PI3 kinase PIK3CB (p110beta) in membrane trafficking and metabolism
膜运输和代谢中的 PI3 激酶 PIK3CB (p110beta)
基本信息
- 批准号:10249278
- 负责人:
- 金额:$ 35.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAblationAbnormal CellAddressAllelesAutophagocytosisBindingBiochemicalBioenergeticsBiologicalCancer ModelCell LineCell LineageCell surfaceCellsCellular Metabolic ProcessClinical DataCultured CellsDataDefectDevelopmentEmbryoEndocytosisEventFRAP1 geneFailureG-Protein-Coupled ReceptorsGTP BindingGTPase-Activating ProteinsGeneticGlucoseGrowthGrowth FactorGuanosine TriphosphateHematologic NeoplasmsHematopoieticHomeostasisHumanHydrolysisIntracellular MembranesLeadLymphocyteMCF10A cellsMalignant NeoplasmsMammary glandMediatingMembraneMetabolicMetabolic DiseasesMetabolismMolecularMonomeric GTP-Binding ProteinsMusMutationNutrientOncogenesOncogenicPIK3CA genePIK3CB genePathologicPathway interactionsPhosphotransferasesPhysiologicalProcessProtein IsoformsProtein Tyrosine KinaseProteomeReceptor SignalingReportingRoleSLC2A1 geneSignal PathwaySignal TransductionSignaling MoleculeSurfaceTestingTumor Suppressor Proteinsanimal datacell growthdeprivationdesignglucose uptakehuman diseasein vivoin vivo Modelmutantnovelphosphatidylinositol 3,4,5-triphosphatephosphatidylinositol phosphate, PtdIns(4,5)P2phosphoinositide-3,4,5-triphosphatepreventpublic health relevancereceptorresponsescaffoldsmall hairpin RNAtraffickingtumorigenesis
项目摘要
PROJECT SUMMARY:
The Class IA phosphatidylinositol 3-kinases (PI3Ks) p110a and p110b isoforms are ubiquitously expressed
and respond to membrane receptor signals. They PI(3,4,5)P3, which acts as a signaling molecule to activate
downstream signaling pathways including the Akt/mTOR pathway. Despite their similarities, two isoforms have
distinct biochemical and biological features, one of which is that p110b has a kinase-independent function. We
have reported that p110b positively regulates the small GTPase Rab5 in a manner that is independent of its
catalytic activity. p110b, through a direct binding and as a molecular scaffold, keeps Rab5 in its “active” GTP-
bound form by preventing Rab5 from interacting with its GTPase-activating protein (GAP), which inactivates
Rab5 by hydrolyzing its GTP to GDP. Rab5 is well known for regulating endocytosis. Our preliminary data
strongly indicate that p110b can regulate endocytic turnover of cell surface nutrient transporters such as
glucose transporter 1 (GLUT1) in response to growth factor deprivation. We found that genetic ablation or
shRNA silencing of p110b decreased the level of Rab5-GTP. This resulted in increased cell surface GLUT1
that led to increased glucose utilization of cell lines and promoted their oncogenic transformation. These
findings lead us to propose the hypothesis that p110b, as a molecular scaffold, activates Rab5 and endocytic
turnover of nutrient transporters. We further propose that this novel function of p110b regulates membrane
trafficking and cell metabolism and homeostasis. We have designed two Specific Aims to test this hypothesis
and establish its biological relevance. Aim 1: Test the hypothesis that p110b facilitates Rab5-mediated
endocytic turnover of nutrient transporters. We will use FL5.12, MEFs, HK-2, and MCF10A cells to determine
that p110b deficiency can lead to the stabilization of nutrient transporters, and to determine if the failure of
endocytic turnover is the result of Rab5 inactivation. Aim 2. Determine the molecular and cell biological
consequence of the stabilized nutrient transporters in p110b-deficient cells (with a focus on GLUT1). We will
characterize the metabolic features associated with the nutrient transporter stabilization, and characterize the
growth/proliferation signaling in p110b-deficient cells. We will also determine the physiological effects of the
p110b-Rab5 interaction in vivo.
!
项目总结:
IA类磷脂酰肌醇3-激酶(PI3Ks)p110a和p110b亚型广泛表达
并对膜受体信号做出反应。他们PI(3,4,5)P3,作为信号分子激活
下游信号通路包括Akt/mTOR通路。尽管它们有相似之处,但有两种同工酶
P110b具有不同的生化和生物学特征,其中之一是p110b具有不依赖于激酶的功能。我们
已经报道p110b以一种独立于其自身的方式正向调节小GTP酶Rab5
催化活性。P110b通过直接结合并作为分子支架,使Rab5保持其活性的GTP-
通过阻止Rab5与其失活的GTP酶激活蛋白(GAP)相互作用形成结合形式
Rab5通过将其GTP水解为GDP。Rab5是众所周知的调节内吞作用的药物。我们的初步数据
有力地表明p110b可以调节细胞表面营养物质转运体的内吞,如
葡萄糖转运蛋白1(GLUT1)对生长因子剥夺的反应。我们发现基因消融或
P110b的shRNA沉默降低了Rab5-GTP的水平。这导致细胞表面GLUT1增加
这导致了细胞系对葡萄糖的利用增加,并促进了它们的致癌转化。这些
这些发现导致我们提出假设,p110b作为一种分子支架,激活Rab5和内吞
营养物质转运体的周转率。我们进一步提出,p110b的这一新功能调节细胞膜
贩运、细胞代谢和动态平衡。我们设计了两个具体的目标来检验这一假设
并确定其生物学相关性。目的1:验证p110b促进Rab5介导的假设
营养转运蛋白的胞内周转。我们将使用FL5.12、MEFS、HK-2和MCF10A细胞来确定
P110b缺乏可以导致营养转运蛋白的稳定,并确定如果
内吞是Rab5失活的结果。目的2.分子和细胞生物学测定
P110b缺陷细胞中稳定的营养转运体的结果(重点是GLUT1)。我们会
描述与营养转运体稳定性相关的代谢特征,并描述
P110b缺陷细胞中的生长/增殖信号。我们还将确定这些药物的生理效应。
P110b-Rab5在体内相互作用。
好了!
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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Wei-Xing Zong其他文献
Wei-Xing Zong的其他文献
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{{ truncateString('Wei-Xing Zong', 18)}}的其他基金
Glutamine synthetase in cancer cell metabolism and oncogenesis
谷氨酰胺合成酶在癌细胞代谢和肿瘤发生中的作用
- 批准号:
9981701 - 财政年份:2018
- 资助金额:
$ 35.46万 - 项目类别:
PI3 kinase PIK3CB (p110beta) in membrane trafficking and metabolism
膜运输和代谢中的 PI3 激酶 PIK3CB (p110beta)
- 批准号:
10001471 - 财政年份:2018
- 资助金额:
$ 35.46万 - 项目类别:
PI3 kinase PIK3CB (p110beta) in membrane trafficking and metabolism
膜运输和代谢中的 PI3 激酶 PIK3CB (p110beta)
- 批准号:
10474502 - 财政年份:2018
- 资助金额:
$ 35.46万 - 项目类别:
Glutamine synthetase in cancer cell metabolism and oncogenesis
谷氨酰胺合成酶在癌细胞代谢和肿瘤发生中的作用
- 批准号:
10473698 - 财政年份:2018
- 资助金额:
$ 35.46万 - 项目类别:
Protein and redox homeostasis in cancer development and therapy
癌症发展和治疗中的蛋白质和氧化还原稳态
- 批准号:
10413025 - 财政年份:2008
- 资助金额:
$ 35.46万 - 项目类别:
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