Philip B. Wedegaertner, PhD

Research in this lab focuses on understanding G protein signaling. The heterotrimeric G proteins, composed of alpha-beta-gamma subunits, function as molecular switches. They detect agonist-activated G protein-coupled receptors (GPCRs) and then regulate specific intracellular signal pathways. To function properly, intracellular signaling pathways depend upon appropriate and unique subcellular locations of their constituent proteins.

Mechanisms of reversible membrane targeting of G protein alpha and beta-gamma subunits. Although G proteins must reside at the cytoplasmic surface of the plasma membrane (PM) to interact with GPCRs, they are not statically localized there. We are interested in the basic questions of what are the specific pathways and mechanisms that G proteins use to arrive at the PM, 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.

Mechanisms of localization and signaling by RhoGEFs.
The Rho small GTPases are critical signaling proteins that play central roles in numerous biological responses. A major function is to regulate rapid and reversible changes in the actin cytoskeleton, such as those that occur in migrating cells and extension and retraction of neurites. 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.

Mechanisms of membrane localization and nucleocytoplasmic shuttling of GRKs.
We are identifying and characterizing a novel membrane targeting domain in G protein-coupled receptor kinases (GRK) 4, 5, and 6. Our recent work has demonstrated that GRK6 contains a C-terminal amphipathic helix motif, and, additionally is palmitoylated in the C-terminus. 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.

PhD, University of California, San Diego, Biochemistry - 1991

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