Feedback loop and crosstalk in the mTORC1/2 signaling network

mTORC1/2 信号网络中的反馈环路和串扰

• 批准号: 10424504
• 负责人: Sang-Oh Yoon
• 金额: $ 35.85万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10424504
• 关键词: Apoptosis; Biochemical; Biological Models; CCI-779; Cell Line; Cell Survival; Cell model; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Clinical; Combined Modality Therapy; Complex; Cues; Data; Development; Diabetes Mellitus; Disease; Disease Progression; Drug resistance; Effectiveness; Environment; Epigenetic Process; Equilibrium; FDA approved; FRAP1 gene; Feedback; Focal Adhesion Kinase 1; Focal Adhesions; Foundations; Generations; Genetic; Genetic Translation; Growth; Heterogeneous-Nuclear Ribonucleoproteins; Hydrophobicity; In Vitro; Insulin-Like Growth Factor Receptor; Integrin alpha2; Integrins; Intracellular Membranes; Investigation; Knock-out; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Messenger RNA; Methods; Modification; Molecular; Nutrient; PDPK1 gene; Pathway interactions; Pharmacotherapy; Phosphorylation; Phosphotransferases; Play; Process; Production; Protein Biosynthesis; Proteome; Proteomics; Public Health; Publishing; Receptor Signaling; Research; Resistance; Role; Signal Transduction; Signaling Molecule; Sirolimus; Stress; System; Testing; Therapeutic; Translations; Work; base; cell growth; cell motility; cell type; clinical application; combinatorial; environmental stressor; genetically modified cells; in vivo; inhibitor; insight; interest; knock-down; malignant breast neoplasm; metabolomics; migration; mouse model; neoplastic cell; nervous system disorder; new therapeutic target; novel; novel therapeutic intervention; personalized medicine; protein expression; response; success; targeted treatment; tumor; tumor growth

Project Summary Deciphering feedback control and crosstalk between signaling molecules is critical to understand not only the mechanisms of cell growth/survival but also drug resistance in therapies. mTOR is regarded as one of the primary regulators of cellular fates by sensing and integrating cues from the cellular environment such as nutrients, energy, and stress. Thus, dysregulation of mTOR plays critical roles in the progression of diseases such as cancer, diabetes, and neurological disorders. Feedback signaling from mTOR has been of great interest as this suggests the major mechanisms by which cells adapt to the environmental stress and resist to drug treatment for their growth, proliferation, and survival. Many studies have focused on feedback signaling after partial mTOR complex 1 (mTORC1) inhibition by rapamycin, or knockout or knockdown of components in mTOR complexes. However, the feedback responses to mTOR kinase inhibition or suppression of both mTORC1/2 are not known. Because of the significant importance of mTOR feedback and crosstalk signaling, we have established a robust system to gain deep insight into the rewired signaling which determines cells’ survival and death strategies. Although it is generally believed that mTORC1/2 targeting will be a very promising tumor treatment, our studies using proteomics, metabolomics, glycomics, and biochemical/cellular methods reveal that dual mTORC1/2 inhibition leads to feedback activation of growth/survival signaling through integrin/ focal adhesion kinase/ insulin- like growth factor receptor signaling networks. Unexpectedly, mTORC1/2 suppression also mediates activation of Akt, one of the strongest survival kinase, by increasing phosphorylation at both its hydrophobic motif and turn motif. Considering the current paradigm that mTORC2 is the major kinase responsible for Akt phosphorylation at its hydrophobic motif, mTORC2-independent Akt activation in resistant cells highlights modification of the current paradigm that is extremely important for the successful clinical application of mTOR inhibitors. Also, surprisingly, the resistant cells increase migratory/invasive potential when mTORC1/2 is blocked. To elucidate our unexpected, but clinically pivotal observations, our specific aims are to determine the feedback activation mechanisms and crosstalk in mTOR signaling networks with focuses on 1) determining central molecules or pathway for mTORC2-independent Akt activation, 2) mechanisms by which cells induce cap-independent translation of survival factors and 3) mechanisms by which cells increase migratory and invasive potential following mTORC1/2 inhibition. Our proposed research is of therapeutic significance in that it will contribute to the deep understanding of why and how certain types of cells are sensitive, but other types are resistant to mTORC1/2 targeting, which will provide the basis for personalized medicine. Our study will also provide novel targets for which resistant tumor types can be treated with combinatorial drug treatments to be able to manage these tumors effectively. Thus, we expect that our study will provide a strong foundation to help develop successful mTORC1/2-targeted therapies.

项目摘要 信号分子之间的解密反馈控制和crostalk不仅要了解它们 细胞生长/生存的机制，也是疗法中的耐药性。 通过感测和整合细胞设想的线索，例如营养素，例如营养素， 能量和压力。 癌症，糖尿病和神经系统疾病。 提出细胞适应环境压力的主要机制 为了增长，增殖和生存。 雷帕霉素的复合物1（mTORC1）不自然，或mtor络合物中的组件敲除或敲除。 但是，尚不清楚对MTOR激酶吸入或促进性的反馈反应。 由于MTOR反馈和串扰信号的重要性，我们已经建立了一个强大的 系统以深入了解重新接线信号传导，该信号决定细胞的生存和死亡策略。 千叶普遍认为MTORC1/2靶向将是一种非常有前途的肿瘤治疗，我们的研究 使用蛋白质组学，代谢组学，糖化和生化/细胞方法表明Dualc1/2/2 抑制作用可通过整合素/局灶性粘附激酶/胰岛素 - 像生长因子受体信号网络一样，MTORC1/2抑制激活 Akt是最强的生存激酶之一，通过增加吞噬ATS疏水基序和转弯转弯转弯 假设MTORC2是负责Akt磷酸化的主要激酶 ATTS疏水基序，抗性细胞中MTORC2独立的AKT激活突出了修饰 当前的范式是成功临床应用MTOR抑制剂的范例。 令人惊讶的是，当MTORC1/2被阻止时，抗性细胞会增加迁移/侵入性 我们出乎意料但在临床上关键的观察结果，我们的具体目的是确定反馈激活 MTOR信号网络中的机理和串扰，重点是1）确定中央分子或 MTORC2独立AKT激活的途径，2）细胞诱导帽无关的机制 生存因子的翻译和3）细胞增益和侵入性潜力的机制 MTORC1/2抑制后，我们提出的研究具有治疗意义。 对某些类型的细胞为何和如何敏感的深刻理解，但其他类型具有抵抗力。 MTORC1/2靶向，这将为个性化医学提供基础。 可以通过组合药物治疗可以治疗抗性肿瘤类型的靶标 这些肿瘤有效。 成功的MTORC1/2靶向疗法。