Dissection of the TORC1 Signaling Network in Yeast
酵母中 TORC1 信号网络的剖析
基本信息
- 批准号:9235459
- 负责人:
- 金额:$ 36.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-30 至 2021-02-28
- 项目状态:已结题
- 来源:
- 关键词:Amino AcidsBiochemicalBiologyCellsCellular Metabolic ProcessComplexDataDefectDevelopmentDiabetes MellitusDiseaseDissectionDrug DesignEnsureEukaryotaEventGenomicsGlucoseGrantGrowthHandHormonesHumanLightLysosomesMalignant NeoplasmsMapsMembrane ProteinsMental DepressionModelingMusNitrogenNoiseNutrientObesityOrganismPathogenicityPathway interactionsPharmaceutical PreparationsPhosphorylationPhosphotransferasesPlayPost-Translational Protein ProcessingProteinsPublic HealthRaptorsReactionRegulationResearchRoleSaccharomyces cerevisiaeSaccharomycetalesSignal TransductionSirolimusStarvationStressStructureSystemTestingTimeVacuoleWorkYeastscell growthexperimental studyfallsflyfungusinnovationinsightmanmutantnovelpathogenprion-likeresponsetau Proteinstau-1
项目摘要
SUMMARY/ABSTRACT
The Target of Rapamycin kinase Complex I (TORC1) is a key regulator of cell growth and metabolism in
eukaryotes. Work carried out over the last 15 years has shed light on the mechanisms underlying hormone
and amino acid signaling to TORC1, but it is still unclear how other key signals, such as glucose starvation, are
transmitted to this highly conserved complex. In the last grant period, we examined TORC1 signaling in
budding yeast and found that glucose starvation leads to rapid inactivation of the TORC1 pathway. Then, in a
slower reaction (τ=10min), TORC1 falls apart and the key regulatory component Kog1/Raptor moves into a
single body on the edge of the vacuole/lysosome. The latter event is driven (in part) by AMPK/Snf1 dependent
phosphorylation of Kog1 at Ser 491/494, and two nearby prion-like motifs. Kog1-bodies then serve to increase
the threshold of TORC1 activation and ensure that cells remain committed to a quiescent state in suboptimal
conditions. More recently, we found that the EGO complex (EGOC; Rag/Ragulator in humans)—known to
activate TORC1 in the presence of amino acids—also moves into Kog1-bodies. Following up on these data
we will now determine: (A) How glucose starvation triggers inhibition of the TORC1 pathway; (B) What proteins
are in Kog1/EGOC-bodies; (C) What drives assembly of the Kog1/EGOC-bodies; and, (D) What role
Kog1/EGOC-bodies play in cell signaling. To do this we will: (1) Dissect the structure and function of Kog1-
bodies. In preliminary experiments we have shown that the Kog1/EGOC bodies remain intact on purified
vacuoles. Taking advantage of this, we will now map the composition of the Kog1/EGOC-body and its
assembly pathway. Then, using mutants that have defects in Kog/EGOC-body assembly (including some we
have already isolated), we will test our prediction that Kog1-bodies play a role in (a) bet hedging, (b) noise
dampening, and (c) the coordination of stress and starvation responses. We will also: (2) Identify the proteins
that regulate the TORC1 pathway and Kog1/EGOC-body formation, and dissect their mechanism of action. In
this aim, we will test the predication that glucose starvation and AMPK/Snf1, trigger changes in EGOC to
inactivate TORC1 and drive the formation of Kog1/EGOC–bodies. To do this we will map the circuit that
regulates TORC1 signaling and Kog1-body formation, and then study the function of key regulators (including
two we recently identified) in detail. Our proposal is innovative in that we study new and unexplored aspects of
TORC1 signaling using state-of-the-art systems, genomic, and biochemical approaches. The proposed
research is significant in that it promises to shed light on the mechanisms underlying cell growth control in
humans and/or lower eukaryotes—with implications for (a) understanding TORC1 related diseases such as
cancer, diabetes and obesity, and (b) developing drugs that selectively block the growth of pathogenic fungi.
In addition, our work promises to shed light on the role that protein bodies—formed by hundreds of proteins in
stress and starvation conditions, and in organisms ranging from yeast to man—play in a healthy cell.
总结/摘要
雷帕霉素激酶复合物I(TORC 1)的靶标是细胞生长和代谢的关键调节因子,
真核生物过去15年来的工作揭示了激素的潜在机制,
和氨基酸信号传递到TORC 1,但目前还不清楚其他关键信号,如葡萄糖饥饿,
传递到这个高度保守的复合体。在上一个授权期,我们检查了TORC 1信号,
芽殖酵母,并发现葡萄糖饥饿导致TORC 1途径的快速失活。那么在
较慢的反应(τ= 10分钟),TORC 1福尔斯分开,关键的调节组分Kog 1/Raptor移动到一个
在空泡/溶酶体的边缘上的单体。后一事件(部分)由AMPK/Snf 1依赖性驱动
Kog 1在Ser 491/494处的磷酸化,以及两个附近的朊病毒样基序。Kog 1-bodies则用于增加
TORC 1激活的阈值,并确保细胞在次优状态下保持静止状态,
条件最近,我们发现EGO复合物(EGOC;人类的Rag/Ragulator)-已知
在氨基酸存在下激活TORC 1-也移动到Kog 1-体中。根据这些数据
我们现在将确定:(A)葡萄糖饥饿如何触发TORC 1通路的抑制;(B)哪些蛋白质
(C)是什么驱动Kog 1/EGOC-体的组装;以及(D)什么作用
Kog 1/EGOC体在细胞信号传导中发挥作用。为此,我们将:(1)解剖Kog 1的结构和功能,
尸体在初步的实验中,我们已经表明,Kog 1/EGOC体在纯化的细胞上保持完整。
空泡利用这一点,我们现在将绘制Kog 1/EGOC体的组成及其
组装途径然后,使用在Kog/EGOC体组装中存在缺陷的突变体(包括一些我们发现的突变体),
我们将测试我们的预测,即Kog 1体在(a)赌注对冲,(B)噪声中发挥作用
阻尼,和(c)协调压力和饥饿反应。我们还将:(2)识别蛋白质
调节TORC 1通路和Kog 1/EGOC-体形成,并剖析其作用机制。在
为此,我们将测试葡萄糖饥饿和AMPK/Snf 1触发EGOC变化的预测,
抑制TORC 1并驱动Kog 1/EGOC体的形成。为此,我们将绘制电路图,
调节TORC 1信号传导和Kog 1体形成,然后研究关键调节因子(包括
我们最近发现的两个)。我们的建议是创新的,因为我们研究新的和未探索的方面,
使用最先进的系统,基因组和生物化学方法的TORC 1信号传导。拟议
这项研究的重要性在于,它有望阐明细胞生长控制的潜在机制,
人类和/或低等真核生物-与(a)理解TORC 1相关疾病,
癌症、糖尿病和肥胖症,和(B)开发选择性阻断致病真菌生长的药物。
此外,我们的工作有望阐明蛋白体的作用,蛋白体由数百种蛋白质组成,
压力和饥饿条件,以及从酵母到健康细胞中的人类活动的生物体。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Andrew Paul Capaldi其他文献
Andrew Paul Capaldi的其他文献
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{{ truncateString('Andrew Paul Capaldi', 18)}}的其他基金
Graduate Training in Biochemistry and Molecular Biology
生物化学和分子生物学研究生培训
- 批准号:
10631056 - 财政年份:2020
- 资助金额:
$ 36.89万 - 项目类别:
Graduate Training in Biochemistry and Molecular Biology
生物化学和分子生物学研究生培训
- 批准号:
10194559 - 财政年份:2020
- 资助金额:
$ 36.89万 - 项目类别:
Graduate Training in Biochemistry and Molecular Biology
生物化学和分子生物学研究生培训
- 批准号:
10417183 - 财政年份:2020
- 资助金额:
$ 36.89万 - 项目类别:
Dissection of the TORC1 Signaling Network in Yeast
酵母中 TORC1 信号网络的剖析
- 批准号:
8514645 - 财政年份:2011
- 资助金额:
$ 36.89万 - 项目类别:
Dissection of the TORC1 Signaling Network in Yeast
酵母中 TORC1 信号网络的剖析
- 批准号:
8897388 - 财政年份:2011
- 资助金额:
$ 36.89万 - 项目类别:
Dissection of the TORC1 Signaling Network in Yeast
酵母中 TORC1 信号网络的剖析
- 批准号:
10598274 - 财政年份:2011
- 资助金额:
$ 36.89万 - 项目类别:
Dissection of the TORC1 Signaling Network in Yeast
酵母中 TORC1 信号网络的剖析
- 批准号:
8193982 - 财政年份:2011
- 资助金额:
$ 36.89万 - 项目类别:
Dissection of the TORC1 Signaling Network in Yeast
酵母中 TORC1 信号网络的剖析
- 批准号:
10798367 - 财政年份:2011
- 资助金额:
$ 36.89万 - 项目类别:
Dissection of the TORC1 Signaling Network in Yeast
酵母中 TORC1 信号网络的剖析
- 批准号:
10387226 - 财政年份:2011
- 资助金额:
$ 36.89万 - 项目类别:
Dissection of the TORC1 Signaling Network in Yeast
酵母中 TORC1 信号网络的剖析
- 批准号:
8334661 - 财政年份:2011
- 资助金额:
$ 36.89万 - 项目类别:
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