Regulation of mTOR complexes (mTORCs) by directly acting kinases

通过直接作用的激酶调节 mTOR 复合物 (mTORC)

基本信息

  • 批准号:
    9061678
  • 负责人:
  • 金额:
    $ 33.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-07-18 至 2018-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The mechanistic target of rapamycin (mTOR) responds to diverse environmental signals to control essential cellular functions, playing critical roles in processes related to metabolism, tumorigenesis, and immune function. mTOR constitutes the catalytic core of two functionally distinct signaling complexes, mTORC1 and mTORC2: mTORC1 promotes anabolic cellular processes; while significantly less well understood; mTORC2 promotes cell survival and modulates the actin cytoskeleton. Despite the clear physiologic and therapeutic importance of mTOR, fundamental gaps exist in our knowledge regarding cellular mTOR regulation, especially with regard to the molecular pathways that regulate mTOR activity. Exciting recent work from our laboratory revealed that mTOR phosphorylation plays an important and previously unrecognized role in mTORC1 function. Using phospho specific antibodies and an in vitro kinome screen as tools, we discovered that TBK1/IKKe (kinases that promote innate immune signaling and the host defense response) and AMPK (a kinase that responds to energetic stress) phosphorylate mTOR on distinct sites. Importantly, these phosphorylation events occur in response to physiological signals in cultured cells and in vivo (i.e. mice). Our preliminary data indicate that TBK1/IKKe-mediated phosphorylation of mTOR S2159 promotes mTORC1 signaling while AMPK promotes mTORC2 signaling in response to acute energetic stress. In this application we propose to elucidate roles for these physiologically and pathologically significant signaling molecules in the cellular regulation and function of mTOR. In Aim 1, we investigate the hypothesis that TBK1 and IKKe act directly on mTORC1 to promote growth factor responses and innate immunity; in Aim 2, we investigate the hypothesis that AMPK acts directly on mTORC2 to suppress apoptosis and enhance mitochondrial function to maintain energy homeostasis during acute energetic stress. Emerging data suggest that TBK1/IKKe contribute to chronic inflammatory diseases and obesity-linked insulin resistance; moreover, cancer cells hijack TBK1/IKKe to promote tumorigenesis. As cellular TBK1/IKKe signaling networks remain poorly understood, this research focused on the TBK1/IKKe-mTORC1 axis has potential to impact the future clinical management of chronic inflammatory diseases and cancer. In response to insufficient ATP levels, AMPK stimulates energy producing catabolic and suppresses energy consuming anabolic pathways. This research focused on the AMPK-mTORC2 axis may explain in part the emerging paradox that AMPK can act as a tumor suppressor (by inhibiting cellular anabolism) and a tumor promoter (by inhibiting apoptosis), depending on cellular context. This work will unveil novel regulatory paradigms that directly impact mTOR and will reveal previously unknown links between mTOR and the processes controlled by these kinases, including cell survival, cell metabolism, tumorigenesis, and innate immunity. As the signals that regulate mTORC2 remain virtually unknown, the identification of AMPK as an mTORC2 activator represents a particularly important milestone.
描述(申请人提供):雷帕霉素(MTOR)的机械靶标对不同的环境信号作出反应,以控制基本的细胞功能,发挥关键作用 在与新陈代谢、肿瘤发生和免疫功能相关的过程中的作用。MTOR构成了两个不同功能的信号复合体的催化核心,mTORC1和mTORC2:mTORC1促进细胞的合成代谢过程;而mTORC2则促进细胞存活并调节肌动蛋白细胞骨架。尽管mTOR具有明确的生理和治疗重要性,但我们对细胞mTOR的调节,尤其是对调节mTOR活性的分子途径的认识存在着根本的差距。我们实验室最近令人振奋的工作表明,mTOR磷酸化在mTORC1功能中发挥着以前未被认识到的重要作用。以磷酸化特异性抗体和体外动态组筛选为工具,我们发现TBK1/IKKE(促进天然免疫信号和宿主防御反应的激酶)和AMPK(一种对能量应激做出反应的激酶)在不同的位点上磷酸化mTOR。重要的是,在培养细胞和体内(即小鼠),这些磷酸化事件发生在对生理信号的响应中。我们的初步数据显示 在急性能量应激中,TBK1/IKKE介导的mTOR S2159的磷酸化促进mTORC1信号转导,而AMPK则促进mTORC2信号转导。在这一应用中,我们建议阐明这些具有生理和病理意义的信号分子在细胞调节和mTOR功能中的作用。在目标1中,我们研究了TBK1和IKKE直接作用于mTORC2以促进生长因子反应和天然免疫的假说;在目标2中,我们研究了AMPK直接作用于mTORC2以抑制细胞凋亡和增强线粒体功能以维持急性能量应激时的能量平衡的假说。新出现的数据表明,TBK1/IKKE有助于慢性炎症性疾病和肥胖相关的胰岛素抵抗;此外,癌细胞劫持TBK1/IKKE促进肿瘤发生。由于细胞内的TBK1/IKKE信号网络仍然知之甚少,这项聚焦于TBK1/IKKE-mTORC1轴的研究有可能影响未来慢性炎症性疾病和癌症的临床治疗。在ATP水平不足的情况下,AMPK刺激能量产生分解代谢,抑制能量消耗合成代谢途径。这项专注于AMPK-mTORC2轴的研究可能部分解释了AMPK可以作为肿瘤抑制因子(通过抑制细胞合成代谢)和肿瘤促进剂(通过抑制细胞凋亡)的新出现的悖论,这取决于细胞环境。这项工作将揭示直接影响mTOR的新的调控范式,并揭示mTOR与这些激酶控制的过程之间先前未知的联系,包括细胞生存、细胞代谢、肿瘤发生和先天免疫。由于调控mTORC2的信号实际上仍不清楚,AMPK被确定为mTORC2激活剂是一个特别重要的里程碑。

项目成果

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Diane C. Fingar其他文献

Diane C. Fingar的其他文献

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{{ truncateString('Diane C. Fingar', 18)}}的其他基金

Regulation and function of TBK1-mTOR crosstalk
TBK1-mTOR串扰的调控和功能
  • 批准号:
    10711161
  • 财政年份:
    2023
  • 资助金额:
    $ 33.71万
  • 项目类别:
Integration of innate immune function and metabolism by the TBK1-mTOR axis
TBK1-mTOR 轴整合先天免疫功能和代谢
  • 批准号:
    10161014
  • 财政年份:
    2020
  • 资助金额:
    $ 33.71万
  • 项目类别:
Unexpected role for AMPK and mTORC1 in cellular adaptation to nutrient stress
AMPK 和 mTORC1 在细胞适应营养胁迫中的意外作用
  • 批准号:
    10532375
  • 财政年份:
    2020
  • 资助金额:
    $ 33.71万
  • 项目类别:
Unexpected role for AMPK and mTORC1 in cellular adaptation to nutrient stress
AMPK 和 mTORC1 在细胞适应营养胁迫中的意外作用
  • 批准号:
    10790204
  • 财政年份:
    2020
  • 资助金额:
    $ 33.71万
  • 项目类别:
Unexpected role for AMPK and mTORC1 in cellular adaptation to nutrient stress
AMPK 和 mTORC1 在细胞适应营养胁迫中的意外作用
  • 批准号:
    10321301
  • 财政年份:
    2020
  • 资助金额:
    $ 33.71万
  • 项目类别:
Regulation of mTOR complexes (mTORCs) by directly acting kinases
通过直接作用的激酶调节 mTOR 复合物 (mTORC)
  • 批准号:
    8894499
  • 财政年份:
    2014
  • 资助金额:
    $ 33.71万
  • 项目类别:
Regulation of mTOR complexes (mTORCs) by directly acting kinases
通过直接作用的激酶调节 mTOR 复合物 (mTORC)
  • 批准号:
    9267977
  • 财政年份:
    2014
  • 资助金额:
    $ 33.71万
  • 项目类别:
Direct regulation of mTORC1 and mTORC2 by the IKK-related kinases TBK1 and IKKe
IKK 相关激酶 TBK1 和 IKKe 对 mTORC1 和 mTORC2 的直接调节
  • 批准号:
    8800805
  • 财政年份:
    2014
  • 资助金额:
    $ 33.71万
  • 项目类别:
Direct regulation of mTORC1 and mTORC2 by the IKK-related kinases TBK1 and IKKϵ
IKK 相关激酶 TBK1 和 IKKϵ 对 mTORC1 和 mTORC2 的直接调节
  • 批准号:
    9304201
  • 财政年份:
    2014
  • 资助金额:
    $ 33.71万
  • 项目类别:
Direct regulation of mTORC1 and mTORC2 by the IKK-related kinases TBK1 and IKKe
IKK 相关激酶 TBK1 和 IKKe 对 mTORC1 和 mTORC2 的直接调节
  • 批准号:
    9104154
  • 财政年份:
    2014
  • 资助金额:
    $ 33.71万
  • 项目类别:

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