Molecular mechanisms of Basolateral targeting in polarized epithelial cells
极化上皮细胞基底外侧靶向的分子机制
基本信息
- 批准号:7342844
- 负责人:
- 金额:$ 26.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-02-01 至 2010-01-31
- 项目状态:已结题
- 来源:
- 关键词:Adaptor Signaling ProteinAddressAllelesAnimalsApicalBindingBiochemicalBiochemical GeneticsBiologicalCell PolarityCell membraneCellsClathrin AdaptorsComplexConnective TissueCytoplasmic TailDataDefectDiseaseDisseminated Malignant NeoplasmDominant-Negative MutationEmbryonic DevelopmentEndosomesEnsureEpithelialEpithelial CellsEventFaceFamilyGeneticGoalsGolgi ApparatusGrantIntegral Membrane ProteinLaboratoriesLearningLipidsLocalizedLocationMediatingMembraneMembrane Protein TrafficMembrane ProteinsMolecularMolecular TargetMonomeric GTP-Binding ProteinsNamesOrganOther Agency or OrganizationPathway interactionsPlayProcessProtein OverexpressionProteinsRecyclingRegulationRoleSignal TransductionSiteSorting - Cell MovementStaining methodStainsSurfaceTestingTissuesTranscription Factor AP-1VesicleWorkapical membranebasebasolateral membranecancer cellinterestmonolayerprotein protein interactionreceptortrans-Golgi Networkvesicular stomatitis virus G protein
项目摘要
DESCRIPTION (provided by applicant): Epithelial cells are polarized into distinct apical and basolateral plasma membrane domains. The apical membrane faces the outside of the body and the basolateral membrane is in contact with connective tissues. During the lifetime of any given epithelial cell it is crucial for organ function that this established polarity is maintained. For example, loss of polarity enables a cell to disintegrate from a monolayer, which is an early step in metastatic cancer.
Apical and basolateral plasma membrane domains have distinct sets of lipids and plasma membrane receptors. To maintain this distinct distribution, the cells continuously need to sort newly synthesized proteins along the biosynthetic pathway and recycle internalized receptors to the correct membrane. Basolateral targeting often depends on targeting determinants in the cytoplasmic tail of a transmembrane protein and cytosolic adaptor molecules that recognize them and mediate sorting. We identified one major cytosolic component, the clathrin-adaptor complex AP-1B (Folsch et al., 1999). Clathrin adaptor complexes are tetraheteromers. Typically the medium subunit interacts directly with the sorting signals and is therefore of particular interest. The medium subunit of AP-1B, mu1B is exclusively expressed in epithelial tissues and directly interacts with basolateral cargo molecules (Folsch et al., 2001).
Our work will focus on defining the molecular mechanisms of AP-1B function and its site(s) of action. Moreover, we will analyze how the membrane recruitment of AP-1B is regulated. Furthermore, we will investigate the molecular interactions leading to AP-1B mediated basolateral targeting. My laboratory will combine cell biological, biochemical and genetic approaches to resolve the following specific aims:
1) At which intracellular site(s) does AP-1B fulfill its sorting function?
2) How is AP-1B membrane recruitment and vesicle formation regulated?
3) What is the molecular basis for AP-1B specific sorting events?
A better understanding of the processes by which epithelial cells maintain polarity is essential, if we want to learn which defects in molecular sorting may transform epithelial cells into cancer cells, to name only one example of diseases associated with the loss of cell polarity.
描述(由申请人提供):上皮细胞被极化成不同的顶端和基底外侧质膜区域。顶膜面向体外,基底外侧膜与结缔组织接触。在任何给定上皮细胞的一生中,维持这种既定的极性对于器官功能至关重要。例如,极性的丧失使细胞从单层解体,这是转移性癌症的早期步骤。
顶端和基底外侧质膜结构域具有不同的脂质和质膜受体组。为了维持这种独特的分布,细胞需要不断地沿着生物合成途径对新合成的蛋白质进行分类,并将内化的受体回收到正确的膜上。基底外侧靶向通常取决于跨膜蛋白细胞质尾部的靶向决定簇和识别它们并介导分选的胞质接头分子。我们鉴定了一种主要的胞质成分,即网格蛋白-适配器复合物 AP-1B(Folsch 等人,1999)。网格蛋白接头复合物是四杂异构体。通常,介质子单元直接与分选信号相互作用,因此特别令人感兴趣。 AP-1B 的中等亚基 mu1B 仅在上皮组织中表达,并直接与基底外侧货物分子相互作用 (Folsch et al., 2001)。
我们的工作重点是确定 AP-1B 功能的分子机制及其作用位点。此外,我们将分析 AP-1B 的膜募集是如何调节的。此外,我们将研究导致 AP-1B 介导的基底外侧靶向的分子相互作用。我的实验室将结合细胞生物学、生化和遗传学方法来解决以下具体目标:
1) AP-1B 在哪个细胞内位点发挥其分选功能?
2) AP-1B 膜募集和囊泡形成是如何调节的?
3) AP-1B 特异性分选事件的分子基础是什么?
如果我们想了解分子分选中的哪些缺陷可能会将上皮细胞转化为癌细胞(仅举与细胞极性丧失相关的疾病的一个例子),更好地了解上皮细胞保持极性的过程至关重要。
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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HEIKE FOLSCH其他文献
HEIKE FOLSCH的其他文献
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{{ truncateString('HEIKE FOLSCH', 18)}}的其他基金
Role of Membrane Trafficking in Epithelial Homeostasis
膜运输在上皮稳态中的作用
- 批准号:
10365484 - 财政年份:2022
- 资助金额:
$ 26.53万 - 项目类别:
Role of Membrane Trafficking in Epithelial Homeostasis
膜运输在上皮稳态中的作用
- 批准号:
10543529 - 财政年份:2022
- 资助金额:
$ 26.53万 - 项目类别:
Role of Membrane Trafficking in Epithelial Homeostasis
膜运输在上皮稳态中的作用
- 批准号:
10796580 - 财政年份:2022
- 资助金额:
$ 26.53万 - 项目类别:
Molecular mechanisms of Basolateral targeting in polarized epithelial cells
极化上皮细胞基底外侧靶向的分子机制
- 批准号:
7924961 - 财政年份:2009
- 资助金额:
$ 26.53万 - 项目类别:
Molecular mechanisms of Basolateral targeting in polarized epithelial cells
极化上皮细胞基底外侧靶向的分子机制
- 批准号:
7175353 - 财政年份:2005
- 资助金额:
$ 26.53万 - 项目类别:
Molecular mechanisms of basolateral targeting in polarized epithelial cells
极化上皮细胞基底外侧靶向的分子机制
- 批准号:
8318152 - 财政年份:2005
- 资助金额:
$ 26.53万 - 项目类别:
Molecular mechanisms of basolateral targeting in polarized epithelial cells
极化上皮细胞基底外侧靶向的分子机制
- 批准号:
8537925 - 财政年份:2005
- 资助金额:
$ 26.53万 - 项目类别:
Molecular mechanisms of Basolateral targeting in polarized epithelial cells
极化上皮细胞基底外侧靶向的分子机制
- 批准号:
7578891 - 财政年份:2005
- 资助金额:
$ 26.53万 - 项目类别:
Molecular Mechanisms of Basolateral Targeting in Polarized Epithelial Cells
极化上皮细胞基底外侧靶向的分子机制
- 批准号:
9135451 - 财政年份:2005
- 资助金额:
$ 26.53万 - 项目类别:
Molecular mechanisms of basolateral targeting in polarized epithelial cells
极化上皮细胞基底外侧靶向的分子机制
- 批准号:
8133705 - 财政年份:2005
- 资助金额:
$ 26.53万 - 项目类别:
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