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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，作为分子开关将G蛋白偶联受体（gpcr）的多种信号传递给细胞内效应器。我们证明GPCR信号通过Gq和JNK负向调节神经祖细胞迁移。此外，我们发现ric8和flotillins是一种新的gq结合调节蛋白。Ric-8A促进了g - αq的鸟嘌呤核苷酸交换，并放大了gq介导的细胞反应，如细胞内Ca的动员和JNK的激活。结果表明，Ric-8A在受体刺激下从细胞质转移到细胞膜。通过siRNA敲低flotillins（已知是脂质筏制造蛋白）可以减弱gpcr诱导的p38 MAPK激活和酪氨酸磷酸化。用Src酪氨酸激酶抑制剂和胆固醇消耗剂甲基- β -环糊精治疗也能抑制gpcr诱导的p38 MAPK活化和酪氨酸磷酸化。这些证据表明，Gq偶联受体通过脂筏和Src激活p38 MAPK，其中flotillins积极调节Gq信号。之前，我们证明了FRG是Cdc42的一种新型RhoGEF，在gq偶联受体下游被激活。在本研究中，我们发现FRG在CD47和Src下游的信号通路中发挥作用，参与海马神经元轴突和树突的发育。另一种RhoGEF P-Rex1被G蛋白βγ亚基激活，是中性粒细胞产生活性氧（ROS）所必需的。我们发现P-Rex1的分子内相互作用对于g βγ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