Regulation of heterotrimeric G proteins by non-receptor activators

非受体激活剂对异源三聚体 G 蛋白的调节

基本信息

  • 批准号:
    8757091
  • 负责人:
  • 金额:
    $ 32.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-01 至 2018-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Ric-8A and Ric-8B are positive regulators of heterotrimeric G protein a subunit function. We have recently defined the cellular action of Ric-8 proteins towards Ga subunits. Ric-8 proteins act as molecular chaperones of nucleotide-free Ga conformations during biosynthetic Ga protein folding. In cells in which Ric-8 genes are deleted, cellular abundances of subsets of Ga subunits were reduced by 95%. Ric-8 proteins also exhibit in vitro guanine nucleotide exchange stimulatory activity towards Ga subunits, and we now believe this to be an in vitro phenomenon stemming from the capacity of Ric-8 to induce a partially folded Ga state that has reduced affinity for GDP. We will develop our hypothesis that Ric-8 proteins are Ga subunit molecular chaperones and investigate the mechanisms by which Ric-8 proteins work with other cellular chaperones including the TRiC/CCT (Chaperonin) complex and HSC70/90 systems to fold individual Ga subunits. We have preliminary evidence that there are complex rules and unique chaperone requirements of individual Ga subunits. We will then test a hypothesis that mouse tissue-specific Ric-8A gene deletion can genetically suppress oncogenic G protein or overactive GPCR-driven cancers. Two mouse melanoma models will be used in which GNAQ/11-Q209L (constitutively-active) alleles are the oncogenic driver mutations of metastatic ocular melanoma, and ectopic mGluR5 expression from a melanocyte promoter elicited robust melanoma. We hypothesize that melanocyte mGluR5 inappropriately activates Gq/11 to promote melanoma. Upon proof-of-concept that Ric-8 deletion will suppress the actions of these oncogenes by reducing Gaq/11 cellular abundances, we will perform screens to identify small molecule inhibitors of Ric-8 and G protein interactions. Our goal is to develop Ric-8 inhibitors as a means to indirectly block G protein disease signaling by reducing the abundance of (mutant) Ga subunits folded by Ric-8. Ric-8 inhibitors may prove efficacious against oncogenic G protein diseases and/or as augmentation therapies for existing GPCR therapeutics. We will also conduct a small project to investigate Ric-8A regulation by phosphorylation events and 14-3-3 binding to Ric-8A.
描述(由申请人提供):Ric-8A和Ric-8B是异源三聚体G蛋白a亚基功能的正调节剂。我们最近定义了 Ric-8 蛋白对 Ga 亚基的细胞作用。 Ric-8 蛋白在生物合成 Ga 蛋白折叠过程中充当无核苷酸 Ga 构象的分子伴侣。在删除 Ric-8 基因的细胞中,Ga 亚基子集的细胞丰度减少了 95%。 Ric-8 蛋白还表现出对 Ga 亚基的体外鸟嘌呤核苷酸交换刺激活性,我们现在认为这是一种体外现象,源于 Ric-8 诱导部分折叠的 Ga 状态的能力,从而降低了对 GDP 的亲和力。我们将提出 Ric-8 蛋白是 Ga 亚基分子伴侣的假设,并研究 Ric-8 蛋白与其他细胞伴侣(包括 TRiC/CCT(伴侣蛋白)复合物和 HSC70/90 系统)一起折叠单个 Ga 亚基的机制。我们有初步证据表明单个 Ga 亚基存在复杂的规则和独特的伴侣要求。然后,我们将测试一个假设,即小鼠组织特异性 Ric-8A 基因缺失可以从基因上抑制致癌 G 蛋白或过度活跃的 GPCR 驱动的癌症。将使用两种小鼠黑色素瘤模型,其中 GNAQ/11-Q209L(组成型活性)等位基因是转移性眼部黑色素瘤的致癌驱动突变,并且黑色素细胞启动子的异位 mGluR5 表达引发了强烈的黑色素瘤。我们假设黑色素细胞 mGluR5 不适当地激活 Gq/11 以促进黑色素瘤。概念证明 Ric-8 缺失将通过减少 Gaq/11 细胞丰度来抑制这些癌基因的作用,我们将进行筛选以鉴定 Ric-8 和 G 蛋白相互作用的小分子抑制剂。我们的目标是开发 Ric-8 抑制剂,通过减少 Ric-8 折叠的(突变)Ga 亚基的丰度来间接阻断 G 蛋白疾病信号传导。 Ric-8 抑制剂可能被证明可有效对抗致癌 G 蛋白疾病和/或作为现有 GPCR 疗法的增强疗法。我们还将开展一个小型项目来研究磷酸化事件和 14-3-3 与 Ric-8A 结合对 Ric-8A 的调节。

项目成果

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Gregory Gordon Tall其他文献

Gregory Gordon Tall的其他文献

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{{ truncateString('Gregory Gordon Tall', 18)}}的其他基金

Investigation of Adhesion GPCR and Ric-8 protein control of heterotrimeric G proteins
异三聚体 G 蛋白粘附 GPCR 和 Ric-8 蛋白控制的研究
  • 批准号:
    10622696
  • 财政年份:
    2023
  • 资助金额:
    $ 32.2万
  • 项目类别:
Development of Chemical Probes to Investigate Adhesion GPCR Tethered Agonism
开发用于研究粘附 GPCR 系链激动作用的化学探针
  • 批准号:
    9917826
  • 财政年份:
    2018
  • 资助金额:
    $ 32.2万
  • 项目类别:
Mechanisms of Adhesion GPCR Action
粘附 GPCR 作用机制
  • 批准号:
    9352861
  • 财政年份:
    2016
  • 资助金额:
    $ 32.2万
  • 项目类别:
Mechanisms of Adhesion GPCR Action
粘附 GPCR 作用机制
  • 批准号:
    10374884
  • 财政年份:
    2016
  • 资助金额:
    $ 32.2万
  • 项目类别:
Mechanisms of Adhesion GPCR Action
粘附 GPCR 作用机制
  • 批准号:
    9981283
  • 财政年份:
    2016
  • 资助金额:
    $ 32.2万
  • 项目类别:
Mechanisms of Adhesion GPCR Action
粘附 GPCR 作用机制
  • 批准号:
    9155400
  • 财政年份:
    2016
  • 资助金额:
    $ 32.2万
  • 项目类别:
Mechanisms of Adhesion GPCR Action
粘附 GPCR 作用机制
  • 批准号:
    10569532
  • 财政年份:
    2016
  • 资助金额:
    $ 32.2万
  • 项目类别:
Regulation of heterotrimeric G proteins by non-receptor activators
非受体激活剂对异源三聚体 G 蛋白的调节
  • 批准号:
    8534176
  • 财政年份:
    2009
  • 资助金额:
    $ 32.2万
  • 项目类别:
Regulation of heterotrimeric G proteins by non-receptor activators
非受体激活剂对异源三聚体 G 蛋白的调节
  • 批准号:
    9336939
  • 财政年份:
    2009
  • 资助金额:
    $ 32.2万
  • 项目类别:
Regulation of heterotrimeric G proteins by non-receptor activators
非受体激活剂对异源三聚体 G 蛋白的调节
  • 批准号:
    8136505
  • 财政年份:
    2009
  • 资助金额:
    $ 32.2万
  • 项目类别:

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