权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The cadherin Desmoglein-2 controls cell spreading and extracellular matrix gene expression.

钙粘蛋白 Desmoglein-2 控制细胞扩散和细胞外基质基因表达。

基本信息

批准号：
10653447
负责人：
Adi D Dubash
金额：
$ 36.47万
依托单位：
FURMAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653447
关键词：
Adhesives Apoptosis Behavior Binding Biological Biological Process Cadherins Cell membrane Cell physiology Cell-Cell Adhesion Cell-Matrix Junction Cells Collagen Complex Cytoskeletal Filaments Data Desmosomes Epithelium Extracellular Domain Extracellular Matrix Extracellular Matrix Proteins Extracellular Space Fibronectins Fostering Foundational Skills Gene Expression Gene Structure Guanosine Triphosphate Phosphohydrolases Institution Intermediate Filaments Knock-out Link Maintenance Mechanical Stress Mediating Membrane Methods Modeling Molecular Morphogenesis NF-kappa B Pathway interactions Play Process Proliferating Proteins Regulation Role Science Signal Transduction Structure Tail Testing Tissues Training Universities Work career cell motility desmocollin desmoglein desmoglein 2 desmoplakin experimental study extracellular insight knock-down migration novel organizational structure plakoglobin plakophilins protein complex response tissue repair undergraduate student wound healing

项目摘要

PROJECT SUMMARY The desmosome cell-cell adhesion complex plays an important role in the maintenance of tissue structure and integrity in response to mechanical stress. In addition to this central adhesive role, desmosomal proteins also coordinate multiple processes such as proliferation, apoptosis, differentiation and cell migration. Prior studies show that desmosomal cadherins, the proteins responsible for mediating the extracellular attachment between cells, can have both pro- and anti-migratory functions, indicating that their influence on migration is more complex than a simple consequence of defective cell-cell attachment. Our recent work has shown that loss of the cadherin Desmoglein-2 (DSG2) triggers increased activation of the Rap1 GTPase, leading to enhanced cell spreading on extracellular matrix (ECM) proteins (such as fibronectin and collagen). As these experiments were performed on singly spreading cells, we have identified a novel cell-autonomous, cell-cell adhesion independent role for DSG2 in the regulation of cell spreading. Nevertheless, the signaling mechanisms via which DSG2 regulates Rap1 activity remain unknown. Our preliminary data also shows that localization of the Rap1 activator PDZ-GEF2 is dramatically altered in DSG2 knockout cells, and that knockdown of the desmosomal protein Desmoplakin (DSP) can rescue both the enhanced spreading and mis-localization of PDZ-GEF2 seen in these cells. Further, we have obtained evidence that loss of DSG2 increases ECM gene expression via deregulated Src and NF-kB signaling. In this proposal, we will test the central hypothesis that DSG2 orchestrates cell-matrix adhesion and spreading through control of both inside-out signaling (via Rap1 GEFs) and outside-in signaling (via ECM gene expression). In Aim 1, we will investigate whether binding of PDZ-GEF2 to DSG2 or DSP reduces its activity, thereby inducing inside-out control of cell spreading via inhibition of Rap1 signaling. In Aim 2, we will explore a role for NF-kB and Src signaling in DSG2-dependent ECM gene expression, and whether this promotes outside-in control of cell-matrix spreading and migration. Finally, in Aim 3, we will explore the hypothesis that the ability of DSG2 to regulate cell migration is independent of its extracellular domains and/or localization to the cell membrane. The scientific impact of these data will be to produce a comprehensive picture of the molecular mechanisms by which the desmosomal cadherin DSG2 coordinates both inside-out and outside-in signaling to control cell-matrix adhesion, spreading and migration, functions critical for biological processes such as tissue morphogenesis, wound healing and re- epithelialization. The training impact of these data will be to provide undergraduate students at Furman University (a primarily undergraduate institution) with foundational skills in the scientific method, foster their desire to tackle important biological problems and pursue a career in the biomedical sciences.

项目总结