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Receptor type protein tyrosine phosphatase, RPTPbeta on the surface of platelets:relationship to the Helicobacter pylori-related disease

血小板表面受体型蛋白酪氨酸磷酸酶、RPTPβ：与幽门螺杆菌相关疾病的关系

基本信息

批准号：
18591051
负责人：
OZAKI Yukio
金额：
$ 2.49万
依托单位：
University of Yamanashi
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-18591051/
关键词：
platelets VacA Gitl

项目摘要

Helicobacter pylori is reportedly related to gastric ulcer/cancer, idiopathic thrombocytopenic purpura, and ischemic heart disease. We hypothesized that one of the causes of pylori-related diseases is VacA-stimulated platelet activation through interaction with RPTPbeta. The aim of this study in 2007 is to prove that VacA stimulates platelets by interacting with RPTPbeta using RPTPbeta-deficient mice and that in 2007 is to investigate signal transduction pathway mediated through RPTPbeta. In 2006, we failed to prove that VacA stimulates platelets by interacting with RPTPbeta and lost opportunity to use RPTPbeta-deficient mice. Therefore, we sought to identify another VacA receptor in platelets. MS/MS analysis revealed a macromolecule that is stored in the platelet alpha granule (named protein X) as one of the proteins associated with VacA-coated beads. We confirmed the binding between VacA and GST-protein X fusion protein using Biacore. We are now investigating VacA binding site in pro … More tein X. In other cells, an adapter protein, Git 1 is reported to undergo tyrosine phosphorylation downstream of RPTPbeta upon stimulation with VacA. Although VacA did not stimulate tyrosine phosphorylation of Git 1 in platelets, it is tyrosine-phosphorylated by outside-in signals downstream of integrin αIIbβ3. Since there has been no report about Git 1 expression in platelets, we decided to investigate regulation of Git 1 in platelets. We found that GIT 1 was abundantly expressed in platelets and underwent tyrosine phosphorylation downstream of integrin αIIbβ3, which was inhibited by the Src kinase inhibitor PP2. Furthermore, GIT1 constitutively associated with betaPlX, a guanine nucleotide exchange factor for Rac. The GIT1/betaPIX complex associated with allbp3, concomitantly with GIT1 tyrosine phosphorylation. Moreover, both GIT1 and αIIbβ3 rapidly translocated to the cytoskeletal fraction during platelet aggregation, which was not observed in the absence of aggregation. These results suggest that tyrosine phosphorylation of GIT1 by Src kinases may regulate cytoskeletal reorganization downstream of αIIbβ3 by bringing the Rac GEF betaPlX to the vicinity of the integrin. Less

据报道，幽门螺杆菌与胃溃疡/癌症、特发性血小板减少性紫癜和缺血性心脏病有关。我们假设幽门相关疾病的原因之一是VacA通过与RPTP β相互作用刺激血小板活化。2007年的研究目的是利用RPTP β缺陷小鼠证明VacA通过与RPTP β相互作用刺激血小板，2007年的研究目的是研究RPTP β介导的信号转导途径。2006年，我们未能证明VacA通过与RPTP β相互作用刺激血小板，失去了使用RPTP β缺陷小鼠的机会。因此，我们试图在血小板中鉴定另一种VacA受体。MS/MS分析揭示了储存在血小板α颗粒中的大分子（称为蛋白X），作为与VacA包被珠相关的蛋白质之一。我们使用Biacore证实了VacA与GST-蛋白X融合蛋白之间的结合。我们现在正在研究蛋白质中的VacA结合位点， ...更多信息泰恩X在其他细胞中，据报道，衔接蛋白Git 1在用VacA刺激后在RPTP β下游进行酪氨酸磷酸化。虽然VacA不刺激血小板中Git 1的酪氨酸磷酸化，但其通过整合素αIIbβ3下游的由外向内信号而酪氨酸磷酸化。由于血小板中Git 1表达的研究尚未见报道，因此我们决定研究血小板中Git 1的调控。我们发现GIT 1在血小板中大量表达，并在整合素αIIbβ3下游进行酪氨酸磷酸化，这可被Src激酶抑制剂PP 2抑制。此外，GIT 1与β PlX（Rac的鸟嘌呤核苷酸交换因子）组成型相关。GIT 1/betaPIX复合物与allbp 3相关，伴随GIT 1酪氨酸磷酸化。此外，在血小板聚集过程中，GIT 1和αIIbβ3均迅速移位至细胞骨架部分，而在无聚集时未观察到。这些结果表明，Src激酶对GIT 1的酪氨酸磷酸化可能通过将Rac GEF betaPlX带到整联蛋白附近来调节αIIbβ3下游的细胞骨架重组。少