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

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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