The long term objective of this project is to study the signaling mechanisms of G protein coupled receptors. In this application, the PI proposes to identify and characterize the signaling components in the vertebrate G protein MAPK (mitogen activated protein kinase) pathways. The MAPK pathway is ubiquitous in eukaryotic organisms and plays important roles in may cellular processes. G proteins and their coupled receptors can activate the MAPK cascade. The mechanism by which G protein coupled receptors activate MAPK in vertebrates is pertinent to many physiological functions. Tremendously aided by a powerful genetic approach, the biochemical mechanism of activation of the MAPK pathway by receptors with intrinsic tyrosine kinase activity in both invertebrates and vertebrates is well understood. However, the mechanisms utilized by G protein coupled receptors to activate the MAPK pathway in vertebrates are less clear. Most previous studies on vertebrate G protein MAPK pathways have employed pharmacological inhibitors to implicate molecules in the signaling cascade. Although these studies have provided some insights into the mode of transduction of the G protein signals, they have failed to definitively identify the specific components of the transduction pathway. In this proposal, the PI hypothesizes specific functional requirements for some specific molecular components in the vertebrate G protein MAPK pathways. He proposes experiments to test the hypothesis using a genetic approach to generate knock out mutants of these components in a model cell line that has a distinct advantage for this molecular genetic approach due to its extremely high frequency of homologous recombination. Although the studies outlined are designed to identify signaling components in the G protein MAPK pathway, the information obtained on the interactions between G protein subunits, between G proteins and effectors, and downstream signaling components is expected to contribute in a more general way to our understanding of the physiological functions of G protein coupled receptors.
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