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: 9797783
• 负责人: Sang-Oh Yoon
• 金额: $ 37.81万
• 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/9797783
• 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; genetically modified cells; in vivo; inhibitor/antagonist; 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 破译信号分子之间的反馈控制和串扰不仅对理解信号分子的功能至关重要， 细胞生长/存活的机制以及治疗中的耐药性。mTOR被认为是主要的 通过感知和整合来自细胞环境的线索，如营养素， 能量和压力因此，mTOR的失调在疾病的进展中起关键作用， 癌症糖尿病和神经系统疾病来自mTOR的反馈信号已经引起了极大的兴趣，因为这 表明细胞适应环境压力和抵抗药物治疗的主要机制 它们的生长增殖和生存。许多研究都集中在部分mTOR后的反馈信号 通过雷帕霉素抑制mTOR复合物1（mTORC 1），或敲除或敲低mTOR复合物中的组分。 然而，对mTOR激酶抑制或抑制mTORC 1/2的反馈反应尚不清楚。 由于mTOR反馈和串扰信号的显著重要性，我们已经建立了一个鲁棒的 该系统可以深入了解决定细胞生存和死亡策略的重新连接信号。 尽管人们普遍认为mTORC 1/2靶向治疗将是一种非常有前途的肿瘤治疗方法，但我们的研究表明， 利用蛋白质组学、代谢组学、糖组学和生化/细胞方法，揭示了双重mTORC 1/2 抑制通过整联蛋白/粘着斑激酶/胰岛素导致生长/存活信号传导的反馈激活， 比如生长因子受体信号网络。出乎意料的是，mTORC 1/2抑制也介导激活 Akt是最强的生存激酶之一，通过增加其疏水基序和转折点的磷酸化， 母题考虑到mTORC 2是负责Akt磷酸化的主要激酶的当前范例， 在其疏水基序上，耐药细胞中的mTORC 2非依赖性Akt活化突出了 目前的范例，这是非常重要的mTOR抑制剂的成功临床应用。还有， 令人惊讶的是，当mTORC 1/2被阻断时，抗性细胞增加了迁移/侵袭潜力。阐明 我们意想不到的，但临床关键的观察，我们的具体目标是确定反馈激活 mTOR信号网络中的机制和串扰，重点是1）确定中心分子或 mTORC 2非依赖性Akt活化的途径，2）细胞诱导帽非依赖性Akt活化的机制， 存活因子的翻译和3）细胞增加迁移和侵袭潜力的机制 mTORC 1/2抑制后。我们提出的研究具有治疗意义，因为它将有助于 深入了解为什么以及如何某些类型的细胞是敏感的，但其他类型的细胞是抵抗 mTORC 1/2靶向，这将为个性化医疗提供基础。我们的研究还将提供新的 可以用组合药物治疗来治疗耐药肿瘤类型的靶点， 这些肿瘤有效。因此，我们希望我们的研究将提供一个坚实的基础，以帮助发展 成功的mTORC 1/2靶向治疗。