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Molecular mechanism of thrombin receptor pathway that mediated apoptosis in neural cells

凝血酶受体途径介导神经细胞凋亡的分子机制

基本信息

批准号：
10680605
负责人：
IDO Masaru
金额：
$ 1.79万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10680605/
关键词：
Thrombin receptor Serine threonin kinase Platenet PCR

项目摘要

Thrombin is a multifunctional serine protease that plays an important role in hemostasis and wound healings. High concentrations of thrombin in the central nervous system is often associated with neural cell death. Protease-activated receptor 1 (PAR1/ thrombin receptor) is a member of the G protein-coupled receptor containing seven transmembrane domains. Thrombin cleaves the receptor at the Arg41/Ser42 peptide bond and unmasks a tethered amino-terminal sequence beginning with the Ser-Phe-Leu-Leu-Arg-Asn (thrombin receptor agonist peptide/TRAP) ; subsequent binding of this ligand sequence to the body of the receptor is coupled with a transmembrane signaling mediated by G proteins. Neural cell death by thrombin is mediated by the activation of PAR1. Thus, regulation is coupled with internalization and PAR1. Phosphorylation of Ser and/or Thr in this region by Ala residue or truncation of this region results in resistance to desensitization and internalization. However, protein kinase capable of phosphorylating PAR1 in human platelet is unknown. In the present study, we identified the 33-kDa Ser/Thr protein kinase, which was activated by thrombin, TRAP, but not by hirudin-treated thrombin or diisopropylfluoro- phosphate-inactivated thrombin, suggesting that it is activated through PAR1. Furthermore, treatment of cells with thromboxane AィイD22ィエD2 analog, STAィイD22ィエD2, led to an activation of this protein kinase and phosphorylation of PAR1. In conclusion, the present study provides evidence of homologous and heterologous activation of a novel 33-kDa Ser/Thr kinase that phosphorylates the cytoplasmic tail of PAR1.

凝血酶是一种多功能丝氨酸蛋白酶，在止血和伤口愈合中起重要作用。中枢神经系统中高浓度的凝血酶通常与神经细胞死亡有关。蛋白酶激活受体1（PAR 1/ thrombin receptor 1，PAR 1/ thrombin receptor 1）是G蛋白偶联受体（G protein coupled receptor 1，G蛋白偶联受体）的一个成员。凝血酶在Arg 41/Ser 42肽键处切割受体，并揭开以Ser-Phe-Leu-Leu-Arg-Asn（凝血酶受体激动剂肽/TRAP）开始的束缚的氨基末端序列;随后该配体序列与受体体的结合与G蛋白介导的跨膜信号传导偶联。凝血酶引起的神经细胞死亡是由PAR 1的激活介导的。因此，调节与内化和PAR 1相结合。通过Ala残基磷酸化该区域中的Ser和/或Thr或该区域的截短导致对脱敏和内化的抗性。然而，能够磷酸化人血小板中PAR 1的蛋白激酶是未知的。在本研究中，我们鉴定了33-kDa Ser/Thr蛋白激酶，其被凝血酶TRAP激活，但不被水蛭素处理的凝血酶或二异丙基氟磷酸盐失活的凝血酶激活，这表明其通过PAR 1激活。此外，用血栓烷A β D22 β D2类似物STA β D22 β D2处理细胞，导致该蛋白激酶的活化和PAR 1的磷酸化。总之，本研究提供了一种新的33 kDa的丝氨酸/苏氨酸激酶，磷酸化的PAR 1的胞质尾同源和异源激活的证据。