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:9797783
- 负责人:
- 金额:$ 37.81万
- 依托单位:
- 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:
- 关键词:ApoptosisBiochemicalBiological ModelsCCI-779Cell LineCell SurvivalCell modelCell physiologyCellsCellular Metabolic ProcessCessation of lifeClinicalCombined Modality TherapyComplexCuesDataDevelopmentDiabetes MellitusDiseaseDisease ProgressionDrug resistanceEffectivenessEnvironmentEpigenetic ProcessEquilibriumFDA approvedFRAP1 geneFeedbackFocal Adhesion Kinase 1Focal AdhesionsFoundationsGenerationsGeneticGenetic TranslationGrowthHeterogeneous-Nuclear RibonucleoproteinsHydrophobicityIn VitroInsulin-Like Growth Factor ReceptorIntegrin alpha2IntegrinsIntracellular MembranesInvestigationKnock-outMalignant NeoplasmsMass Spectrum AnalysisMediatingMessenger RNAMethodsModificationMolecularNutrientPDPK1 genePathway interactionsPharmacotherapyPhosphorylationPhosphotransferasesPlayProcessProductionProtein BiosynthesisProteomeProteomicsPublic HealthPublishingReceptor SignalingResearchResistanceRoleSignal TransductionSignaling MoleculeSirolimusStressSystemTestingTherapeuticTranslationsWorkbasecell growthcell motilitycell typeclinical applicationcombinatorialgenetically modified cellsin vivoinhibitor/antagonistinsightinterestknock-downmalignant breast neoplasmmetabolomicsmigrationmouse modelneoplastic cellnervous system disordernew therapeutic targetnovelnovel therapeutic interventionpersonalized medicineprotein expressionresponsesuccesstargeted treatmenttumortumor 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.
项目摘要
信号分子之间的解密反馈控制和串扰,不仅要了解
细胞生长/生存的机制,也是疗法中的耐药性。 MTOR被认为是主要的
通过感测和整合细胞环境(例如营养素)的线索来调节细胞命运的调节因子,
能量和压力。 MTOR的失调在疾病的进展中起着关键作用
癌症,糖尿病和神经系统疾病。 MTOR的反馈信号引起了极大的兴趣
提出细胞适应环境压力和对药物治疗的抗性的主要机制
为了增长,增殖和生存。许多研究重点是部分MTOR后的反馈信号传导
雷帕霉素抑制复合物1(MTORC1),或MTOR复合物中成分的敲除或敲除。
但是,尚不清楚对MTOR激酶抑制或抑制MTOR抑制的反馈反应。
由于MTOR反馈和串扰信号的重要性,我们建立了一个强大的
系统以深入了解重新连接的信号传导,该信号决定细胞的生存和死亡策略。
尽管通常认为MTORC1/2靶向将是一种非常有前途的肿瘤治疗,但我们的研究
使用蛋白质组学,代谢组学,糖果学和生化/细胞方法表明,双MTORC1/2
抑制作用导致通过整合素/局灶性粘合剂激酶/胰岛素 -
像生长因子受体信号网络一样。出乎意料的是,MTORC1/2抑制也介导了激活
通过在其疏水基序上增加磷酸化和转弯,Akt是强生存激酶之一
主题。考虑到当前MTORC2是负责AKT磷酸化的主要激酶的范式
在其疏水基序中,抗性细胞中非依赖MTORC2的AKT激活突出了修饰
当前的范式对于成功的MTOR抑制剂的临床应用至关重要。还,
令人惊讶的是,当MTORC1/2被阻断时,抗性细胞会增加迁移/侵入性。阐明
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信号网络中的机制和串扰,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)细胞增加迁移和侵入性潜力的机制
在MTORC1/2抑制之后。我们提出的研究具有热重要性,因为它将有助于
对某些类型的细胞为何和如何敏感的深刻理解,但其他类型对
MTORC1/2靶向,这将为个性化医学提供基础。我们的研究还将提供小说
可以通过组合药物治疗来治疗抗性肿瘤类型的靶标
这些肿瘤有效。这就是我们希望我们的研究将为发展提供坚实的基础
成功的MTORC1/2靶向疗法。
项目成果
期刊论文数量(0)
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Sang-Oh Yoon其他文献
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{{ truncateString('Sang-Oh Yoon', 18)}}的其他基金
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:
10651817 - 财政年份:2019
- 资助金额:
$ 37.81万 - 项目类别:
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:
10194420 - 财政年份:2019
- 资助金额:
$ 37.81万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 37.81万 - 项目类别:
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