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Signal Transduction Systems for Cell Proliferation, Differentiation and Adhesion with Emphasis upon the Role of GTP-binding Proteins

细胞增殖、分化和粘附的信号转导系统，重点关注 GTP 结合蛋白的作用

基本信息

批准号：
04404091
负责人：
UI Michio
金额：
$ 18.56万
依托单位：
The Institute of Physical and Chemical Chemical Research (RIKEN) (1993-1994)The University of Tokyo (1992)
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

Most parts of the present research depend on two experimental systems : i.e., primary cultured rat hepatocytes and phagocytes from guinea pig peritoneal fluids or cultured cell lines. The adult liver cells retained their differentiated liver functions during primary culture at the high-cell densities, whereas they entered the cell cycle or underwent proliferation exhibiting active DNA systhesis when cultured at the low-cell densities. As regards adrenergic receptor subtypes, the alpha_1-receptor-mediated signal was one of the differentiated liver functions ; beta_2-receptor-mediated cell responses developed quickly, at the expense of alpha_1-receptor-mediated ones, upon the G_0-to-G_1/S phase transition in the cell cycle. The development of beta_2-responses was inhibited by addition of the cell membrane fraction into the low-cell density culture, indicating essential roles of the cell adhesion via cell surface glycoproteins. Activation of glycogen phosphorylase, the eventual cell respo … More nse to either alpha_1-or beta_2-receptor stimulation, was never inhibited by wortmannin, a selective inhibitor of phosphatidylinositol (PI) 3-kinase, when the latter subtype receptors were stimulated. In contrast, wortmannin was partially inhibitory to the cell response to alpha_1-receptor stimulation, being suggestive of occurrence of dual signaling systems, PI 3-kinase-dependent and -independent, in alpha_1-receptor initated Ca^<2+> signaling. In the case of phagocytes whose major functions inclde chemotaxis via cell-to-cell adhesion, we found, taking advantage of wortmannin again, PI 3-kinase to play an essential role in Fcgamma receptor-initiated signalng that is characterized by predominance of protein tyrosine kinase systems. A proten with a molcular weight of 115 kDa, tyrosine-phosphorylated upon the receptor stimulation, bound to the p85-regulatory subunit of PI 3-kinase, probably as a physiological activator of PI 3-kinase inphagocytes. This novel finding will afford an important problem to be solved in future studies. Stimulation of CR3, a complement receptor coupled to a pertussis toxin-susceptible heterotrimeric G protein, or concanavalin A receptors, consisting of the two types of G protein-coupled and non-coupled ones, gave rise to phagocytosis in a wortmannin-sensitive manner, providing evidence for involvement of PI 3-kinase in these signaling systems, too. Less

目前的大部分研究依赖于两种实验系统：即原代培养的大鼠肝细胞和来自豚鼠腹膜液或培养细胞系的吞噬细胞。在高细胞密度的原代培养中，成体肝细胞保持了其分化的肝功能，而在低细胞密度的培养中，成体肝细胞进入细胞周期或进行增殖，表现出活跃的DNA合成。就肾上腺素能受体亚型而言，α _1受体介导的信号是分化的肝功能之一；在细胞周期的g_0到g_1 /S阶段，β 2受体介导的细胞应答以α _1受体介导的应答为代价迅速发展。在低细胞密度培养中加入细胞膜组分可以抑制β 2-反应的发展，这表明通过细胞表面糖蛋白的细胞粘附起重要作用。糖原磷酸化酶的激活是细胞对α _1或β _2受体刺激的最终反应，当α _1或β _2受体受到刺激时，糖原磷酸化酶的激活从未被wortmannin（一种选择性磷脂酰肌醇（PI） 3-激酶抑制剂）所抑制。相比之下，wortmannin部分抑制细胞对alpha_1受体刺激的反应，提示在alpha_1受体启动的Ca^<2+>信号传导中存在PI 3激酶依赖和PI 3激酶独立的双重信号系统。在吞噬细胞的情况下，其主要功能包括通过细胞间粘附趋化，我们发现，再次利用wortmannin， PI 3-激酶在Fcgamma受体启动的信号传导中发挥重要作用，其特征是蛋白酪氨酸激酶系统的优势。一种分子量为115 kDa的蛋白质，酪氨酸在受体刺激下被磷酸化，与PI - 3激酶的p85调节亚基结合，可能作为PI - 3激酶吞噬细胞的生理激活剂。这一新发现将为今后的研究提供一个重要的问题。CR3是一种补体受体，偶联于百日咳毒素敏感的异三聚体G蛋白，或由两种G蛋白偶联和非偶联组成的豆豆蛋白a受体，刺激CR3会以wortmannin敏感的方式引起吞噬，这也为PI 3-激酶参与这些信号系统提供了证据。少