Wedegaertner, Philip B.
Philip B. Wedegaertner, PhD
Philadelphia, PA 19107
PhD, University of California, San Diego, Biochemistry - 1991
Expertise and Research Interests
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.
Heterotrimeric G protein; RhoGEF; lipid modification; membrane targeting; protein trafficking; signal transduction
Most Recent Peer-Reviewed Publications
- Effects of oncogenic Gα
qand Gα 11inhibition by FR900359 in uveal melanoma
- G protein-coupled receptor kinase 4-induced cellular senescence and its senescence-associated gene expression profiling
- Functional selectivity of GPCR-directed drug action through location bias
- Dysregulated GPCR signaling and therapeutic options in uveal melanoma
- Inducible inhibition of Gβγ reveals localization-dependent functions at the plasma membrane and Golgi
- Mitotic-dependent phosphorylation of leukemia-associated RhoGEF (LARG) by Cdk1
- PAQR3 regulates Golgi vesicle fission and transport via the Gβγ-PKD signaling pathway
- G protein βγ subunits regulate cardiomyocyte hypertrophy through a perinuclear Golgi phosphatidylinositol 4-phosphate hydrolysis pathway
- The regulator of G protein signaling (RGS) domain of G protein-coupled receptor kinase 5 (GRK5) regulates plasma membrane localization and function
- Leukemia-associated RhoGEF (LARG) is a novel RhoGEF in cytokinesis and required for the proper completion of abscission
- G Protein Traf ficking
- Non-canonical signaling and localizations of heterotrimeric G proteins
- Reversible palmitoylation in g protein signaling
- Regulation of constitutive cargo transport from the trans-Golgi network to plasma membrane by Golgi-localized G protein βγ subunits
- An N-terminal polybasic motif of Gα
qis required for signaling and influences membrane nanodomain distribution
- The amino acid motif L/IIxxFE defines a novel actin-binding sequence in PDZ-RhoGEF
- Differences in Gα12- and Gα13-mediated plasma membrane recruitment of p115-RhoGEF
- N-terminal polybasic motifs are required for plasma membrane localization of Gαs and Gαq
- FAK, PDZ-RhoGEF and ROCKII cooperate to regulate adhesion movement and trailing-edge retraction in fibroblasts
- Disruption of oligomerization induces nucleocytoplasmic shuttling of leukemia-associated Rho guanine-nucleotide exchange factor