mTOR Signaling Pathways

mTOR 信号通路

• 批准号: 7450741
• 负责人: THOMAS W STURGILL
• 金额: $ 33.3万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-21 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7450741
• 关键词: 1-Phosphatidylinositol 3-Kinase; Actins; Adenylate Cyclase; Adipocytes; Amino Acids; Anabolism; Antibodies; Antigen-Antibody Complex; Binding; Carbamyl Phosphate; Cell Proliferation; Cell physiology; Cells; Complex; Cyclic AMP; Cytoskeletal Modeling; Cytoskeleton; Dictyostelium discoideum; Enzymes; Event; GTP-Binding Protein beta Subunits; Genetic Translation; Growth Factor; Heterotrimeric G Protein Subunit; Homologous Protein; Immunosuppressive Agents; Incubated; Indium; Insulin; Insulin Resistance; KRP protein; Ligase; Malignant Neoplasms; Mediating; Mutate; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathway interactions; Peptide Initiation Factors; Phosphorylation; Phosphorylation Site; Phosphotransferases; Production; Progress Reports; Protein Binding; Protein Kinase; Proteins; Pyrimidine; Pyrimidines; Raptors; Rate; Regulatory Element; Role; Screening procedure; Signal Transduction; Sirolimus; Site; Testing; Translations; Yeasts; base; cell growth; human FRAP1 protein; mTOR Inhibitor; mTOR Signaling Pathway; mTOR protein; novel; polymerization; prevent; response; rho; yeast protein; yeast two hybrid system

DESCRIPTION (provided by applicant): mTOR is a protein kinase that signals in pathways involved in the control of cell growth and proliferation. mTOR function is stimulated by both insulin/growth factors and certain amino acids; however, just how the essential kinase activity is controlled in cells is a mystery. Inappropriate activation of mTOR leads to insulin resistance, a contributing factor in the pathogenesis of type 2 diabetes. mTOR inhibitors are used as immunosuppressants, and trials are underway to evaluate their efficacy in treating cancer. Clearly, there is a need to understand better the control and function of mTOR. Two mTOR signaling complexes were recently discovered. mTORC1 contains mTOR, mLST8 (homologous to G protein beta subunits), and raptor, which binds substrates phosphorylated by mTOR. Rapamycin inhibits mTORC1, which probably mediates most of the functions now attributed to mTOR. mTORC2 is not inhibited by rapamycin, and the downstream targets of mTORC2 are largely unknown. mTORC2 contains mTOR, mLST8, and pianissimo, a protein originally implicated in the control of adenylate cyclase. We have searched for new mTOR interacting proteins by yeast two hybrid screening and by performing mass spectrometric (MS) analyses of proteins that immunoprecipitate with mTOR. In investigating an interaction involving eIF3, a key translation initiation factor, we discovered a dramatic rapamycin-sensitive action of insulin to stimulate the association of eIF3 and eIF4G. Aim 1 is to investigate this novel and potentially important effect of insulin. Aim 2 is to investigate the function and control of mTORC1 and mTORC2. We will test the hypothesis that insulin increases mTORC1 activity by increasing substrate binding to raptor. Based on preliminary findings, we also propose to test the hypothesis that insulin promotes formation of mTORC2, to identify the phosphorylation sites in pianissimo, and to investigate connections between mTORC2 and cAMP production. Aim 3 is to identify new upstream effectors and downstream targets of mTORC1 and mTORC2. We will investigate novel candidate mTOR-interacting proteins identified by MS. Finally, to understand better the mechanisms involved in mTORC2, we propose to identify pianissimo-interacting proteins.

描述（由申请人提供）：mTOR是一种蛋白激酶，在参与控制细胞生长和增殖的途径中发出信号。mTOR功能受到胰岛素/生长因子和某些氨基酸的刺激;然而，细胞中基本激酶活性是如何控制的仍然是一个谜。mTOR的不适当激活导致胰岛素抵抗，这是2型糖尿病发病机制中的一个促成因素。mTOR抑制剂被用作免疫抑制剂，并且正在进行试验以评估它们在治疗癌症中的功效。显然，有必要更好地了解mTOR的控制和功能。最近发现了两种mTOR信号复合物。mTORC 1包含mTOR、mLST 8（与G蛋白β亚基同源）和raptor，raptor结合mTOR磷酸化的底物。雷帕霉素抑制mTORC 1，其可能介导现在归因于mTOR的大部分功能。mTORC 2不被雷帕霉素抑制，mTORC 2的下游靶点在很大程度上是未知的。mTORC 2包含mTOR、mLST 8和panissimo，panissimo是一种最初参与腺苷酸环化酶控制的蛋白质。我们已经通过酵母双杂交筛选和通过对与mTOR免疫沉淀的蛋白质进行质谱（MS）分析来寻找新的mTOR相互作用蛋白。在研究涉及eIF 3（一种关键的翻译起始因子）的相互作用时，我们发现胰岛素具有显著的雷帕霉素敏感性作用，可刺激eIF 3和eIF 4G的结合。目的1是研究胰岛素的这种新的和潜在的重要作用。目的二是研究mTORC 1和mTORC 2的功能和调控。我们将检验胰岛素通过增加底物与raptor的结合来增加mTORC 1活性的假设。基于初步的研究结果，我们还建议测试的假设，胰岛素促进mTORC 2的形成，以确定panissimo的磷酸化位点，并调查mTORC 2和cAMP的生产之间的连接。目的3是鉴定mTORC 1和mTORC 2的新的上游效应物和下游靶标。我们将研究新的候选人mTOR相互作用的蛋白质MS确定。最后，为了更好地了解mTORC 2参与的机制，我们建议确定pianissimo相互作用的蛋白质。