mTOR Signaling Pathways

mTOR 信号通路

基本信息

批准号：
7633146
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
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-21 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7633146
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 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

项目摘要

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，在涉及细胞生长和增殖控制的途径中发出信号。 mTOR 功能受到胰岛素/生长因子和某些氨基酸的刺激；然而，细胞中关键激酶活性是如何控制的仍然是个谜。 mTOR 的不当激活会导致胰岛素抵抗，这是 2 型糖尿病发病机制的一个促成因素。 mTOR 抑制剂被用作免疫抑制剂，并且正在进行试验来评估其治疗癌症的功效。显然，需要更好地了解 mTOR 的控制和功能。最近发现了两种 mTOR 信号复合物。 mTORC1 包含 mTOR、mLST8（与 G 蛋白 β 亚基同源）和 raptor，后者与 mTOR 磷酸化的底物结合。雷帕霉素抑制 mTORC1，mTORC1 可能介导目前归因于 mTOR 的大部分功能。 mTORC2 不受雷帕霉素抑制，并且 mTORC2 的下游靶标很大程度上未知。 mTORC2 包含 mTOR、mLST8 和 pianissimo（一种最初与腺苷酸环化酶控制有关的蛋白质）。我们通过酵母两种杂交筛选以及对与 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。在研究涉及关键翻译起始因子 eIF3 的相互作用时，我们发现胰岛素具有显着的雷帕霉素敏感性作用，可以刺激 eIF3 和 eIF4G 的结合。目标 1 是研究胰岛素的这种新颖且潜在的重要作用。目标 2 是研究 mTORC1 和 mTORC2 的功能和控制。我们将测试胰岛素通过增加与 raptor 的底物结合来增加 mTORC1 活性的假设。基于初步研究结果，我们还建议测试胰岛素促进 mTORC2 形成的假设，以确定 pianissimo 中的磷酸化位点，并研究 mTORC2 和 cAMP 产生之间的联系。目标 3 是确定 mTORC1 和 mTORC2 的新上游效应器和下游靶标。我们将研究通过 MS 鉴定的新型候选 mTOR 相互作用蛋白。最后，为了更好地了解 mTORC2 所涉及的机制，我们建议鉴定极弱相互作用蛋白。