Heterotrimeric G-proteins play a prominent role in signaling between the superfamily of G-protein-linked receptors and a smaller, but diverse group of effectors, such as adenylylcyclases, phospholipase CBeta, ion channels, and others. Recently, G-proteins have been implicated in more complex biological processes, such as oncogenesis, cell growth and differentiation, as well as neonatal development. G-proteins and their receptors are known loci for human disease states, such as Albright hereditary osteodystrophy, McCune-Albright syndrome, and various endocrine tumors, but to name a few. The overaching goal of the research plan is to establish the role of heterotrimeric Gproteins in cell signaling and function. The central hypothesis, based upon compelling experimental evidence, is that the G-proteins Gsalpha and Gialpha2 control differentiation and early mouse development. The prominent role of Gsalpha in repressing adipogenesis by mouse 3T3-L1 embryonal fibroblasts will be investigated using structure/function analysis and the signaling downstream from Gsalpha established by expression of both activated and dominant-negative mutants of key elements to activate, disrupt, an probe the signaling. The progression of embryonic stem cells to primitive and parietal endoderm is a fundamental aspect of development, approachable using the totipotent, mouse F9 teratocarcinoma cells in culture. Gialpha controls progression to primitive endoderm in these cells. The domain(s) of the protein functionally important to the control of progression will be identified by structure/function analysis. The pathways obligate for signaling the commitment of the F9 stem cells to primitive as compared to parietal endoderm will be established using both activated and dominant-negative mutant forms of key elements in the ras, PKC, ras/Raf/MAPK pathways to dissect signaling contributed by each. These critical studies will illuminate the role of heterotrimeric G- proteins in pathways fundamental to signaling, cell function, and human disease.
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