Mechanosensitive cadherin adhesion and its regulation
机械敏感钙粘蛋白粘附及其调控
基本信息
- 批准号:10553124
- 负责人:
- 金额:$ 37.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-15 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalActinsAdhesionsAdhesivesBindingBinding ProteinsBiomechanicsCadherinsCancer ClusterCell Adhesion MoleculesCell physiologyCell-Cell AdhesionCellsCharacteristicsComplexCoupledCytoplasmic ProteinCytoplasmic TailCytoskeletonDataDissociationE-CadherinEpithelial CellsEpitheliumExhibitsFunctional disorderIntercellular JunctionsInvadedKnowledgeLaboratoriesLinkMalignant NeoplasmsMeasuresMediatingMembraneModelingMolecularMolecular ConformationMovementMutationNatural regenerationNeoplasm MetastasisPatternPropertyProteinsRegulationResearchRoleStructural ModelsStructureTimeTissuesVertebral columnVinculinalpha catenincancer cellcell motilityextracellulargenetic regulatory proteininsightmigrationmonolayermutantsingle moleculetissue regenerationtumor progressiontumorigenesiswound closurewound healing
项目摘要
ABSTRACT
Cellular rearrangements during tissue formation, tissue regeneration and cancer metastasis occur via
the coupled movement of groups of cells, a phenomenon known as collective cell migration. A key protein
involved in the collective migration of epithelial cells is E-cadherin (Ecad), an essential cell-cell adhesion protein.
Ecad adhesion is carefully regulated to orchestrate complex movement of cell monolayers and dysregulation of
adhesion is a characteristic of certain cancers. However, little is known about how Ecad structure and adhesion
are regulated and how this manifests in collective cell migration.
The extracellular region of Ecad mediates adhesion, while its intracellular domain binds to regulatory
proteins such as p120-catenin, α-catenin and vinculin, which link Ecad to the actin cytoskeleton. We hypothesize
that α-catenin, vinculin and p120-catenin regulate adhesion by allosterically controlling the conformation of the
Ecad extracellular region. We also propose that some Ecad cancer mutations impede the inside-out regulation
of Ecad conformation and that understanding their mechanism of action will provide molecular insights into
adhesion regulation in tumorigenesis.
In aim 1 of this proposal, we will assign distinct roles to α-catenin, p120-catenin, and vinculin binding in
modulating Ecad conformation and measure how cancer mutations impede inside-out regulation of adhesion. In
aim 2, we will establish how cytoplasmic proteins alter the conformation of the Ecad extracellular region by
building detailed structural models for intercellular junctions, with and without Ecad cancer mutations. Finally, in
aim 3, we will resolve the role of different Ecad conformations and cancer mutants on the migratory patterns of
epithelial cells.
Our proposed research will provide a detailed mechanistic understanding of Ecad mediated adhesion
and resolve adhesive states that are important in epithelial tissue formation, wound healing, and cancer. This
knowledge will enable selective targeting and inhibition of specific Ecad structures, which can compromise
cancer progression.
摘要
在组织形成、组织再生和癌症转移期间的细胞重排通过以下方式发生:
细胞群的耦合运动,这种现象被称为集体细胞迁移。的关键蛋白
参与上皮细胞集体迁移的是E-钙粘蛋白(Ecad),一种必需的细胞-细胞粘附蛋白。
ECAD粘附被小心地调节以协调细胞单层的复杂运动和细胞粘附的失调。
粘附是某些癌症的特征。然而,很少有人知道如何Ecad结构和粘附
以及这在集体细胞迁移中的表现。
Ecad的细胞外区域介导粘附,而其细胞内结构域结合调节因子
连接Ecad与肌动蛋白细胞骨架的蛋白质如p120-连环蛋白、α-连环蛋白和黏着斑蛋白。我们假设
α-catenin、vinculin和p120-catenin通过变构控制粘附分子的构象来调节粘附。
Ecad胞外区。我们还提出一些Ecad癌症突变阻碍了由内而外的调节
的Ecad构象,并了解其作用机制将提供分子的见解,
肿瘤发生中的粘附调节。
在本提案的目标1中,我们将赋予α-catenin、p120-catenin和黏着斑蛋白在细胞内的不同作用。
调节Ecad构象,并测量癌症突变如何阻碍粘附的由内而外调节。在
目的2,我们将建立细胞质蛋白如何改变Ecad胞外区的构象,
建立细胞间连接的详细结构模型,有和没有Ecad癌症突变。最后在
目的3,我们将解决不同的Ecad构象和癌症突变体的迁移模式的作用,
上皮细胞
我们提出的研究将提供一个详细的机制理解Ecad介导的粘附
并解决在上皮组织形成、伤口愈合和癌症中重要的粘附状态。这
知识将使选择性靶向和抑制特定的Ecad结构,这可能会损害
癌症进展
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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Sanjeevi Sivasankar其他文献
Sanjeevi Sivasankar的其他文献
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{{ truncateString('Sanjeevi Sivasankar', 18)}}的其他基金
Mechanosensitive cadherin adhesion and its regulation
机械敏感钙粘蛋白粘附及其调控
- 批准号:
10352421 - 财政年份:2021
- 资助金额:
$ 37.44万 - 项目类别:
Microscope for ultrasensitive measurement of single-molecule interaction and conformation
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- 批准号:
9219009 - 财政年份:2017
- 资助金额:
$ 37.44万 - 项目类别:
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