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

基本信息

批准号：
10194420
负责人：
Sang-Oh Yoon
金额：
$ 36.58万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
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/10194420
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/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

项目摘要

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.

项目概要破译信号分子之间的反馈控制和串扰对于理解不仅是至关重要的细胞生长/存活的机制以及治疗中的耐药性被认为是主要的机制之一。通过感知和整合来自细胞环境的线索（例如营养物质）来调节细胞命运，因此，mTOR 的失调在疾病的进展中起着至关重要的作用，例如 mTOR 的反馈信号引起了人们的极大兴趣。揭示了细胞适应环境压力和抵抗药物治疗的主要机制许多研究都集中于部分 mTOR 后的反馈信号。雷帕霉素抑制复合物 1 (mTORC1)，或敲除或敲低 mTOR 复合物中的成分。然而，对 mTOR 激酶抑制或 mTORC1/2 抑制的反馈反应尚不清楚。由于 mTOR 反馈和串扰信号的重要性，我们建立了一个强大的系统来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 mTORC1/2 靶向将是一种非常有前途的肿瘤治疗方法，但我们的研究使用蛋白质组学、代谢组学、糖组学和生化/细胞方法揭示双 mTORC1/2 抑制导致通过整合素/粘着斑激酶/胰岛素反馈激活生长/生存信号出乎意料的是，mTORC1/2 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角的磷酸化考虑到当前的范例，mTORC2 是负责 Akt 磷酸化的主要激酶。在其疏水基序上，耐药细胞中不依赖于 mTORC2 的 Akt 激活突出显示了当前的范例对于 mTOR 抑制剂的成功临床应用极其重要。令人惊讶的是，当 mTORC1/2 被阻断时，耐药细胞的迁移/侵袭潜力增加。我们意想不到但临床关键的观察结果，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，重点关注 1) 确定中心分子或 mTORC2 独立的 Akt 激活途径，2) 细胞诱导 cap 独立的机制生存因子的翻译和 3) 细胞增加迁移和侵袭潜力的机制 mTORC1/2 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某些类型的细胞为何以及如何敏感，而其他类型的细胞则具有抵抗力 mTORC1/2靶向，这将为个性化医疗提供基础，也将提供新颖的。可以通过组合药物治疗来治疗耐药肿瘤类型的目标，以便能够控制因此，我们期望我们的研究将为帮助发展提供坚实的基础。成功的 mTORC1/2 靶向疗法。