The roles of heterotrimeric GTP-binding proteins in signal transduction

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This research project was organized by ten and a couple of investigators in order to study the roles of alphabetagamma-heterotrimeric GTP-binding proteins (G proteins) in signal transduction from 1993 to 1995. The major findings obtained in this research project are summarized as follows. 1) The cDNAs of membrane-bound receptors that coupled to G proteins were cloned. Such included a novel photo-receptor, pinopsin, which may play an important role in the circadian rhythm of melatonin synthesis, and various types of prostaglandin receptors. 2) The betagamma subunits of G proteins stimulated the phosphorylation of G protein-coupled membrane receptors (GR) such as muscarinic acetylcholine receptors by GR kinases (GRKs). This receptor phosphorylation by GRKs appeared to be involved in the internalization of the phosphorylated receptor molecules. 3) Wortmannin was found to be a specific inhibitor of phosphoinositide (PI) 3-kinase. Using this specific inhibitor, PI 3-kinase was shown to be involved signal transduction pathways mediated through two different types of membrane receptors, one possessing tyrosine kinase activity and the other activating G proteins. 4) Phospholipase D activity was stimulated not only by G proteins but also by small GTP-binding proteins such as Rho and ARF.5) The Post-translational modification of G proteins, fatty-acid addition to alpha subunits, isoprenylation and phosphorylation of gamma subunits, playd important roles in the functional regulation of the signal-transducing proteins.