调控mRNA生物发生的新的分子细节(目标3)。通过这些目标，我们将识别和表征mTORC1的新的上游调控因子和下游效应因子，进一步解释mTORC1的不当调控如何导致多种人类疾病。此外，我们的研究将导致识别新的生物标记物和潜在的治疗靶点，用于检测和干预由不正确的mTOR信号引起的人类疾病。

DESCRIPTION (provided by applicant): Signaling by the mTOR protein kinase complex 1 (mTORC1) plays a major role in proper differentiation and development, and in regulating normal cellular homeostasis. When improperly regulated this signaling systems has been linked to a variety of diseases associated with altered metabolism such as aging, diabetes, obesity, immune disorders, neurodegeneration, diseased muscle physiology, benign tumor syndromes and malignant cancers. The overall goals of the previous funding period were to begin to define at a molecular and biochemical level how mTOR signaling controls cell growth through the regulation of protein synthesis, to initiate efforts to define the signaling landscape (the mTORC1 phospho-proteome) and biological processes regulated downstream of mTORC1, and to develop high-throughput, RNAi-based screens to extensively evaluate how mTORC1 is regulated by growth factors, oncogenes, tumor suppressors, nutrients, stress and cellular energy status. Our continuing success on all fronts has provided the foundation for the current proposal. From our innovative approaches and proposed research, we will illuminate previously unknown roles of C3G and various GEFs in mTORC1 activation (aim #1); define how and why AAs regulate the Ran gradient and the nuclear entry of Rags and/or mTORC1 (aim #2); and identify new molecular details of how mTORC1 regulates mRNA biogenesis (aim #3). Through these aims, we will identify and characterize new upstream regulators and downstream effectors of mTORC1, further explaining how improper regulation of mTORC1 contributes to a variety of human diseases. Furthermore, our research will result in the identification of new biomarkers and potential therapeutic targets needed for detection and intervention in human diseases resulting from improper mTOR signaling.