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.
抽象的
组织形成、组织再生和癌症转移过程中的细胞重排通过
细胞群的耦合运动,这种现象称为集体细胞迁移。关键蛋白质
参与上皮细胞集体迁移的是E-钙粘蛋白(Ecad),一种重要的细胞间粘附蛋白。
Ecad 粘附受到仔细调节,以协调单层细胞的复杂运动和细胞的失调。
粘附是某些癌症的特征。然而,人们对 Ecad 结构和粘附力如何了解知之甚少。
受到调节以及这如何在集体细胞迁移中体现。
Ecad 的胞外区域介导粘附,而其胞内区域则与调节结合
p120-连环蛋白、α-连环蛋白和纽蛋白等蛋白质将 Ecad 与肌动蛋白细胞骨架连接起来。我们假设
α-连环蛋白、纽蛋白和 p120-连环蛋白通过变构控制构象来调节粘附
Ecad 细胞外区。我们还提出一些 Ecad 癌症突变阻碍了由内而外的调节
Ecad 构象的研究以及了解其作用机制将为以下方面提供分子见解
肿瘤发生中的粘附调节。
在本提案的目标 1 中,我们将在 α-连环蛋白、p120-连环蛋白和纽蛋白结合中赋予不同的作用。
调节 Ecad 构象并测量癌症突变如何阻碍由内而外的粘附调节。在
目标 2,我们将确定细胞质蛋白如何通过以下方式改变 Ecad 胞外区的构象:
建立细胞间连接的详细结构模型,无论是否存在 Ecad 癌症突变。最后,在
目标3,我们将解决不同Ecad构象和癌症突变体对迁移模式的作用
上皮细胞。
我们提出的研究将为 Ecad 介导的粘附提供详细的机制理解
并解决对上皮组织形成、伤口愈合和癌症很重要的粘附状态。这
知识将能够选择性地瞄准和抑制特定的 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)
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会议论文数量(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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