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Rap1-and R-Ras-regulated vascular endothelial cell-cell adhesion

Rap1 和 R-Ras 调节血管内皮细胞-细胞粘附

基本信息

批准号：
17370075
负责人：
MOCHIZUKI Naoki
金额：
$ 10.02万
依托单位：
National Cardiovascular Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17370075/
关键词：
intercellular adhesion GTP-binding protein vascular endothelial cells

项目摘要

While vascular integrity is maintained to prevent the leakage of fluid from the lumen to the tissues, angiogenis sprouting and branching is required for angiogenesis. Thus, balance between vascular endothelial cell-cell adhesion and deadheison control vascular quiescence and angiogenesis. However, it remains elusive how vascular endothelial cell-cell adhesion is regulated by small GTPases, Rap1 and R-Ras. We here identified two novel signaling pathways which tighten the endothelial cell-cell adhesion and inhibit the vascular permeability ; (1) cAMP-Epac-Rap1 and (2) Vascular endothelial cadherin(VE- cadherin) -MAGI-1-PDZ-GEF1-Rap1. cAMP has been proven to stabilize the cell-cell contacts and reduce the permeability.In vascular endothelial cells, cAMP activates. Epac, a guanine nucleotide exchange factor for Rap1, thereby increase GTP-bound Rap1. We found that increased GTP-Rap1 leads to tightening of intercellular adhesion and to reduced vascular permeability. Furthermore, Rap1 activat … More ion induces the rearrangement of actin cytoskeleton that support the VE-cadherin- mediated cell-cell adhesion via alph- and beta- catenins. In animal model, cAMP-increasing reagents indeed reduced the leakage of dye from vasculature, indicating the important role of Rap1 for vascular stability.Homophilic association of VE-cadherin is essential for formation of endothelial adherens junction that constitute an essential intercellular adhesion. Ve-cadherin is linked to actin cytoskeleton via beta-catenin and alpha-cateni. n. We found that the trans-association of VE-cadherin recruits MAGI-1/PDZ-GEF1 complex to the cell-cell contacts. Since PDZ-GEF1 functions a GEF for Rap1, the association of VE-cadherin results in the activation of Rap1 at the cell-cell contacts, thereby stabilizing the intercellular adhesion.The two sigmalign pathways we identified in this research provide the evidence that the activation of Rap1 in endothelial cells results in the stabilization of cell-cell contacts and the possibility that Rap1-activating reagent can be used for the reduction of permeability such as edema. We have not yet identified the downstream of Rap1 in detail. Therefore, further research focusing on the Rap1 signaling in endothelial cells will contribute to understanding the regulation of vascular quiescence and angiogenesis. Less

虽然维持血管完整性以防止液体从管腔渗漏到组织，但血管生成需要血管生成发芽和分支。因此，血管内皮细胞-细胞粘附和deadheison之间的平衡控制血管静止和血管生成。然而，小 GTPase、Rap1 和 R-Ras 如何调节血管内皮细胞间粘附仍不清楚。我们在此发现了两种新的信号传导途径，可以加强内皮细胞-细胞粘附并抑制血管通透性； (1) cAMP-Epac-Rap1 和 (2) 血管内皮钙粘蛋白 (VE-钙粘蛋白) -MAGI-1-PDZ-GEF1-Rap1。 cAMP 已被证明可以稳定细胞与细胞的接触并降低通透性。在血管内皮细胞中，cAMP 被激活。 Epac 是 Rap1 的鸟嘌呤核苷酸交换因子，从而增加 GTP 结合的 Rap1。我们发现 GTP-Rap1 增加会导致细胞间粘附收紧并降低血管通透性。此外，Rap1 激活离子诱导肌动蛋白细胞骨架的重排，从而通过 α- 和 β- 连环蛋白支持 VE-钙粘蛋白介导的细胞间粘附。在动物模型中，cAMP 增加试剂确实减少了染料从脉管系统的渗漏，表明 Rap1 对于血管稳定性的重要作用。VE-钙粘蛋白的同亲缔合对于内皮粘附连接的形成至关重要，内皮粘附连接构成了重要的细胞间粘附。 Ve-钙粘蛋白通过 β-连环蛋白和 α-连环蛋白与肌动蛋白细胞骨架相连。名词我们发现 VE-钙粘蛋白的反式缔合将 MAGI-1/PDZ-GEF1 复合物招募到细胞-细胞接触处。由于PDZ-GEF1对Rap1起到GEF的作用，VE-钙粘蛋白的结合导致细胞-细胞接触处的Rap1激活，从而稳定细胞间粘附。我们在本研究中确定的两条sigmalign通路提供了内皮细胞中Rap1的激活导致细胞-细胞接触稳定的证据，以及Rap1激活试剂可用于减少细胞间粘附的可能性。渗透性，如水肿。我们尚未详细确定 Rap1 的下游。因此，进一步研究内皮细胞中的 Rap1 信号传导将有助于了解血管静止和血管生成的调节。较少的

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）

Interaction of Fox01 and TSC2 induces insulin resistance through activation of mTOR/p70S6K pathway.

Fox01 和 TSC2 的相互作用通过激活 mTOR/p70S6K 通路诱导胰岛素抵抗。

DOI：
发表时间：
2006
期刊：
J.Biol.Chem. 281
影响因子：
0
作者：
Nakayama T;Yoshida M;Noel MH;Kawachi M;Inouye I;八田達夫;Tatsuo HATTA;八田達夫;西村重男;八田達夫;西村重男;Tatsuo Hatta;Tatsuo Hatta;Tatsuo HATTA;Shigeo NISHIMURA;Tatsuo HATTA;Shigeo NISHIMURA;Tatsuo HATTA;八田達夫;西村重男;八田達夫;西村重男;西村重男;Tatsuo HATTA;Shigeo Nishimura;Yoshizaki H;Tatsuo Hatta;Shigeo Nishimura;Nakaoka Y;Shigeo NISHIMURA;Seguchi O;Myoishi M;西村重男;Tatsuo HATTA;Min JK;Kaoru INOUE;Nakaoka Y;八田達夫;Seguchi O;Myoishi M;Tatsuo Hatta;Min JK;Yoshizaki H;Maeng YS.;Cao Y;Masuda M;Kogata N;Shigeo Nishimura;Fukuhara S;Cao Y
通讯作者：
Cao Y

Akt-PDK1 Complex Mediates EGF-induced Membrane Protrusion through Ral Activation.

Akt-PDK1 复合物通过 Ral 激活介导 EGF 诱导的膜突出。