Physiological Roles of Heterotrimeric G-proteins in Signal Transduction

PI 3-激酶被磷酸酪氨酸通过其结合SH2结构域激活，在G蛋白介导的信号系统（m.i i）中发挥重要作用。这一发现是通过使用这种酶的一种新型抑制剂wortmannin获得的，并且是第一个表明G蛋白参与酪氨酸磷酸化系统的发现，该系统迄今为止被认为是通过刺激生长因子（或细胞粘附）受体而没有G蛋白的介导而触发的。T.Kataca研究表明，G蛋白在HL-60细胞分化过程中对视黄酸处理释放的自分泌因子的反应中发挥了额外的作用。野村（U.Nomura）在神经元细胞分化过程中也发现了G蛋白作为突触可塑性机制的类似作用。Y.Nozawa、f.o 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，他们分析了磷脂酶C和D的激活，分别抑制磷脂酶C和嘌呤能受体介导的磷脂A_2的激活。偶联的分子机制是A Ichikawa和T.Haga的课题。Ichikawa纯化了3种前列腺素E受体的异构体，成功克隆并测序了氨基酸，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betaganma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对β - γ γ的异构体形式进行了分析，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继续他最初的工作，研究NDP激酶作为G蛋白的生理调节剂的作用。因此，本课题组对目前对受体- g蛋白-效应物偶联的细胞和分子机制的理解做出了重大贡献。

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.