Study on function and molecular mechanism of G protein signal network

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G protein-coupled receptors(GPCRs) constitute the largest family of seven-transmembrane receptors and are responsible for converting a diverse array of extracellular stimuli into intracellular signaling events with activation of the heterotrimeric GTP-binding regulatory proteins (G proteins). However, the mechanism by which GPCRs lead the multiple cellular responses is not fully understood. We demonstrated that the G protein signaling controls the cell proliferation and cell migration through MAP kinase cascades. In this project, we investigated the molecular mechanism between G protein signaling and MAP kinase cascade in the neural stem cells and transformed cells. In the transformed 293T cells, a novel guanine nucleotide exchange factor(GEF), FRG, was identified to function downstream of G protein. Endothelin-1 stimulated the GEF activity of FRG for Cdc42. We found that FRG is tyrosine-phosphorylated and activated by Src, and involved in the regulation of cell migration by endothelin-1. Furthermore, we demonstrated that an adaptor protein, Nck1, acts as the signal mediator between downstream of GPCR and upstream of Cdc42. Next crucial step is to investigate the relationship between FRG and Nck1. Using the combination of the adenovirus-expression system and the brain slice culture system, we found that GPCR signaling through Gq and JNK negatively regulates the neural progenitor cell migration. Moreover, the crosstalk between G protein signaling and dioxin signaling was revealed.