Many important biological processes are regulated by signaling pathways. Understanding the mechanisms by which such regulation occurs is an important component in developing a detailed picture of the origins of varied diseases, such as cancers, cardiovascular and mental disorders. A large number of extracellular molecules signal through heterotrimeric G proteins. G protein coupled pathways in turn regulate many key biological processes including metabolism, proliferation and possibly differentiation. Although G protein pathways have long been studied as linear signaling entities, and many important biological effects are observed by linear signal transfer, various signaling pathways can and do interact with one another and thus become parts of signaling networks. Current research is focused on developing a detailed understanding of how these signaling pathways may connect with one another and the properties these signaling networks possess. In the previous term our research had focused on interactions between the Galphas/adenylyl cyclase and Ras-Raf-MAP-kinase 1,2 pathways and their effects on proliferation. In the up coming term we will focus on developing a detailed understanding of how G protein subunits regulate signaling pathways in developmental processes. In preliminary experiments we have found that Galphao regulates src and the transcription factor STAT-3 in NIH-3T3 cells The proposed studies will attempt to identify and characterize direct effectors for Galphao and determine how these effectors may connect the G protein pathways to the STAT pathways to regulate neurite outgrowth in PC-12 cells. We have also found that Gbetagamma subunits activate the transcriptional factors Tcf/Lef which are crucial components of the wnt signaling pathway. In the coming term we will determine the mechanisms by which Gbetagamma subunits activate Tcf/Lef, and if Gbetagamma subunits play a role in axis duplication in Xenopus embryos. To understand the properties of signaling networks, we will experimentally analyze a simple network of two pathways to determine how the properties of the network define the threshold for stimulation, switching between states and the capability for deactivation. From the experimental data we will build a refined model of how such a system might function. We anticipate that the proposed studies should provide new insights into how G protein coupling to other signal pathways can be used to evoke biological effects.
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