Functional analysis of regulatory mechanism of G protein signal network

G蛋白信号网络调控机制的功能分析

基本信息

批准号：
17370051
负责人：
ITOH Hiroshi
金额：
$ 9.22万
依托单位：
Nara Institute of Science and Technology
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 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17370051/
关键词：
G protein Signal transduction Tyrosine kinase Neural progenitor cells Cell migration Signal amplifier 低分子量GTP結合タンパク質 Rho GEF MAPキナーゼ

项目摘要

G proteins are composed of a, p, and y subunits, and transmit a variety of signals from G protein-coupled receptors (GPCRs) to intracellular effectors by acting as molecular switch. We demonstrated that the GPCR signaling through Gq and JNK negatively regulates the neural progenitor cell migration. Moreover, we found that Ric-8 and flotillins are a new type of Gq-binding regulatory proteins. Ric-8A promoted the guanine nucleotide exchange of Gαq, and amplified the Gq-mediated cellular responses, such as intracellular Ca mobilization and JNK activation. It was revealed that Ric-8A translocates from cytosol to membrane upon receptor stimulation. The knockdown of flotillins, which are known to be lipid raft maker proteins, by siRNA attenuated the GPCR-induced p38 MAPK activation and tyrosine phosphorylation. Treatment with Src tyrosine kinase inhibitors and cholesterol depleting agent methyl-beta-cyclodextrin also inhibited the GPCR-induced p38 MAPK activation and tyrosine phosphorylation. These lines of evidence suggested that a Gq-coupled receptor activates p38 MAPK through lipid rafts and Src, in which flotillins positively regulates the Gq signaling. Previously, we demonstrated that FRG, a novel RhoGEF for Cdc42, is activated downstream of Gq-coupled receptor. In this research, we found that FRG functions in the signaling pathway downstream CD47 and Src and is involved in the development of axons and dendrites in hippocampal neurons. Another RhoGEF P-Rex1 is activated by G protein βγ subunit and essential for reactive oxygen species (ROS) production in neutrophils. We found that intramolecular domain interaction of P-Rex1 is critical for Gβγ-induced activation and PKA-induced inhibition.

G蛋白由A，P和Y亚基组成，并通过充当分子开关来从G蛋白偶联受体（GPCR）传输各种信号到细胞内效应。我们证明了通过GQ和JNK的GPCR信号对神经祖细胞的迁移产生负调节。此外，我们发现RIC-8和鞭毛蛋白是GQ结合调节蛋白的一种新型。 RIC-8A促进了GαQ的鸟嘌呤核交换，并扩增了GQ介导的细胞反应，例如细胞内CA动员和JNK激活。结果表明，在受体刺激下，RIC-8A从细胞质转向膜。 siRNA敲低氟替林，已知是脂质筏制造蛋白。用SRC酪氨酸激酶抑制剂和胆固醇耗尽剂甲基-Beta-Cyclodextrin治疗也抑制了GPCR诱导的P38 MAPK激活和酪氨酸磷酸化。这些证据表明，GQ耦合受体通过脂质筏和SRC激活p38 MAPK，其中氟替林积极调节GQ信号传导。以前，我们证明了FRG是一种用于CDC42的新型RhoGEF，被激活的GQ耦合受体的下游激活。在这项研究中，我们发现FRG在下游CD47和SRC的信号通路中起作用，并且参与了海马神经元中轴突和树突的发展。另一个Rhogef P-Rex1被G蛋白βγ亚基激活，对于中性粒细胞中的活性氧（ROS）产生至关重要。我们发现P-REX1的分子内结构域相互作用对于Gβγ诱导的激活和PKA诱导的抑制至关重要。

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）

G protein-coupled receptor signaling through Gq and JNK negatively regulates neural progenitor cell migration

通过 Gq 和 JNK 的 G 蛋白偶联受体信号传导负向调节神经祖细胞迁移

DOI：
发表时间：
2005
期刊：
Proc.Natl.Acad.Sci.USA 102
影响因子：
0
作者：
海津正賢(Umitsu;Masataka);H.Saito;I.Kawamura;I.Kawamura;I.Kawamura;A.Naito;K.Nishimura;K.Yamamoto;M.Umeyama;A.Naito;M.Kamihira;K.Nishimura;A.Naito;K.Yamamoto;K.Nishimura;T.Uezono;S.Toraya;H.Saito;内藤晶(分担執筆);Y.Sugawara et al.;A.Nishimura et al.;T.Murata et al.;A.Nishimura et al.;N.Mizuno et al.
通讯作者：
N.Mizuno et al.

Ric-8A potentiates Gq-mediated signal transduction by acting downstream of G protein-coupled receptor in intact cells