Philip Wedegaertner, PhD

Contact Dr. Wedegaertner

233 South 10th Street
839 BLSB
Philadelphia, PA 19107

(215) 503-3137
fax

How are Signaling Proteins Targeted to Different Locations Within A Cell?

My research focuses on understanding G protein signaling. The heterotrimeric G proteins, composed of 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 and 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.

We anticipate that a detailed under-standing of localization and trafficking mechanisms will reveal new therapeutic targets for inhibiting unwanted signaling pathways.

Publications

Most recent Peer-reviewed Publications

1. Non-canonical signaling and localizations of heterotrimeric G proteins
2. Regulation of constitutive cargo transport from the trans-Golgi network to plasma membrane by Golgi-localized G protein βγ subunits
3. An N-terminal polybasic motif of Gαq is required for signaling and influences membrane nanodomain distribution
4. The amino acid motif L/IIxxFE defines a novel actin-binding sequence in PDZ-RhoGEF
5. Differences in Gα12- and Gα13-mediated plasma membrane recruitment of p115-RhoGEF
6. N-terminal polybasic motifs are required for plasma membrane localization of Gαs and Gαq
7. FAK, PDZ-RhoGEF and ROCKII cooperate to regulate adhesion movement and trailing-edge retraction in fibroblasts
8. Disruption of oligomerization induces nucleocytoplasmic shuttling of leukemia-associated Rho guanine-nucleotide exchange factor
9. Plasma membrane and nuclear localization of G protein-coupled receptor kinase 6A
10. Assembly and trafficking of heterotrimeric G proteins
11. Lipid-protein interactions in GPCR-associated signaling
12. Cooperative regulation of p70S6 kinase by receptor tyrosine kinases and G protein-coupled receptors augments airway smooth muscle growth
13. Loss of association between activated Gαq and Gβγ disrupts receptor-dependent and receptor-independent signaling
14. Functional consequences of Gα13 mutations that disrupt interaction with p115RhoGEF
15. Identification of a specific domain responsible for JNK2α2 autophosphorylation
16. Palmitoylation and plasma membrane targeting of RGS7 are promoted by αo
17. Characterization of the GRK2 binding site of Gαq
18. Analysis of G-protein-coupled receptor kinase RGS homology domains
19. Exocytic pathway-independent plasma membrane targeting of heterotrimeric G proteins
20. A Predicted Amphipathic Helix Mediates Plasma Membrane Localization of GRK5

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