RECEPTOR INTERACTION WITH GTP-REGULATORY PROTEINS

异三聚体gtp结合蛋白家族，称为G

The family of heterotrimeric GTP-binding proteins, referred to as G proteins, function by coupling cell surface receptors to the control of intracellular signal transduction pathways. G protein-coupled receptors have a characteristic seven transmembrane structure (STM). The extracellular and membrane domains of STM receptors vary in sequence to allow selective binding of different ligands including photons, ions, odorants, molecules like acetylcholine and catecholamines, peptides and proteases. The STM receptors differentially couple to members of the G protein family. The known G proteins can be categorized into four families based on sequence and functional homologies. Known effectors for G proteins include adenylyl cyclases, phosphotidylinositol phospholipase Cbeta, cGMP-phosphodiesterase and specific ion channels. The list of G protein effectors is certain to grow and may include specific tyrosine kinases, phosphatases and the Na+/H+ antiporter. A number of human diseases have now been found to result from mutation of specific STM receptors and G protein alpha subunits. In the thyroid and pituitary gain of function mutations in receptors and the Galpha(s) polypeptide result in hyperfunctioning adenomas. STM neuropeptide receptors are also involved in stimulating hyperplasia of vascular smooth muscle cells and epithelial cells of the colon and lung. The aim of this proposal is to define the signal transduction pathways regulated by G proteins that control cell proliferation and the differentiated phenotype. G protein stimulated Ras GTP loading is a major component of STM receptor regulation of mitogenesis. The G protein regulation of Ras activation will be defined. The integration of G protein-regulated signaling with growth factor receptor tyrosine kinase signal transduction pathways and the involvement of Ras function in this process will also be characterized. These studies will include the analysis of STM receptor regulation of non-Ras small G proteins (i.e. Rac and Rho) and sequential protein phosphorylation pathways controlling the activity of different MAP kinases. G protein-coupled receptors can positively and negatively regulate the responsiveness of tyrosine kinase stimulated mitogenic signals. The positive or negative regulation of tyrosine kinase stimulated signals by STM receptors is dictated by the cell specific expression of the numerous isoforms of G protein-coupled effectors like adenylyl cyclase and phospholipase Cbeta. These studies will define the signal transduction pathways whose regulation is altered as a result of STM receptor and Galpha subunit mutation or change in expression. It will be possible to treat human diseases resulting from gain or loss of function of G protein and/or tyrosine kinases by selectively manipulating the activity of specific response pathways regulated by these different receptor systems.