Philip B. Wedegaertner, Ph.D.

Research

My research focuses on understanding G protein signaling. We are interested in the basic questions of what are the specific pathways and mechanisms that G proteins use to arrive at the plasma membrane, how and where in the cell are the G protein subunits assembled, and what are the mechanisms of GPCR-activated G protein translocation and recycling back to the PM. Importantly, we also wish to understand how trafficking affects signaling, and thus we are addressing non-canonical signaling roles for G proteins at intracellular organelle locations. A sub-family of three Rho guanine-nucleotide exchange factors (RhoGEFs) are directly activated by heterotrimeric G proteins, thus providing a direct link between the big G proteins and the small GTPases. We are defining how these RhoGEFs regulate G protein activation of Rho signaling and defining a novel role for one RhoGEF in mitosis and cytokinesis. We are also identifying and characterizing a novel membrane targeting domain in G protein-coupled receptor kinases (GRK) 4, 5, and 6. Our results with GRK6 suggest a novel mechanism in which positive and negative forces in the C-terminus function to regulate plasma membrane localization such that changes in palmitoylation allow movement of GRK6 from the plasma membrane to the cytoplasm and nucleus. Further work seeks to identify signals in GRK6 that regulate nuclear transport and to understand the functional significance of nuclear targeting. Moreover, we are currently examining the cell biology of GRK4, the most poorly characterized member of the GRK family.