Analysis of disease susceptibility genes on Rho family signaling molecules

Rho家族信号分子疾病易感基因分析

基本信息

批准号：
18590261
负责人：
AMANO Mutsuki
金额：
$ 2.57万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590261/
关键词：
Rho Rac Rho-kinase eNOS PAR-3 sienal transduction ARHGAP9 STEF SNP

项目摘要

Rho family small GTPases regulate cell adhesion and cell motility. Among them, Rho participates in the regulation of smooth muscle contraction and cell migration. It has been suggested that the aberrant activation of Rho/Rho-kinase is associated with vasospasm, hypertension and progression of atherosclerosis via promotion of cell contraction and migration. However, involvement of other Rho .family GTPases such as Rac and Cdc42 has been less documented, even though Rac and Cdc42 are generally believed to be important in cell migration and adhesion and to cross talk with Rho signaling pathway.1. Endothelial NOS (eNOS) produces NO, which is involved in various physiological functions of the cardiovascular system. eNOS is activated by phosphorylation at Ser1177, and by dephosphorylaton at Thr495. However, little is known about the protein kinases responsible for phosphorylation at Thr495. In this study, vie found that Rho-kinase phosphorylated eNOS at Thr495 both in vitro and endothelium, … More suggesting that Rbo-kinase can suppress NO production in endothelium through direct phosphorylation of eNOS.2. A polarity complex of PAR-3, PAR-6, and aPAC functions in various cell polarization events, and PAR-3 interacts with RacGEF, STEP which leads to Rac activation. Rho and Rbo-kinase antagonize Rae in certain cell types, but the underlying mechanisms remain elusive. We here hind that Rho-kinase phospborylated PAR-3 at Thr333 and thereby disrupted its interaction with aPAC and PAR-6, and that Rlxykinam also phosphorylated STEF and modulated its functions. We propose that RholRbo-Kinase inhibits Rae activity through phosphorylation of PAR-3 and STEF.3. Previous reports have shown that Rbo family GTPases are related to cardiovascular diseases. In this study, we hypothesized that there exist susceptibility genes f cardiovascular diseases in Rho family signaling molecules. We analyzed association of 38 gems (57 SNPs) of Rho family signaling molecules with coronary artery spasm, and found significant association of ARHGAP9 (Ala370Ser), which is negative regulator for Rac in vivo. Less

Rho 家族小 GTP 酶调节细胞粘附和细胞运动，其中 Rho 参与调节平滑肌收缩和细胞迁移，Rho/Rho 激酶的异常激活与血管痉挛、高血压和疾病进展有关。然而，尽管 Rac 和 Cdc42 等其他 Rho 家族 GTPase 的参与却鲜有报道。人们普遍认为Cdc42在细胞迁移和粘附以及与Rho信号通路的交叉作用中发挥着重要作用。1．内皮NOS（eNOS）产生NO，参与心血管系统的多种生理功能。，并通过 Thr495 去磷酸化。然而，对于负责 Thr495 磷酸化的蛋白激酶知之甚少，vie 发现。 Rho 激酶在体外和内皮细胞中的 Thr495 处磷酸化 eNOS，……更多表明 Rbo 激酶可以通过直接磷酸化 eNOS 来抑制内皮细胞中 NO 的产生。2 PAR-3、PAR-6 和 aPAC 功能的极性复合物。各种细胞极化事件，PAR-3 与 RacGEF、STEP 相互作用，导致 Rho 和 Rbo 激酶拮抗。 Rae 在某些细胞类型中存在，但其潜在机制仍然难以捉摸，我们认为 Rho 激酶在 Thr333 处磷酸化 PAR-3，从而破坏其与 aPAC 和 PAR-6 的相互作用，并且 Rlxykinam 也磷酸化 STEF 并调节其功能。 RholRbo-Kinase 通过 PAR-3 和 STEF.3 的磷酸化抑制 Rae 活性。 GTP酶与心血管疾病相关。本研究探讨了Rho家族信号分子中是否存在心血管疾病的易感基因，我们分析了Rho家族信号分子的38个gems（57个SNP）与冠状动脉痉挛的相关性。 ARHGAP9 (Ala370Ser) 的关联，它是体内 Rac 的负调节因子。