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Glycan regulation of cell-cell junction dynamics and architecture

细胞-细胞连接动力学和结构的聚糖调节

基本信息

批准号：
227925-2013
负责人：
Nabi, Ivan
金额：
$ 3.64万
依托单位：
University of British Columbia
依托单位国家：
加拿大
项目类别：
Discovery Grants Program - Individual
财政年份：
2018
资助国家：
加拿大
起止时间：
2018-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=660548
关键词：
Glycan regulation cell junction dynamics

项目摘要

Glycosylation is a common posttranslational modification of glycoproteins, glycolipids and proteoglycans that generates extracellular binding sites for galactose-specific lectins or galectins. Cadherins are glycoproteins involved in cell-cell contacts whose extracellular domain mediates homotypic interactions with adjacent cells and cytoplasmic domain interacts through catenins with the underlying actin cytoskeleton. We have shown that galectin-3 destabilizes cell-cell junctions and increases mobility of N-cadherin and the lipid raft-associated glycosphingolipid GM1 ganglioside within cell-cell junctions. We hypothesize that galectin-3 regulation of glycoprotein and glycolipid residency and dynamics in cell-cell junctions drives local endocytosis impacting the underlying actin cytoskeleton and junctional stability. In this proposal, we will study the role of galectin-3 and lipid rafts in the regulation of N-cadherin dynamics and cell-cell junction architecture.****Aim 1: Galectin lattice and cell-cell junction dynamics **We will characterize study the impact of galectin-3 and raft domains on N-cadherin, GM1 and galectin-3 endocytosis and F-actin dynamics at cell-cell junctions.****Aim 2: Mediators of galectin lattice regulation of junctional stability **We will test the role of glycosphingolipids and candidate signaling and actin-regulatory proteins on galectin-3 stabilization of cell-cell junctions and on the dynamics of junction-associated molecules.****Aim 3: The architecture of the cell-cell junction by super-resolution microscopy**We will use super resolution microscopy to study the organization of galectin-3, raft markers, N-cadherin, catenins and the underlying actin cytoskeleton in the cell-cell junction.**

糖基化是糖蛋白、糖脂和蛋白聚糖的常见翻译后修饰，其产生半乳糖特异性凝集素或半乳糖凝集素的细胞外结合位点。钙粘蛋白是参与细胞-细胞接触的糖蛋白，其胞外结构域介导与相邻细胞的同型相互作用，胞质结构域通过连环蛋白与底层肌动蛋白细胞骨架相互作用。我们已经表明，半乳糖凝集素-3破坏细胞-细胞连接，并增加细胞-细胞连接内的N-钙粘蛋白和脂筏相关鞘糖脂GM 1神经节苷脂的流动性。我们假设半乳糖凝集素-3调节糖蛋白和糖脂的驻留和细胞-细胞连接中的动力学驱动局部内吞作用，影响潜在的肌动蛋白细胞骨架和连接稳定性。在这个提议中，我们将研究半乳糖凝集素-3和脂筏在调节N-钙粘蛋白动力学和细胞-细胞连接结构中的作用。目标1：半乳糖凝集素晶格和细胞-细胞连接动力学 ** 我们将表征研究半乳糖凝集素-3和筏结构域对细胞-细胞连接处的N-钙粘蛋白、GM 1和半乳糖凝集素-3内吞作用和F-肌动蛋白动力学的影响。*目标二：半乳糖凝集素晶格调节连接稳定性的介体 ** 我们将测试鞘糖脂和候选信号传导和肌动蛋白调节蛋白对半乳糖凝集素-3稳定细胞-细胞连接和连接相关分子动力学的作用。*目标三：通过超分辨率显微镜观察细胞-细胞连接的结构 ** 我们将使用超分辨率显微镜来研究半乳糖凝集素-3、筏标记物、N-钙粘蛋白、连环蛋白和细胞-细胞连接中潜在的肌动蛋白细胞骨架的组织。**