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Thomas Jefferson University - Philip B. Wedegaertner, PhD
Philip B. Wedegaertner, PhD

Biochemistry & Molecular Biology
Professor
Thomas Jefferson University
Department of Biochemistry and
Molecular Biology
Kimmel Cancer Center

Mailing Address
233 S. 10th St., 839 BLSB
Philadelphia, Pennsylvania 19107
United States
Contact Information
Phone: 215-503-3137
Philip.Wedegaertner@mail.jci.tju.edu
Qualifications
Ph.D., 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.

Keywords
Heterotrimeric G protein; RhoGEF; lipid modification; membrane targeting; protein trafficking; signal transduction
Publications
  • SELECTED PUBLICATIONS
  • Irannejad, R. and Wedegaertner, P.B. (2010) Golgi-localized G protein beta-gamma subunits regulate trans-Golgi network to plasma membrane transport, Journal of Biological Chemistry, 285:32393-32404.
  • Crouthamel M., Abankwa D., Zhang L., Dilizio C., Manning D.R., Hancock J.F., Wedegaertner P.B. (2010) An N-terminal polybasic motif of G alpha q is required for signaling and influences membrane nanodomain distribution, Molecular Pharmacology, 78:767-777.
  • Wedegaertner, P.B. (2009) Signal Transduction, Chapter 6, in Pharmacology and Therapeutics: Principles to Practice, Waldman, S. and Terzic, A, eds., Elsevier, 67-81.
  • Banerjee, J, Fischer, C.C., and Wedegaertner, P.B. (2009) The amino acid motif L/IIxxFE defines a novel actin-binding sequence in PDZ-RhoGEF, Biochemistry, 48, 8032-8043.
  • Bhattacharyya, R., Banerjee, J., Khalili, K., and Wedegaertner, P.B. (2009) Differences in G±12- and G±13-mediated plasma membrane recruitment of p115-RhoGEF, Cellular Signalling, 21, 996-1006.
  • Crouthamel, M., Thiyagarajan, M.M., Evanko, D.S., and Wedegaertner, P.B., (2008) N-terminal polybasic motifs are required for plasma membrane localization of G±s and G±q, Cellular Signalling, 20, 1900-1910.
  • Iwanicki M.P., Vomastek T., Tilghman R.W., Martin K.H., Banerjee J., Wedegaertner P.B., and Parsons J.T. (2008) FAK, PDZ-RhoGEF and ROCKII cooperate to regulate adhesion movement and trailing-edge retraction in fibroblasts, J. Cell Sci., 121, 895-905.
  • Marrari, Y., Crouthamel, M., Irannejad, R., and Wedegaertner, P.B. (2007) Assembly and Trafficking of Heterotrimeric G Proteins, Biochemistry, 46, 7665-7677.
  • Jiang, X., Benovic, J.L., and Wedegaertner, P.B. (2007) Plasma membrane and nuclear localization of G protein-coupled receptor kinase 6A, Mol. Biol. Cell, 18, 2960-2969.
  • Evanko, D.S., Thiyagarajan, M.M., Takida, S., and Wedegaertner, P.B. (2005) Loss of association between activated G alpha q and G beta-gamma disrupts receptor-dependent and receptor-independent signaling, Cellular Signaling, 17, 1218-1228.
  • Grabocka, E. and Wedegaertner, P.B. (2005) Functional consequences of G alpha 13 mutations that disrupt interaction with p115RhoGEF, Oncogene, 24, 2155-2165.
  • Takida, S., Fischer, C.C., and Wedegaertner, P.B. (2005) Palmitoylation and plasma membrane targeting of RGS7 are promoted by alpha o, Mol. Pharm., 67, 132-139.
  • Day, P.W., Tesmer, J.J.G., Sterne-Marr, R., Benovic, J.L., and Wedegaertner, P.B. (2004) Characterization of the GRK2 binding site of G alpha q, J. Biol. Chem., 279, 53643-53652.
  • Takida, S. and Wedegaertner, P.B. (2004) Exocytic pathway-independent plasma membrane targeting of heterotrimeric G proteins, FEBS Lett., 567, 209-213.
  • Thiyagarajan, M.M., Stracquatanio, R.P., Pronin, A.N., Evanko, D.S., Benovic, J.L., and Wedegaertner, P.B. (2004) A predicted amphipathic helix mediates plasma membrane localization of GRK5, J. Biol. Chem., 279, 17989-17995.
  • Banerjee, J. and Wedegaertner, P.B. (2004) Identification of a novel sequence in PDZ-RhoGEF that mediates interaction with the actin cytoskeleton, Mol. Biol. Cell, 15, 1760-1775.
  • Day, P.W., Carman, C.V., Sterne-Marr, R., Benovic, J.L., and Wedegaertner, P.B. (2003) Differential interaction of GRK2 with members of the G alpha q family, Biochemistry, 42, 9176-9184.
  • Takida, S. and Wedegaertner, P.B. (2003) Heterotrimer formation, together with isoprenylation, is required for plasma membrane targeting of G beta-gamma, J. Biol. Chem., 278, 17284-17290.
  • Bhattacharyya, R. and Wedegaertner, P.B. (2003) Characterization of G alpha 13-dependent plasma membrane recruitment of p115RhoGEF, Biochem. J., 371, 709-720.
  • Bhattacharyya, R. and Wedegaertner, P.B. (2003) Mutation of an N-terminal acidic-rich region of p115RhoGEF dissociates alpha 13 binding and alpha 13-promoted plasma membrane recruitment, FEBS Lett., 540, 211-216.
  • Sterne-Marr, R., Tesmer, J.J.G., Day, P.W., Stracquatanio, R.P., Cliente, J.E., OConnor, K.E., Pronin, A.N., Benovic, J.L., and Wedegaertner, P.B. (2003) GRK2/G alpha q/11 interaction: A novel surface on an RGS homology domain for binding G alpha subunits, J. Biol. Chem., 278, 6050-6058.
  • Thiyagarajan, M.M., Bigras, E., Van Tol, H.H.M., Hébert, T.E., Evanko, D.S. and Wedegaertner, P.B. (2002) Activation-induced subcellular redistribution of G alpha s is dependent upon its unique N-terminus, Biochemistry, 41, 9470-9484.
  • Evanko, D.S., Thiyagarajan, M.M., Siderovski, D.P., and Wedegaertner, P.B. (2001) G beta-gamma isoforms selectively rescue plasma membrane localization and palmitoylation of mutant G alpha s and G alpha q,, J. Biol. Chem. 276, 23945-23953.
  • Bhattacharyya, R., and Wedegaertner, P. B. (2000) G alpha 13 requires palmitoylation for plasma membrane localization, rho-dependent signaling, and promotion of p115rhoGEF membrane binding. J. Biol. Chem. 275, 14992-14999.
  • Evanko, D.S., Thiyagarajan, M.M., and Wedegaertner, P.B. (2000) Interaction with G beta-gamma is required for membrane targeting and palmitoylation of G alpha s and G alpha q,, J. Biol. Chem. 275, 1327-1336.
  • Carman, C.V., Parent, J.-L., Day, P.D., Pronin, A.N., Sternweis, P.M., Wedegaertner, P.B., Gilman, A.G., Benovic, J.L., and Kozasa, T. (1999) Selective regulation of G alpha q/11 by an RGS domain in the G Protein-coupled receptor kinase, GRK2, J. Biol. Chem. 274, 34483-34492.
  • Iiri, T., Backlund, P.S., Jones, T.L.Z., Wedegaertner, P.B., and Bourne, H.R. (1996) Reciprocal regulation of Gs alpha by palmitate and the beta-gamma subunit. Proc. Natl. Acad Sci. U.S.A. 93, 14592-14597.
  • Wedegaertner, P.B., Bourne, H.R., and von Zastrow, M. (1996) Activation-induced subcellular redistribution of Gs alpha. Mol. Biol. Cell. 7, 1225-1233.
  • Wedegaertner, P.B. and Bourne, H.R. (1994) Activation and depalmitoylation of Gs alpha. Cell 77, 1063-1070.
  • Wedegaertner, P.B., Chu, D.H., Wilson, P.T., Levis, M.J. and Bourne, H.R. (1993) Palmitoylation is required for signaling functions and membrane attachment of Gq alpha and Gs alpha. J. Biol. Chem. 268, 25001-25008.

Individual Expertise profile of Philip B. Wedegaertner, PhD, Copyright © Philip B. Wedegaertner, PhD.
Last Updated by Admin : Tuesday, June 5, 2012 3:59:20 PM



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