Physiological Roles of Heterotrimeric G-proteins in Signal Transduction

PI 3-激酶通过其与SH 2结构域的结合被磷酸酪氨酸激活，被发现在G蛋白介导的信号传导系统中起重要作用（M.Ui）。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，并且是第一个显示G蛋白参与酪氨酸磷酸化系统的发现，该酪氨酸磷酸化系统迄今为止一直被认为是通过刺激生长因子（或细胞粘附）受体而不介导G蛋白来实现的。T.Kataca在HL-60细胞的分化中显示了G蛋白的另一个作用，该分化响应于用视黄酸处理细胞所释放的自分泌因子。野村发现G蛋白在神经元细胞分化中的类似作用是突触可塑性的一种机制。Y.Nozawa、F.Okajima和N.Nakahata对受体-G蛋白-磷脂酶的偶联机制进行了广泛的研究，他们分别分析了磷脂酶C和D在磷脂酶C的hibitino和嘌呤能受体介导的磷脂酶A_2的活化中的活化。A Ichikawa和T. Haga研究了偶联的分子机制。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β-亚基作为G蛋白偶联受体激酶的抑制剂，其生理作用有助于信号接收的脱敏。T.Asano分析了β-γ的异构体形式，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继续了他关于NDP激酶作为G蛋白的生理调节剂的作用的原始工作。因此，本课题组为目前对受体-G蛋白-效应器偶联的细胞和分子机制的理解做出了巨大贡献。

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.