Biological functions of a lipid mediator, sphingosine 1-phosphate

脂质介质 1-磷酸鞘氨醇的生物学功能

• 批准号: 11480174
• 负责人: IGARASHI Yasuyuki
• 金额: $ 8.7万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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/en/grant/KAKENHI-PROJECT-11480174/
• 关键词: sphingolipid; bioactive lipids; sphingosine 1-phosphate; microdomain (raft); sphingosine kinase; GPCR; receptor; lipid signaling; 糖脂質; Edg受容体; 細胞膜ミクロドメイン; シグナル伝達; G蛋白質; リゾリン脂質受容体; 脂質メディエーター; スフィンゴミエリン回路; スフィンゴシン

1) Roles of Sphingosine 1 -phosphate (Sph- 1 -P) in Platelet-related blood vessel biology.(A) By RT-PCR analysis, we identified that Edg2, 4, 6, and 7 are expressed in human platelets. (B) We purified a novel sphingosine kinase from human platelets. (C) We found for the first time that both Sph-1-P and LPA are released from activated platelets by using new two dimensional TPC separation system. (D) We showed that Sph-1-P released from activated platelets induces in vitro angiogenesis and smooth muscle cell contraction.2) Besides so-far known sphingosine kinases (1 and 2), we identified and cloned two novel sphingosine kinases (3 and 4).3) Activation of Rho and FAK through Edg-5 was suggested to regulate cell motility.4) Studies on Sph-1-P receptors.(A) We first showed that Edg 1 and Edg 6 are N-glycosylated on Asp residue and suggested the roles of glycosylyation on the receptor dynamics toward microdomain in plasmamembrane. (B) We identified ligand- binding amino acid residues in Edg-6 from computer modeling and mutant analysis.

1) Sphingosine 1 -phosphate （Sph- 1 -p）在血小板相关血管生物学中的作用。(A)通过RT-PCR分析，我们发现Edg2、4、6和7在人血小板中表达。(B)我们从人血小板中纯化了一种新的鞘氨醇激酶。(C)利用新的二维TPC分离系统，首次发现活化血小板可同时释放Sph-1-P和LPA。(D)我们发现活化血小板释放的Sph-1-P诱导体外血管生成和平滑肌细胞收缩。2)除了已知的鞘氨醇激酶（1和2）外，我们还鉴定并克隆了两个新的鞘氨醇激酶（3和4）。3)通过Edg-5激活Rho和FAK可以调节细胞运动。4) Sph-1-P受体的研究。(A)我们首先发现edg1和edg6在Asp残基上被n -糖基化，并提出糖基化在质膜上向微结构域的受体动力学中的作用。(B)我们通过计算机建模和突变体分析确定了Edg-6中的配体结合氨基酸残基。

项目成果

五十嵐靖之: "新しい脂質メディエーターとしてのスフィンゴ脂質の役割 ―スフィンゴ生理学とスフィンゴ栄養学の構築をめざして―"道薬誌. 16(5). 4-11 (1999)

Yasuyuki Igarashi：“鞘脂作为新脂质介质的作用 - 旨在建立鞘氨醇生理学和鞘氨醇营养”Doyaku Journal 16（5）（1999）。

Motohashi K., Shibata S., Ozaki Y., Yatomi Y., Igarashi Y.: "Identification of lysophospholipid receptors in human platelets: the relation of two agonists, lyso-phosphatidic acid and sphingosine 1-phosphate"FEBS Lett.. 468. 189-193 (2000)

Motohashi K.、Shibata S.、Ozaki Y.、Yatomi Y.、Igarashi Y.：“人血小板中溶血磷脂受体的鉴定：两种激动剂溶血磷脂酸和 1-磷酸鞘氨醇的关系”FEBS Lett.. 468

Yamamura S.: "Sphingosinel-phosphate inhibits haptotactic motility by overproduction of focal adhesion site in B16 melanoma cells through Edg-induced activation of Rho."Ann.N.Y.Acad Sci. 905. 301-307 (2000)

Yamamura S.：“磷酸鞘氨醇通过 Edg 诱导的 Rho 激活，在 B16 黑色素瘤细胞中过量产生粘着斑位点，从而抑制趋触运动。”Ann.N.Y.Acad Sci。

Yamamura, S.: "Sphingosine 1-phosphate inhibits haptotactic motility by overproduction of focal adhesion site in B16 melanoma cells through Edg-induced activation of Rho"Ann. N. Y. Acad. Sci.. (in press). (2000)

Yamamura, S.：“1-磷酸鞘氨醇通过 Edg 诱导的 Rho 激活，在 B16 黑色素瘤细胞中过度产生粘着斑位点，从而抑制趋触运动”Ann。

Yatomi Y.: "Sphingosine 1-phosphate : synthesis and release"Plastaglandins & other lipid mediators. 64. 107-122 (2001)

Yatomi Y.：“1-磷酸鞘氨醇：合成和释放”前列腺素