Molecular mechanism underlying cell polarity and cell migration

细胞极性和细胞迁移的分子机制

基本信息

批准号：
15GS0319
负责人：
KAIBUCHI Kozo
金额：
$ 203.51万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Creative Scientific Research
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2007
项目状态：
已结题

项目摘要

Cell polarization is an essential step for cellular functions, but the underlying mechanisms to establish and maintain cell polarity are not fully understood. We tried to clarify the signal transduction mechanisms controlling cell polarization by the use of cell migration and neuronal axon/dendrite determination as model systems.1. Identification of extracellular signals modulating neuronal polarity and following signaling pathways.Extracellular signals such as laminin induced the production of PIP3, inactivation of GSK-3β, and resultant activation of CRMP-2. Active CRMP-2 bound to tubulin, Sra-1, and Numb, and regulated tubulin polymerization, actin remodeling, and L1 endocytosis at growth cone, which contributed to the axon elongation and neuronal axon/dendrite determination. In addition, Par complex composed of Par-3, Pare and aPKC modulated the Rac activity through Rac GEF (Tiam1/Tiam2) to establish neuronal polarity and front-rear polarity of migrating cells.2. Analysis of signali … More ng pathways underlying cell migrationDuring establishment and maintenance of front-rear polarity in cell migration, Rac/IAGAP1 regulated dynamics of both actin and microtubules through APC/CLIP-170. Rho/Rho-kinase inhibited Par complex formation and adjusted the Rac activity properly both at the front and rear.3. Role of molecular and vesicular traffic in cell polarization and migrationCRMP-2 interacted with tubulin, Sra-1 and Slp1/TrkB, and transported them to the tip of axon as a “cargo receptor". Numb regulated integrin endocytosis at the front of migrating cell, which is supposed to be necessary for directional migration.4. Analysis of signal networks by computer simulationThe computational model for endothelial cell contraction (activation of myosin) suggested the existence of unidentified pathway for sustained cell contraction in silico, and the novel pathway mediated by iPLA2 was identified in vivo. The computational model for establishment of front-rear polarity of migrating cells by Rho family GTPases was developed. Less

细胞极化是细胞功能的重要步骤，但建立和维持细胞极性的基本机制尚未完全了解，我们试图通过使用细胞迁移和神经元轴突/树突确定作为模型来阐明控制细胞极化的信号转导机制。系统.1.调节神经元极性和遵循信号通路的细胞外信号的鉴定。细胞外信号如层粘连蛋白诱导PIP3的产生、GSK-3β的失活以及由此产生的CRMP-2的激活。活性 CRMP-2 与微管蛋白、Sra-1 和 Numb 结合，并调节生长锥处的微管蛋白聚合、肌动蛋白重塑和 L1 内吞作用，这有助于轴突伸长和神经元轴突/树突决定。 Par-3、Pare 和 aPKC 通过 Rac GEF (Tiam1/Tiam2) 调节 Rac 活性，以建立神经极性和前后极性2. 细胞迁移的信号通路分析在细胞迁移过程中前后极性的建立和维持过程中，Rac/IAGAP1 通过抑制 APC/CLIP-170 来调节肌动蛋白和微管的动态。分子和囊泡运输在细胞极化和迁移中的作用CRMP-2与细胞相互作用。微管蛋白、Sra-1和Slp1/TrkB，并将它们作为迁移细胞前端的“货物受体”转运至轴突尖端，这被认为是定向迁移所必需的。4．计算机模拟信号网络内皮细胞收缩（肌球蛋白激活）的计算模型表明，计算机模拟中存在未识别的持续细胞收缩途径，并且由开发了 Rho 家族 GTPases 建立迁移细胞前后极性的计算模型。