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Physiological Roles of Heterotrimeric G-proteins in Signal Transduction

异源三聚体 G 蛋白在信号转导中的生理作用

基本信息

批准号：
04304048
负责人：
UI Michio
金额：
$ 23.04万
依托单位：
The Institute of Physical and Chemical Research (RIKEN) (1993)The University of Tokyo (1992)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Co-operative Research (A)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

项目摘要

PI 3-kinase, which is activated by phosphotyrosines through its binding via the SH2 domain, was found to play an essential role in G protein-mediated signaling systems (M.Ui). This finding was achieved with the use of a novel inhibitor of this enzyme, wortmannin, and is the first to show involvement of G proteins in the tyrosine phosphorylation system that has been so far considered to be triggerred by stimulation of growth factor (or cell adhesion) receptors without mediation of G proteins. An additional role of G proteins was shown by T.Kataca in differentiation of HL-60 cells in response to autocrine factors released by treatment of the cells with retinoic acid. Similar role of G proteins was found by U.Nomura in differentiation of neuronal cells as a mechanism of synapse plasticity. Coupling mechanisms for receptorp-G protein-phospholipase has been studied extensively by Y.Nozawa, F.Okajima and N.Nakahata who analyzed activation of phosphlipases C and D, in hibitino of phospholipase C and purinergic receptor-mediated activation or phospholipse A_2, respectively. Molecular mechanisms of the coupling were the subject of A Ichikawa and T.Haga. Ichikawa purified three isoforms of prostaglandin E receptors, succeeded in cDNA cloning and sequencing of amino acids, and identified G proteins specifically coupled to these receptors. Haga found a physiological role of betaganmma-subunit of G proteins as an inhibitor of G protein-coupled receptor kinase which contributed to desensitization of signal reception. Isomeric forms of the betagamma were analyzed by T.Asano who purified and cloned these isomers providing evidence for their functional differences. N.Kimura continued his original work on the role of NDP kinase as a physiological regulator of G proteins. Thus, thjis research group has made great contributions to current understanding of cellular and molecular mechanisms for receptorp-G protein-effector coupling.

PI 3-激酶通过 SH2 结构域结合被磷酸酪氨酸激活，被发现在 G 蛋白介导的信号系统 (M.Ui) 中发挥重要作用。这一发现是通过使用这种酶的新型抑制剂渥曼青霉素实现的，并且首次表明 G 蛋白参与酪氨酸磷酸化系统，迄今为止，该系统被认为是通过刺激生长因子（或细胞粘附）受体而触发的，而不需要 G 蛋白的介导。 T.Kataca 证明了 G 蛋白在 HL-60 细胞分化中的另一个作用，该分化是对视黄酸处理细胞所释放的自分泌因子的反应。 U.Nomura 发现 G 蛋白在神经元细胞分化中发挥类似作用，作为突触可塑性的机制。 Y.Nozawa、F.Okajima 和 N.Nakahata 对受体 p-G 蛋白-磷脂酶的偶联机制进行了广泛研究，他们分别分析了磷脂酶 C 和 D 的激活、磷脂酶 C 的抑制素和嘌呤受体介导的激活或磷脂酶 A_2。耦合的分子机制是 A Ichikawa 和 T.Haga 的主题。 Ichikawa纯化了前列腺素E受体的三种亚型，成功地进行了cDNA克隆和氨基酸测序，并鉴定了与这些受体特异性偶联的G蛋白。 Haga 发现 G 蛋白的 betaganmma 亚基作为 G 蛋白偶联受体激酶抑制剂的生理作用，有助于信号接收的脱敏。 T.Asano 分析了 βamma 的异构形式，他纯化并克隆了这些异构体，为它们的功能差异提供了证据。 N.Kimura 继续他关于 NDP 激酶作为 G 蛋白生理调节剂的作用的原创工作。因此，该研究小组为当前对受体p-G蛋白-效应子偶联的细胞和分子机制的理解做出了巨大贡献。