Dr Julie Pitcher
G-protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors. They share a common 7 transmembrane domain configuration and act to transduce extracellular stimuli to the interior of the cell. GPCRs are expressed in virtually every cell type and modulate an extremely wide range of physiological processes. They represent a rich source of targets for the pharmaceutical industry with approximately 30-50% of current pharmaceuticals targeting these proteins.
Following repeated or continuous exposure to agonists GPCRs exhibit diminished responsiveness, a phenomenon termed receptor desensitisation. For many GPCRs rapid desensitisation is mediated by a family of serine/threonine kinases, the G protein-coupled receptor kinases (GRKs). GRKs phosphorylate agonist-occupied GPCRs and the phosphorylated receptor serves as a binding site for a member of the arrestin family. Arrestin binding uncouples the GPCR from G proteins and targets the phosphorylated receptor for internalisation via clathrin-coated pits. Given their role in regulating GPCR function it is not surprising that changes in the expression levels, or activities, of the GRKs are associated with a number of disease states. For example, GRK2 and 5 upregulation are responsible for alterations in myocardial function in chronic heart failure.
In addition to their role in mediating GPCR desensitisation several lines of evidence suggest the GRKs have other cellular functions. It is our aim to elucidate at the molecular level the cellular functions of the GRKs, work which may aid in the design of therapeutically useful GRK inhibitors.
Finding neuronal signalling pathways with genetics
Regulation of G Protein-Coupled Receptor Function by the G Protein-Coupled Receptor Kinase Family
Regulation of signal processing in neurons
Dr Martin Stocker; Dr Adolfo Saiardi; Dr Paola Pedarzani; Prof Daniel Cutler; Dr Stephen Nurrish; Prof Chris Richards; Prof Dominic Withers
- Lima-Fernandes E, Enslen H, Camand E, Kotelevets L, Boularan C, Achour L, Benmerah A, Gibson LCD, Baillie GS, Pitcher JA, Chastre E, Etienne-Manneville S, Marullo S, Scott MGH (2011). Distinct functional outputs of PTEN signalling are controlled by dynamic association with beta-arrestins. EMBO J, 30(13), 2557 - 2568. doi:10.1038/emboj.2011.178
- Martini JS, Raake P, Vinge LE, DeGeorge Jr BR, Chuprun JK, Harris DM, Gao E, Eckhart AD, Pitcher JA, Koch WJ (2008). Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes (Proceedings of the National Academy of Sciences of the United States of America (2008) 105, (12457-12462) DOI: 10.1073/pnas.0803153105). Proceedings of the National Academy of Sciences of the United States of America, 105(44), 17206 - 17206. doi:10.1073/pnas.0808974105
- Martini JS, Raake P, Vinge LE, Degeorge BJ, Chuprun JK, Harris DM, Gao E, Eckhart AD, Pitcher JA, W J (2008). Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes.. Proceedings of the National Academy of Sciences of the United States of America, 105(34), 12457 - 12462. doi:10.1073/pnas.0803153105
- Martini J, Rakke P, Vinge L, DeGeorge B, Chuprun K, Harris D, Eckhart A, Pitcher J, Koch W (2007). A novel nuclear function for GRK5 and its potential role in the hypertrophic response.
- Sorriento D, Pitcher J, Santulli G, Campanile A, Ciccarelli M, Trimarco B, Iaccarino G (2007). G protein-coupled Receptor Kinase 5 (GRK5) modulates NFkB transcription activity in endothelial cells. EUROPEAN HEART JOURNAL, 28, 747 - 748.
- Martini JS, Raake P, Vinge LE, Chuprun K, III DBR, Harris DM, Eckhart A, Pitcher J, Koch WJ (2007). A novel nuclear function for GRK5 and its potential role in the 336 hypertrophic response.
- Cotton M, Boulay P-L, Houndolo T, Vitale N, Pitcher JA, Claing A (2007). Endogenous ARF6 interacts with Rac1 upon angiotensinII stimulation to regulate membrane ruffling and cell migration. Molecular and Cellular Biology, 18(2), 501 - 511. doi:10.1091/mbc.E06-06-0567
- Scott MGH, Pierotti V, Storez H, Lindberg E, Thuret A, Muntaner O, Labbe-Jullie C, Pitcher JA, Marullo S (2006). Cooperative regulation of ERK activation and cell shape change by filamin A and beta-arrestins. Molecular and Cellular Biology, 26(9), 3432 - 3445. doi:10.1128/MCB.26.9.3432-3445.2006
- Cant SH, Pitcher JA (2005). G protein-coupled receptor kinase 2-mediated phosphorylation of ezrin is required for G protein-coupled receptor-dependent reorganization of the actin cytoskeleton.. Molecular Biology of the Cell, 16(7), 3088 - 3099. doi:10.1091/mbc.E04-10-0877
- Johnson LR, Scott MG, Pitcher JA (2004). G protein-coupled receptor kinase 5 contains a DNA-binding nuclear localization sequence.. Molecular and Cellular Biology, 24(23), 10169 - 10179. doi:10.1128/MCB.24.23.10169-10179.2004
- Fairfax BP, Pitcher JA, Scott MG, Calver AR, Pangalos MN, Moss SJ, Couve A (2004). Phosphorylation and chronic agonist treatment atypically modulate GABAB receptor cell surface stability.. Journal of Biological Chemistry, 279(13), 12565 - 12573. doi:10.1074/jbc.M311389200
- Lodowski DT, Barnhill JF, Pitcher JA, Capel WD, Lefkowitz RJ, Tesmer JJ (2003). Purification, crystallization and preliminary X-ray diffraction studies of a complex between G protein-coupled receptor kinase 2 and Gbeta1gamma2.. Acta Crystallogr D Biol Crystallogr, 59(Pt 5), 936 - 939.
- Lodowski DT, Pitcher JA, Capel WD, Lefkowitz RJ, Tesmer JJ (2003). Keeping G proteins at bay: a complex between G protein-coupled receptor kinase 2 and Gbetagamma.. Science, 300(5623), 1256 - 1262. doi:10.1126/science.1082348
- Lodowski DT, Barnhill JF, Pitcher JA, Capel WD, Lefkowitz RJ, Tesmer JJ (2003). Purification, crystallization and preliminary X-ray diffraction studies of a complex between G protein-coupled receptor kinase 2 and Gbeta1gamma2.. Acta Crystallographica Section D, 59(5), 936 - 939. doi:10.1107/S0907444903002622
- Freeman JL, Gonzalo P, Pitcher JA, Claing A, Lavergne JP, Reboud JP, Lefkowitz RJ (2002). Beta 2-adrenergic receptor stimulated, G protein-coupled receptor kinase 2 mediated, phosphorylation of ribosomal protein P2.. Biochemistry, 41(42), 12850 - 12857. doi:10.1021/bi020145d
- Cong M, Perry SJ, Lin FT, Fraser ID, Hu LA, Chen W, Pitcher JA, Scott JD, Lefkowitz RJ (2001). Regulation of membrane targeting of the G protein-coupled receptor kinase 2 by protein kinase A and its anchoring protein AKAP79.. Journal of Biological Chemistry, 276(18), 15192 - 15199. doi:10.1074/jbc.M009130200
- Pitcher JA, Lefkowitz RJ (2000). The G protein-coupled receptor phosphatase. In Benovic JL (Ed.), Regulation of G protein-coupled receptor function and expression (pp. 179 - 195). : A John Wiley and Sons, INC..
- McDonald PH, Cote NL, Lin FT, Premont RT, Pitcher JA, Lefkowitz RJ (1999). Identification of NSF as a beta-arrestin1-binding protein. Implications for beta2-adrenergic receptor regulation.. J Biol Chem, 274(16), 10677 - 10680.
- Pitcher JA, Tesmer JJ, Freeman JL, Capel WD, Stone WC, Lefkowitz RJ (1999). Feedback inhibition of G protein-coupled receptor kinase 2 (GRK2) activity by extracellular signal-regulated kinases.. Journal of Biological Chemistry, 274(49), 34531 - 34534. doi:10.1074/jbc.274.49.34531
- Tang Y, Hu LA, Miller WE, Ringstad N, Hall RA, Pitcher JA, DeCamilli P, Lefkowitz RJ (1999). Identification of the endophilins (SH3p4/p8/p13) as novel binding partners for the beta1-adrenergic receptor.. Proceedings of the National Academy of Sciences of the United States of America, 96(22), 12559 - 12564.
- Hall RA, Spurney RF, Premont RT, Rahman N, Blitzer JT, Pitcher JA, Lefkowitz RJ (1999). G protein-coupled receptor kinase 6A phosphorylates the Na(+)/H(+) exchanger regulatory factor via a PDZ domain-mediated interaction.. Journal of Biological Chemistry, 274(34), 24328 - 24334. doi:10.1074/jbc.274.34.24328
- Premont RT, Claing A, Freeman JLR, Lefkowitz RJ, Vitale N, Patton WA, Moss J, Vaughan M, Pitcher JA (1998). β-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein. Proceedings of the National Academy of Sciences of the United States of America, 95(24), 14082 - 14087. doi:10.1073/pnas.95.24.14082
- Freeman JL, De La Cruz EM, Pollard TD, Lefkowitz RJ, Pitcher JA (1998). Regulation of G protein-coupled receptor kinase 5 (GRK5) by actin.. J Biol Chem, 273(32), 20653 - 20657.
- Premont RT, Claing A, Vitale N, Freeman JL, Pitcher JA, Patton WA, Moss J, Vaughan M, Lefkowitz RJ (1998). beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein.. Proc Natl Acad Sci U S A, 95(24), 14082 - 14087.
- Pitcher JA, Freedman NJ, Lefkowitz RJ (1998). G protein-coupled receptor kinases.. Annu Rev Biochem, 67, 653 - 692. doi:10.1146/annurev.biochem.67.1.653
- Hall RA, Premont RT, Chow CW, Blitzer JT, Pitcher JA, Claing A, Stoffel RH, Barak LS, Shenolikar S, Weinman EJ, Grinstein S, Lefkowitz RJ (1998). The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange.. Nature, 392(6676), 626 - 630. doi:10.1038/33458
- Pitcher JA, Hall RA, Daaka Y, Zhang J, Ferguson SS, Hester S, Miller S, Caron MG, Lefkowitz RJ, Barak LS (1998). The G protein-coupled receptor kinase 2 is a microtubule-associated protein kinase that phosphorylates tubulin.. J Biol Chem, 273(20), 12316 - 12324.
- Lefkowitz RJ, Pitcher J, Krueger K, Daaka Y (1998). Mechanisms of beta-adrenergic receptor desensitization and resensitization.. Adv Pharmacol, 42, 416 - 420.
- Krueger KM, Daaka Y, Pitcher JA, Lefkowitz RJ (1997). The role of sequestration in G protein-coupled receptor resensitization. Regulation of beta2-adrenergic receptor dephosphorylation by vesicular acidification.. J Biol Chem, 272(1), 5 - 8.
- Lefkowitz RJ, Pitcher J, Krueger K, Daaka Y (1997). Mechanisms of β-Adrenergic Receptor Desensitization and Resensitization. Advances in Pharmacology, 42(C), 416 - 420. doi:10.1016/S1054-3589(08)60777-2
- Lin FT, Krueger KM, Kendall HE, Daaka Y, Fredericks ZL, Pitcher JA, Lefkowitz RJ (1997). Clathrin-mediated endocytosis of the beta-adrenergic receptor is regulated by phosphorylation/dephosphorylation of beta-arrestin1.. J Biol Chem, 272(49), 31051 - 31057.
- Stoffel RH, Pitcher JA, Lefkowitz RJ (1997). Targeting G protein-coupled receptor kinases to their receptor substrates.. J Membr Biol, 157(1), 1 - 8.
- Daaka Y, Pitcher JA, Richardson M, Stoffel RH, Robishaw JD, Lefkowitz RJ (1997). Receptor and G betagamma isoform-specific interactions with G protein-coupled receptor kinases.. Proc Natl Acad Sci U S A, 94(6), 2180 - 2185.
- Pitcher JA, Fredericks ZL, Stone WC, Premont RT, Stoffel RH, Koch WJ, Lefkowitz RJ (1996). Phosphatidylinositol 4,5-bisphosphate (PIP2)-enhanced G protein-coupled receptor kinase (GRK) activity. Location, structure, and regulation of the PIP2 binding site distinguishes the GRK subfamilies.. J Biol Chem, 271(40), 24907 - 24913.
- Premont RT, Macrae AD, Stoffel RH, Chung N, Pitcher JA, Ambrose C, Inglese J, MacDonald ME, Lefkowitz RJ (1996). Characterization of the G protein-coupled receptor kinase GRK4. Identification of four splice variants.. J Biol Chem, 271(11), 6403 - 6410.
- Fredericks ZL, Pitcher JA, Lefkowitz RJ (1996). Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor.. J Biol Chem, 271(23), 13796 - 13803.
- Pitcher JA, Touhara K, Payne ES, Lefkowitz RJ (1995). Pleckstrin homology domain-mediated membrane association and activation of the beta-adrenergic receptor kinase requires coordinate interaction with G beta gamma subunits and lipid.. J Biol Chem, 270(20), 11707 - 11710.
- Pitcher JA, Payne ES, Csortos C, DePaoli-Roach AA, Lefkowitz RJ (1995). The G-protein-coupled receptor phosphatase: a protein phosphatase type 2A with a distinct subcellular distribution and substrate specificity.. Proc Natl Acad Sci U S A, 92(18), 8343 - 8347.
- Touhara K, Inglese J, Pitcher JA, Shaw G, Lefkowitz RJ (1994). Binding of G protein beta gamma-subunits to pleckstrin homology domains.. J Biol Chem, 269(14), 10217 - 10220.
- Lefkowitz RJ, Cotecchia S, Kjelsberg MA, Pitcher J, Koch WJ, Inglese J, Caron MG (1993). Adrenergic receptors: recent insights into their mechanism of activation and desensitization.. Adv Second Messenger Phosphoprotein Res, 28, 1 - 9.
- Lefkowitz RJ, Inglese J, Koch WJ, Pitcher J, Attramadal H, Caron MG (1992). G-protein-coupled receptors: regulatory role of receptor kinases and arrestin proteins.. Cold Spring Harb Symp Quant Biol, 57, 127 - 133.
- Pitcher J, Lohse MJ, Codina J, Caron MG, Lefkowitz RJ (1992). Desensitization of the isolated beta 2-adrenergic receptor by beta-adrenergic receptor kinase, cAMP-dependent protein kinase, and protein kinase C occurs via distinct molecular mechanisms.. Biochemistry, 31(12), 3193 - 3197.
- Lohse MJ, Andexinger S, Pitcher J, Trukawinski S, Codina J, Faure JP, Caron MG, Lefkowitz RJ (1992). Receptor-specific desensitization with purified proteins. Kinase dependence and receptor specificity of beta-arrestin and arrestin in the beta 2-adrenergic receptor and rhodopsin systems.. J Biol Chem, 267(12), 8558 - 8564.
- Pitcher JA, Inglese J, Higgins JB, Arriza JL, Casey PJ, Kim C, Benovic JL, Kwatra MM, Caron MG, Lefkowitz RJ (1992). Role of beta gamma subunits of G proteins in targeting the beta-adrenergic receptor kinase to membrane-bound receptors.. Science, 257(5074), 1264 - 1267.
- Hausdorff WP, Pitcher JA, Luttrell DK, Linder ME, Kurose H, Parsons SJ, Caron MG, Lefkowitz RJ (1992). Tyrosine phosphorylation of G protein alpha subunits by pp60c-src.. Proc Natl Acad Sci U S A, 89(13), 5720 - 5724.
- Poulter L, Ang SG, Gibson BW, Williams DH, Holmes CF, Caudwell FB, Pitcher J, Cohen P (1988). Analysis of the in vivo phosphorylation state of rabbit skeletal muscle glycogen synthase by fast-atom-bombardment mass spectrometry.. Eur J Biochem, 175(3), 497 - 510.
- Leighton B, Lozeman FJ, Vlachonikolis IG, Challiss RA, Pitcher JA, Newsholme EA (1988). Effects of adenosine deaminase on the sensitivity of glucose transport, glycolysis and glycogen synthesis to insulin in muscles of the rat.. Int J Biochem, 20(1), 23 - 27.
- Pitcher J, Smythe C, Cohen P (1988). Glycogenin is the priming glucosyltransferase required for the initiation of glycogen biogenesis in rabbit skeletal muscle.. Eur J Biochem, 176(2), 391 - 395.
- Pitcher J, Smythe C, Campbell DG, Cohen P (1987). Identification of the 38-kDa subunit of rabbit skeletal muscle glycogen synthase as glycogenin.. Eur J Biochem, 169(3), 497 - 502.
- Newsholme EA, Blomstrand E, Newell J, Pitcher J (1985). Maximal activities of enzymes involved in adenosine metabolism in muscle and adipose tissue of rats under conditions of variations in insulin sensitivity.. FEBS Lett, 181(1), 189 - 192.
- Pitcher JA, Johnson LR, Robinson JR (). Distinct structural features of G protein-coupled receptor kinase 5 (GRK5) regulate its nuclear localization and DNA-binding ability. PLoS One, , - .
- Pitcher JA, Lester K (). G protein-coupled receptor kinase 5 (GRK5) acts as a transcriptional repressor. , , - .
- Pitcher JA, Robinson, JR (). G protein-coupled receptor kinase 2 (GRK2) is a Rho-activated scaffold protein for the ERK MAP kinase cascade. , , - .
- Pitcher JA, Webb K (). Beta-arrestin 1 is localized to and regulates trafficking through the Golgi complex.. , , - .