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:10352421
- 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:
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
组织形成期间的细胞重排,组织再生和癌症转移通过
细胞组的耦合运动,一种被称为集体细胞迁移的现象。关键蛋白
参与上皮细胞集体迁移的是E-钙粘蛋白(ECAD),这是一种必需的细胞 - 细胞粘合剂蛋白。
ECAD粘附受到仔细调节,以使细胞单层的复杂运动和失调失调
粘附是某些癌症的特征。但是,关于ECAD结构和粘合剂的了解知之甚少
受调节以及这在集体细胞迁移中如何表现。
ECAD的细胞外区域介导粘附,而其细胞内结构域与调节结合
蛋白质,例如P120-catenin,α-钙蛋白和vinculin,它们将ECAD与肌动蛋白细胞骨架联系起来。我们假设
α-catenin,vinculin和p120-catenin通过变构控制了粘合剂
ECAD细胞外区域。我们还建议某些ECAD癌症突变阻碍了内而外的调节
ECAD的构象和理解其作用机理将提供分子见解
肿瘤发生中的粘附调节。
在本提案的目标1中,我们将为α-catenin,p120-catenin和vinculin结合分配不同的作用
调节ECAD构象和测量癌症突变如何阻碍内而外的粘合剂调节。在
AIM 2,我们将确定细胞质蛋白如何通过
建立详细的结构模型,用于具有和没有ECAD癌突变的细胞间连接。最后,在
AIM 3,我们将解决不同ECAD构象和癌症突变体在迁移模式中的作用
上皮细胞。
我们提出的研究将对ECAD介导的粘附有详细的机械理解
并解决在上皮组织形成,伤口愈合和癌症中很重要的粘合剂状态。
知识将使特定ECAD结构的选择性定位和抑制可以妥协
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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数据更新时间:2024-06-01
Sanjeevi Sivasank...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:1055312410553124
- 财政年份:2021
- 资助金额:$ 37.44万$ 37.44万
- 项目类别:
Methods for mapping cell adhesion receptors
绘制细胞粘附受体图谱的方法
- 批准号:1068530610685306
- 财政年份:2017
- 资助金额:$ 37.44万$ 37.44万
- 项目类别:
Microscope for ultrasensitive measurement of single-molecule interaction and conformation
用于超灵敏测量单分子相互作用和构象的显微镜
- 批准号:92190099219009
- 财政年份:2017
- 资助金额:$ 37.44万$ 37.44万
- 项目类别:
Methods for mapping cell adhesion receptors
绘制细胞粘附受体图谱的方法
- 批准号:1029767810297678
- 财政年份:2017
- 资助金额:$ 37.44万$ 37.44万
- 项目类别:
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