权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Studies of the signals mediated through the cytokine receptor gp130

通过细胞因子受体 gp130 介导的信号研究

基本信息

批准号：
11670321
负责人：
HIBI Masahiko
金额：
$ 2.62万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670321/
关键词：
gp130 STAT3 SHP2 Pim-1 c-Myc Gab1 cell proliferation knockin mouse サイトカイン受容体 SHP-2 Gabファミリー蛋白 VCP

项目摘要

gp130 is a subunit that is common to the receptors for the interleukin-6 family cytokines. Biological responses elicited by gp130 are thought to be mediated through the three major signals : a signal dependent on phosphorylation of tyrosine 759 (possibly involves SHP2), a signal dependent on phosphorylation of YXXQ motifs and mediated through STAT3, and signal (s) independent on tyrosine phosphorylation of gp130. 1. We previously demonstrated that both the tyrosine759-mediated and the STAT3-mediated signals are required for the gp130-mediated cell proliferation. In this project, we identified Pim genes (Pim-1, 2) and c-myc as direct targets for STAT3. We found that Pim-1 and c-Myc cooperatively regulate G1-S phase cell-cycle progression and prevent apoptosis. We also found that VCP/Cdc48 is a target for the Pim-1-mediated signal and VCP/Cdc48 is involved in anti-apoptosis. 2. We previously found that Gab1 is involved in the tyrosine 759-mediated signal using cell lines. In this project, we generated Gab1 -deficient mice and found that Gab1 is required for heart, placenta, and skin development, and grow factor (EGF, PDGF, HGF)- and cytokine (gp130)-induced ERK MAP kinase activation. 3. To reveal roles of the gp130-mediated signals in vivo, we generated a series of knockin mouse lines, in which the STAT3- and/or tyrosine 759-mediated signals are disrupted, by replacing the mouse gp13O gene with human gp130 mutant cDNAs. We found that the STAT3-mediated signal is involved in IgG2a and IgG2b production and Th1-type cytokine production, and the tyrosine 759-mediated signal negatively regulates the STAT3-mediated biological responses.

Gp130是白介素6家族细胞因子受体所共有的一个亚基。目前认为gp130诱导的生物反应主要通过三种信号传递：依赖于酪氨酸759磷酸化的信号(可能涉及SHP2)、依赖于YXXQ基序磷酸化的信号(通过STAT3)和不依赖于gp130酪氨酸磷酸化的信号(S)。1.我们先前的研究表明，酪氨酸759介导的信号和STAT3介导的信号都是gp130介导的细胞增殖所必需的。在这个项目中，我们确定了Pim基因(Pim-1，2)和c-myc作为STAT3的直接靶点。我们发现PIM-1和c-Myc协同调控G1-S期细胞周期进程，阻止细胞凋亡。我们还发现VCP/CDC48是Pim-1介导的信号的靶点，VCP/CDC48参与抗细胞凋亡。2.我们利用细胞系发现GAB1参与酪氨酸759介导的信号传导。在这个项目中，我们建立了GAB1缺陷小鼠，发现GAB1是心脏、胎盘和皮肤发育所必需的，生长因子(EGF、PDGF、HGF)和细胞因子(Gp130)诱导ERK MAP激酶激活。3.为了揭示gp130介导的信号在体内的作用，我们用人gp130突变的cDNA取代了小鼠的gp13O基因，建立了一系列敲打小鼠系，其中STAT3和/或酪氨酸759介导的信号被破坏。我们发现，STAT3介导的信号参与了IgG2a和IgG2b的产生和Th1型细胞因子的产生，而酪氨酸759介导的信号负调控STAT3介导的生物反应。