The Phospholipase C Isozymes and Their Regulation

  • Aurelie Gresset
  • John Sondek
  • T. Kendall HardenEmail author
Part of the Subcellular Biochemistry book series (SCBI, volume 58)


The physiological effects of many extracellular neurotransmitters, hormones, growth factors, and other stimuli are mediated by receptor-promoted activation of phospholipase C (PLC) and consequential activation of inositol lipid signaling pathways. These signaling responses include the classically described conversion of phosphatidylinositol(4,5)P2 to the Ca2+-mobilizing second messenger inositol(1,4,5)P3 and the protein kinase C-activating second messenger diacylglycerol as well as alterations in membrane association or activity of many proteins that harbor phosphoinositide binding domains. The 13 mammalian PLCs elaborate a minimal catalytic core typified by PLC-d to confer multiple modes of regulation of lipase activity. PLC-b isozymes are activated by Gaq- and Gbg-subunits of heterotrimeric G proteins, and activation of PLC-g isozymes occurs through phosphorylation promoted by receptor and non-receptor tyrosine kinases. PLC-e and certain members of the PLC-b and PLC-g subclasses of isozymes are activated by direct binding of small G proteins of the Ras, Rho, and Rac subfamilies of GTPases. Recent high resolution three dimensional structures together with biochemical studies have illustrated that the X/Y linker region of the catalytic core mediates autoinhibition of most if not all PLC isozymes. Activation occurs as a consequence of removal of this autoinhibition.


Phospholipase C Inositol lipid signaling Heterotrimeric G protein Ras GTPase Tyrosine kinase X/Y-linker-mediated autoinhibition 


  1. Adamski FM, Timms KM, Shieh BH (1999) A unique isoform of phospholipase C-β4 highly expressed in the cerebellum and eye. Biochim Biophys Acta 1444:55–60PubMedCrossRefGoogle Scholar
  2. Aittaleb M, Boguth CA, Tesmer JJ (2010) Structure and function of heterotrimeric G protein-regulated Rho guanine nucleotide exchange factors. Mol Pharmacol 77:111–125PubMedCrossRefGoogle Scholar
  3. Allen V, Swigart P, Cheung R, Cockcroft S, Katan M (1997) Regulation of inositol lipid-specific phospholipase C-δ by changes in Ca2+ ion concentrations. Biochem J 327(Pt 2):545–552PubMedGoogle Scholar
  4. Ananthanarayanan B, Das S, Rhee SG, Murray D, Cho W (2002) Membrane targeting of C2 domains of phospholipase C-δ isoforms. J Biol Chem 277:3568–3575PubMedCrossRefGoogle Scholar
  5. Andoh T, Yoko T, Matsui Y, Toh A (1995) Molecular cloning of the plc1+ gene of Schizosaccharomyces pombe, which encodes a putative phosphoinositide-specific phospholipase C. Yeast 11:179–185PubMedCrossRefGoogle Scholar
  6. Arteaga CL, Johnson MD, Todderud G, Coffey RJ, Carpenter G, Page DL (1991) Elevated content of the tyrosine kinase substrate phospholipase C-γ1 in primary human breast carcinomas. Proc Natl Acad Sci USA 88:10435–10439PubMedCrossRefGoogle Scholar
  7. Bae YS, Cantley LG, Chen CS, Kim SR, Kwon KS, Rhee SG (1998) Activation of phospholipase C-γ by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:4465–4469PubMedCrossRefGoogle Scholar
  8. Bae JH, Lew ED, Yuzawa S, Tome F, Lax I, Schlessinger J (2009) The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site. Cell 138:514–524PubMedCrossRefGoogle Scholar
  9. Bai Y, Edamatsu H, Maeda S, Saito H, Suzuki N, Satoh T, Kataoka T (2004) Crucial role of phospholipase C-ε in chemical carcinogen-induced skin tumor development. Cancer Res 64:8808–8810PubMedCrossRefGoogle Scholar
  10. Barr AJ, Ali H, Haribabu B, Snyderman R, Smrcka AV (2000) Identification of a region at the N-terminus of phospholipase C-β3 that interacts with G protein βγ subunits. Biochemistry 39:1800–1806PubMedCrossRefGoogle Scholar
  11. Berridge MJ (1987) Inositol trisphosphate and diacylglycerol: two interacting second messengers. Annu Rev Biochem 56:159–193PubMedCrossRefGoogle Scholar
  12. Berstein G, Blank JL, Jhon DY, Exton JH, Rhee SG, Ross EM (1992) Phospholipase C-β1 is a GTPase-activating protein for Gq/11, its physiologic regulator. Cell 70:411–418PubMedCrossRefGoogle Scholar
  13. Biddlecome GH, Berstein G, Ross EM (1996) Regulation of phospholipase C-β1 by Gq and m1 muscarinic cholinergic receptor. Steady-state balance of receptor-mediated activation and GTPase-activating protein-promoted deactivation. J Biol Chem 271:7999–8007PubMedCrossRefGoogle Scholar
  14. Boguski MS, McCormick F (1993) Proteins regulating Ras and its relatives. Nature 366:643–654PubMedCrossRefGoogle Scholar
  15. Boguslavsky V, Rebecchi M, Morris AJ, Jhon DY, Rhee SG, McLaughlin S (1994) Effect of monolayer surface pressure on the activities of phosphoinositide-specific phospholipase C-β1, -γ1, and -δ1. Biochemistry 33:3032–3037PubMedCrossRefGoogle Scholar
  16. Booker GW, Breeze AL, Downing AK, Panayotou G, Gout I, Waterfield MD, Campbell ID (1992) Structure of an SH2 domain of the p85 alpha subunit of phosphatidylinositol-3-OH kinase. Nature 358:684–687PubMedCrossRefGoogle Scholar
  17. Boyer JL, Waldo GL, Harden TK (1992) βγ-subunit activation of G-protein-regulated phospholipase C. J Biol Chem 267:25451–25456PubMedGoogle Scholar
  18. Braiman A, Barda-Saad M, Sommers CL, Samelson LE (2006) Recruitment and activation of PLC-γ1 in T cells: a new insight into old domains. EMBO J 25:774–784PubMedCrossRefGoogle Scholar
  19. Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, Johnson R, Kong G, Chan AC, Findell PR (1996) Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. J Biol Chem 271:19641–19644PubMedCrossRefGoogle Scholar
  20. Bunney TD, Harris R, Gandarillas NL, Josephs MB, Roe SM, Sorli SC, Paterson HF, Rodrigues-Lima F, Esposito D, Ponting CP, Gierschik P, Pearl LH, Driscoll PC, Katan M (2006) Structural and mechanistic insights into Ras association domains of phospholipase C-ε. Mol Cell 21:495–507PubMedCrossRefGoogle Scholar
  21. Bunney TD, Opaleye O, Roe SM, Vatter P, Baxendale RW, Walliser C, Everett KL, Josephs MB, Christow C, Rodrigues-Lima F, Gierschik P, Pearl LH, Katan M (2009) Structural insights into formation of an active signaling complex between Rac and phospholipase C-γ2. Mol Cell 34:223–233PubMedCrossRefGoogle Scholar
  22. Camps M, Carozzi A, Schnabel P, Scheer A, Parker PJ, Gierschik P (1992) Isozyme-selective stimulation of phospholipase C-β2 by G protein βγ-subunits. Nature 360:684–686PubMedCrossRefGoogle Scholar
  23. Chan AC, Irving BA, Fraser JD, Weiss A (1991) The ζ chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein. Proc Natl Acad Sci USA 88:9166–9170PubMedCrossRefGoogle Scholar
  24. Cheng HF, Jiang MJ, Chen CL, Liu SM, Wong LP, Lomasney JW, King K (1995) Cloning and identification of amino acid residues of human phospholipase C-δ1 essential for catalysis. J Biol Chem 270:5495–5505PubMedCrossRefGoogle Scholar
  25. Citro S, Malik S, Oestreich EA, Radeff-Huang J, Kelley GG, Smrcka AV, Brown JH (2007) Phospholipase C-ε is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation. Proc Natl Acad Sci USA 104:15543–15548PubMedCrossRefGoogle Scholar
  26. Cocco L, Rubbini S, Manzoli L, Billi AM, Faenza I, Peruzzi D, Matteucci A, Artico M, Gilmour RS, Rhee SG (1999) Inositides in the nucleus: presence and characterisation of the isozymes of phospholipase-β family in NIH 3T3 cells. Biochim Biophys Acta 1438:295–299PubMedCrossRefGoogle Scholar
  27. Coggeshall KM, McHugh JC, Altman A (1992) Predominant expression and activation-induced tyrosine phosphorylation of phospholipase C-γ2 in B lymphocytes. Proc Natl Acad Sci USA 89:5660–5664PubMedCrossRefGoogle Scholar
  28. Drayer AL, Haastert PJ van (1992) Molecular cloning and expression of a phosphoinositide-specific phospholipase C of Dictyostelium discoideum. J Biol Chem 267:18387–18392PubMedGoogle Scholar
  29. Ellis MV, Carne A, Katan M (1993) Structural requirements of phosphatidylinositol-specific phospholipase C-δ1 for enzyme activity. Eur J Biochem 213:339–347PubMedCrossRefGoogle Scholar
  30. Ellis MV, Katan SU, Katan M (1995) Mutations within a highly conserved sequence present in the X region of phosphoinositide-specific phospholipase C-δ1. Biochem J 307:69–75PubMedGoogle Scholar
  31. Ellis MV, James SR, Perisic O, Downes CP, Williams RL, Katan M (1998) Catalytic domain of phosphoinositide-specific phospholipase C. Mutational analysis of residues within the active site and hydrophobic ridge of PLC-δ1. J Biol Chem 273:11650–11659PubMedCrossRefGoogle Scholar
  32. Essen LO, Perisic O, Cheung R, Katan M, Williams RL (1996) Crystal structure of a mammalian phosphoinositide-specific phospholipase C-δ. Nature 380:595–602PubMedCrossRefGoogle Scholar
  33. Essen LO, Perisic O, Lynch DE, Katan M, Williams RL (1997) A ternary metal binding site in the C2 domain of phosphoinositide-specific phospholipase C-δ1. Biochemistry 36:2753–2762PubMedCrossRefGoogle Scholar
  34. Evellin S, Nolte J, Tysack K, vom Dorp F, Thiel M, Weernink PA, Jakobs KH, Webb EJ, Lomasney JW, Schmidt M (2002) Stimulation of phospholipase C-ε by the M3 muscarinic acetylcholine receptor mediated by cyclic AMP and the GTPase Rap2B. J Biol Chem 277:16805–16813PubMedCrossRefGoogle Scholar
  35. Everett KL, Buehler A, Bunney TD, Margineanu A, Baxendale RW, Vatter P, Retlich M, Walliser C, Manning HB, Neil MA, Dunsby C, French PM, Gierschik P, Katan M (2011) Membrane environment exerts an important influence on Rac-mediated activation of phospholipase C-γ2. Mol Cell Biol 31(6):1240–1251PubMedCrossRefGoogle Scholar
  36. Exton JH (1996) Regulation of phosphoinositide phospholipases by hormones, neurotransmitters, and other agonists linked to G proteins. Annu Rev Pharmacol Toxicol 36:481–509PubMedCrossRefGoogle Scholar
  37. Faenza I, Matteucci A, Manzoli L, Billi AM, Aluigi M, Peruzzi D, Vitale M, Castorina S, Suh PG, Cocco L (2000) A role for nuclear phospholipase C-β1 in cell cycle control. J Biol Chem 275:30520–30524PubMedCrossRefGoogle Scholar
  38. Falasca M, Logan SK, Lehto VP, Baccante G, Lemmon MA, Schlessinger J (1998) Activation of phospholipase C-γ by PI 3-kinase-induced PH domain-mediated membrane targeting. EMBO J 17:414–422PubMedCrossRefGoogle Scholar
  39. Feng JF, Rhee SG, Im MJ (1996) Evidence that phospholipase-δ1 is the effector in the Gh (transglutaminase II)-mediated signaling. J Biol Chem 271:16451–16454PubMedCrossRefGoogle Scholar
  40. Ferguson KM, Lemmon MA, Schlessinger J, Sigler PB (1995) Structure of the high affinity complex of inositol trisphosphate with a phospholipase C pleckstrin homology domain. Cell 83:1037–1046PubMedCrossRefGoogle Scholar
  41. Fernald AW, Jones GA, Carpenter G (1994) Limited proteolysis of phospholipase C-γ1 indicates stable association of X and Y domains with enhanced catalytic activity. Biochem J 302:503–509PubMedGoogle Scholar
  42. Fiume R, Ramazzotti G, Teti G, Chiarini F, Faenza I, Mazzotti G, Billi AM, Cocco L (2009) Involvement of nuclear PLC-β1 in lamin B1 phosphorylation and G2/M cell cycle progression. FASEB J 23:957–966PubMedCrossRefGoogle Scholar
  43. Fu L, Qin YR, Xie D, Hu L, Kwong DL, Srivastava G, Tsao SW, Guan XY (2007) Characterization of a novel tumor-suppressor gene PLC-δ1 at 3p22 in esophageal squamous cell carcinoma. Cancer Res 67:10720–10726PubMedCrossRefGoogle Scholar
  44. Fukami K, Yoshida M, Inoue T, Kurokawa M, Fissore RA, Yoshida N, Mikoshiba K, Takenawa T (2003) Phospholipase C-δ4 is required for Ca2+ mobilization essential for acrosome reaction in sperm. J Cell Biol 161:79–88PubMedCrossRefGoogle Scholar
  45. Godin CM, Ferreira LT, Dale LB, Gros R, Cregan SP, Ferguson SS (2010) The small GTPase Ral couples the angiotensin II type 1 receptor to the activation of phospholipase C-δ1. Mol Pharmacol 77:388–395PubMedCrossRefGoogle Scholar
  46. Gresset A, Hicks SN, Harden TK, Sondek J (2010) Mechanism of phosphorylation-induced activation of phospholipase C-γ isozymes. J Biol Chem 285:35836–35847PubMedCrossRefGoogle Scholar
  47. Grobler JA, Essen LO, Williams RL, Hurley JH (1996) C2 domain conformational changes in phospholipase C-δ1. Nat Struct Biol 3:788–795PubMedCrossRefGoogle Scholar
  48. Guo Y, Golebiewska U, D’Amico S, Scarlata S (2010) The small G protein Rac1 activates phospholipase C-δ1 through phospholipase C-β2. J Biol Chem 285:24999–25008PubMedCrossRefGoogle Scholar
  49. Gutman O, Walliser C, Piechulek T, Gierschik P, Henis YI (2010) Differential regulation of phospholipase C-β2 activity and membrane interaction by Gαq, Gβ1γ2, and Rac2. J Biol Chem 285:3905–3915PubMedCrossRefGoogle Scholar
  50. Hains MD, Wing MR, Maddileti S, Siderovski DP, Harden TK (2006) Gα12/13- and Rho-dependent activation of phospholipase C-ε by lysophosphatidic acid and thrombin receptors. Mol Pharmacol 69:2068–2075PubMedCrossRefGoogle Scholar
  51. Han SK, Mancino V, Simon MI (2006) Phospholipase C-β3 mediates the scratching response activated by the histamine H1 receptor on C-fiber nociceptive neurons. Neuron 52:691–703PubMedCrossRefGoogle Scholar
  52. Harden TK, Sondek J (2006) Regulation of phospholipase C isozymes by Ras superfamily GTPases. Annu Rev Pharmacol Toxicol 46:355–379PubMedCrossRefGoogle Scholar
  53. Harden TK, Hicks SN, Sondek J (2009) Phospholipase C isozymes as effectors of Ras superfamily GTPases. J Lipid Res 50:S243–S248PubMedCrossRefGoogle Scholar
  54. Heinz DW, Essen LO, Williams RL (1998) Structural and mechanistic comparison of prokaryotic and eukaryotic phosphoinositide-specific phospholipases C. J Mol Biol 275:635–650PubMedCrossRefGoogle Scholar
  55. Hepler JR, Gilman AG (1992) G proteins. Trends Biochem Sci 17:383–387PubMedCrossRefGoogle Scholar
  56. Hicks SN, Jezyk MR, Gershburg S, Seifert JP, Harden TK, Sondek J (2008) General and versatile autoinhibition of PLC isozymes. Mol Cell 31:383–394PubMedCrossRefGoogle Scholar
  57. Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nurnberg G, Garg P, Verma R, Chaib H, Hoskins BE, Ashraf S, Becker C, Hennies HC, Goyal M, Wharram BL, Schachter AD, Mudumana S, Drummond I, Kerjaschki D, Waldherr R, Dietrich A, Ozaltin F, Bakkaloglu A, Cleper R, Basel-Vanagaite L, Pohl M, Griebel M, Tsygin AN, Soylu A, Muller D, Sorli CS, Bunney TD, Katan M, Liu J, Attanasio M, O’Toole J F, Hasselbacher K, Mucha B, Otto EA, Airik R, Kispert A, Kelley GG, Smrcka AV, Gudermann T, Holzman LB, Nurnberg P, Hildebrandt F (2006) Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 38:1397–1405PubMedCrossRefGoogle Scholar
  58. Hofmann SL, Majerus PW (1982) Identification and properties of two distinct phosphatidylinositol-specific phospholipase C enzymes from sheep seminal vesicular glands. J Biol Chem 257:6461–6469PubMedGoogle Scholar
  59. Hokin MR, Hokin LE (1953) Enzyme secretion and the incorporation of 32P into phospholipides of pancreas slices. J Biol Chem 203:967–977PubMedGoogle Scholar
  60. Homma Y, Takenawa T, Emori Y, Sorimachi H, Suzuki K (1989) Tissue- and cell type-specific expression of mRNAs for four types of inositol phospholipid-specific phospholipase C. Biochem Biophys Res Commun 164:406–412PubMedCrossRefGoogle Scholar
  61. Horstman DA, DeStefano K, Carpenter G (1996) Enhanced phospholipase C-γ1 activity produced by association of independently expressed X and Y domain polypeptides. Proc Natl Acad Sci USA 93:7518–7521PubMedCrossRefGoogle Scholar
  62. Hu XT, Zhang FB, Fan YC, Shu XS, Wong AH, Zhou W, Shi QL, Tang HM, Fu L, Guan XY, Rha SY, Tao Q, He C (2009) Phospholipase C-δ1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer. Oncogene 28:2466–2475Google Scholar
  63. Hubbard SR, Till JH (2000) Protein tyrosine kinase structure and function. Annu Rev Biochem 69:373–398PubMedCrossRefGoogle Scholar
  64. Hwang JI, Oh YS, Shin KJ, Kim H, Ryu SH, Suh PG (2005) Molecular cloning and characterization of a novel phospholipase C, PLC-η. Biochem J 389:181–186PubMedCrossRefGoogle Scholar
  65. Ichinohe M, Nakamura Y, Sai K, Nakahara M, Yamaguchi H, Fukami K (2007) Lack of phospholipase C-δ1 induces skin inflammation. Biochem Biophys Res Commun 356:912–918PubMedCrossRefGoogle Scholar
  66. Ilkaeva O, Kinch LN, Paulssen RH, Ross EM (2002) Mutations in the carboxyl-terminal domain of phospholipase C-β1 delineate the dimer interface and a potential Gαq interaction site. J Biol Chem 277:4294–4300PubMedCrossRefGoogle Scholar
  67. Illenberger D, Schwald F, Pimmer D, Binder W, Maier G, Dietrich A, Gierschik P (1998) Stimulation of phospholipase C-β2 by the Rho GTPases Cdc42Hs and Rac1. EMBO J 17:6241–6249PubMedCrossRefGoogle Scholar
  68. Illenberger D, Walliser C, Nurnberg B, Diaz Lorente M, Gierschik P (2003a) Specificity and structural requirements of phospholipase C-β stimulation by Rho GTPases versus G protein βγ dimers. J Biol Chem 278:3006–3014CrossRefGoogle Scholar
  69. Illenberger D, Walliser C, Strobel J, Gutman O, Niv H, Gaidzik V, Kloog Y, Gierschik P, Henis YI (2003b) Rac2 regulation of phospholipase C-β2 activity and mode of membrane interactions in intact cells. J Biol Chem 278:8645–8652CrossRefGoogle Scholar
  70. Irino Y, Cho H, Nakamura Y, Nakahara M, Furutani M, Suh PG, Takenawa T, Fukami K (2004) Phospholipase C δ-type consists of three isozymes: bovine PLC-δ2 is a homologue of human/mouse PLC-δ4. Biochem Biophys Res Commun 320:537–543PubMedCrossRefGoogle Scholar
  71. Jackson LF, Qiu TH, Sunnarborg SW, Chang A, Zhang C, Patterson C, Lee DC (2003) Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling. EMBO J 22:2704–2716PubMedCrossRefGoogle Scholar
  72. Jezyk MR, Snyder JT, Gershberg S, Worthylake DK, Harden TK, Sondek J (2006) Crystal structure of Rac1 bound to its effector phospholipase C-β2. Nat Struct Mol Biol 13:1135–1140PubMedCrossRefGoogle Scholar
  73. Jhon DY, Lee HH, Park D, Lee CW, Lee KH, Yoo OJ, Rhee SG (1993) Cloning, sequencing, purification, and Gq-dependent activation of phospholipase C-β3. J Biol Chem 268:6654–6661PubMedGoogle Scholar
  74. Ji QS, Winnier GE, Niswender KD, Horstman D, Wisdom R, Magnuson MA, Carpenter G (1997) Essential role of the tyrosine kinase substrate phospholipase C-γ1 in mammalian growth and development. Proc Natl Acad Sci USA 94:2999–3003PubMedCrossRefGoogle Scholar
  75. Jiang H, Lyubarsky A, Dodd R, Vardi N, Pugh E, Baylor D, Simon MI, Wu D (1996) Phospholipase C-β4 is involved in modulating the visual response in mice. Proc Natl Acad Sci USA 93:14598–14601PubMedCrossRefGoogle Scholar
  76. Jiang H, Kuang Y, Wu Y, Xie W, Simon MI, Wu D (1997) Roles of phospholipase C-β2 in chemoattractant-elicited responses. Proc Natl Acad Sci USA 94:7971–7975PubMedCrossRefGoogle Scholar
  77. Jin TG, Satoh T, Liao Y, Song C, Gao X, Kariya K, Hu CD, Kataoka T (2001) Role of the CDC25 homology domain of phospholipase C-ε in amplification of Rap1-dependent signaling. J Biol Chem 276:30301–30307PubMedCrossRefGoogle Scholar
  78. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806PubMedCrossRefGoogle Scholar
  79. Kamat A, Carpenter G (1997) Phospholipase C-γ1: regulation of enzyme function and role in growth factor-dependent signal transduction. Cytokine Growth Factor Rev 8:109–117PubMedCrossRefGoogle Scholar
  80. Kanemaru K, Nakahara M, Nakamura Y, Hashiguchi Y, Kouchi Z, Yamaguchi H, Oshima N, Kiyonari H, Fukami K (2010) Phospholipase C-η2 is highly expressed in the habenula and retina. Gene Expr Patterns 10:119–126PubMedCrossRefGoogle Scholar
  81. Katan M, Williams RL (1997) Phosphoinositide-specific phospholipase C: structural basis for catalysis and regulatory interactions. Semin Cell Dev Biol 8:287–296PubMedCrossRefGoogle Scholar
  82. Kawasaki H, Kretsinger RH (1994) Calcium-binding proteins. 1: EF-hands. Protein Profile 1:343–517PubMedGoogle Scholar
  83. Kelley GG, Reks SE, Ondrako JM, Smrcka AV (2001) Phospholipase C-ε: a novel Ras effector. EMBO J 20:743–754PubMedCrossRefGoogle Scholar
  84. Kelley GG, Kaproth-Joslin KA, Reks SE, Smrcka AV, Wojcikiewicz RJ (2006) G-protein-coupled receptor agonists activate endogenous phospholipase C-ε and phospholipase C-β3 in a temporally distinct manner. J Biol Chem 281:2639–2648PubMedCrossRefGoogle Scholar
  85. Kim D, Jun KS, Lee SB, Kang NG, Min DS, Kim YH, Ryu SH, Suh PG, Shin HS (1997) Phospholipase C isozymes selectively couple to specific neurotransmitter receptors. Nature 389:290–293PubMedCrossRefGoogle Scholar
  86. Kim YH, Park TJ, Lee YH, Baek KJ, Suh PG, Ryu SH, Kim KT (1999) Phospholipase C-δ1 is activated by capacitative calcium entry that follows phospholipase C-β activation upon bradykinin stimulation. J Biol Chem 274:26127–26134PubMedCrossRefGoogle Scholar
  87. Kim YJ, Sekiya F, Poulin B, Bae YS, Rhee SG (2004) Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-γ2. Mol Cell Biol 24:9986–9999PubMedCrossRefGoogle Scholar
  88. Kouchi Z, Fukami K, Shikano T, Oda S, Nakamura Y, Takenawa T, Miyazaki S (2004) Recombinant phospholipase C-ζ has high Ca2+ sensitivity and induces Ca2+ oscillations in mouse eggs. J Biol Chem 279:10408–10412PubMedCrossRefGoogle Scholar
  89. Kouchi Z, Shikano T, Nakamura Y, Shirakawa H, Fukami K, Miyazaki S (2005) The role of EF-hand domains and C2 domain in regulation of enzymatic activity of phospholipase C-ζ. J Biol Chem 280:21015–21021PubMedCrossRefGoogle Scholar
  90. Kuroda K, Ito M, Shikano T, Awaji T, Yoda A, Takeuchi H, Kinoshita K, Miyazaki S (2006) The role of X/Y linker region and N-terminal EF-hand domain in nuclear translocation and Ca2+ oscillation-inducing activities of phospholipase C-ζ, a mammalian egg-activating factor. J Biol Chem 281:27794–27805PubMedCrossRefGoogle Scholar
  91. Kurokawa M, Yoon SY, Alfandari D, Fukami K, Sato K, Fissore RA (2007) Proteolytic processing of phospholipase C-ζ and [Ca2+]i oscillations during mammalian fertilization. Dev Biol 312:407–418PubMedCrossRefGoogle Scholar
  92. Larose L, Gish G, Shoelson S, Pawson T (1993) Identification of residues in the beta platelet-derived growth factor receptor that confer specificity for binding to phospholipase C-γ1. Oncogene 8:2493–2499PubMedGoogle Scholar
  93. Lemmon MA (2003) Phosphoinositide recognition domains. Traffic 4:201–213PubMedCrossRefGoogle Scholar
  94. Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D (2000) Roles of PLC-β2 and -β3 and PI3K-γ in chemoattractant-mediated signal transduction. Science 287:1046–1049PubMedCrossRefGoogle Scholar
  95. Liao HJ, Kume T, McKay C, Xu MJ, Ihle JN, Carpenter G (2002) Absence of erythrogenesis and vasculogenesis in PLC-γ1-deficient mice. J Biol Chem 277:9335–9341PubMedCrossRefGoogle Scholar
  96. Ling K, Schill NJ, Wagoner MP, Sun Y, Anderson RA (2006) Movin’ on up: the role of PtdIns(4,5)P2 in cell migration. Trends Cell Biol 16:276–284PubMedCrossRefGoogle Scholar
  97. Lomasney JW, Cheng HF, Wang LP, Kuan Y, Liu S, Fesik SW, King K (1996) Phosphatidylinositol 4,5-bisphosphate binding to the pleckstrin homology domain of phospholipase C-δ1 enhances enzyme activity. J Biol Chem 271:25316–25326PubMedCrossRefGoogle Scholar
  98. Lomasney JW, Cheng HF, Roffler SR, King K (1999) Activation of phospholipase C-δ1 through C2 domain by a Ca2+-enzyme-phosphatidylserine ternary complex. J Biol Chem 274:21995–22001PubMedCrossRefGoogle Scholar
  99. Lopez I, Mak EC, Ding J, Hamm HE, Lomasney JW (2001) A novel bifunctional phospholipase C that is regulated by Gα12 and stimulates the Ras/mitogen-activated protein kinase pathway. J Biol Chem 276:2758–2765PubMedCrossRefGoogle Scholar
  100. Lutz S, Shankaranarayanan A, Coco C, Ridilla M, Nance MR, Vettel C, Baltus D, Evelyn CR, Neubig RR, Wieland T, Tesmer JJ (2007) Structure of Gαq-p63RhoGEF-RhoA complex reveals a pathway for the activation of RhoA by GPCRs. Science 318:1923–1927PubMedCrossRefGoogle Scholar
  101. Marrero MB, Schieffer B, Ma H, Bernstein KE, Ling BN (1996) ANG II-induced tyrosine phosphorylation stimulates phospholipase C-γ1 and Cl-channels in mesangial cells. Am J Physiol 270:C1834–C1842PubMedGoogle Scholar
  102. Martelli AM, Gilmour RS, Bertagnolo V, Neri LM, Manzoli L, Cocco L (1992) Nuclear localization and signalling activity of phosphoinositidase C-β in Swiss 3T3 cells. Nature 358:242–245PubMedCrossRefGoogle Scholar
  103. Matsuda M, Paterson HF, Rodriguez R, Fensome AC, Ellis MV, Swann K, Katan M (2001) Real time fluorescence imaging of PLC-g translocation and its interaction with the epidermal growth factor receptor. J Cell Biol 153:599–612PubMedCrossRefGoogle Scholar
  104. McOmish CE, Burrows E, Howard M, Scarr E, Kim D, Shin HS, Dean B, Buuse M van den, Hannan AJ (2008) Phospholipase C-β1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration. Mol Psychiatry 13:661–672PubMedCrossRefGoogle Scholar
  105. Meisenhelder J, Suh PG, Rhee SG, Hunter T (1989) Phospholipase C-γ is a substrate for the PDGF and EGF receptor protein-tyrosine kinases in vivo and in vitro. Cell 57:1109–1122PubMedCrossRefGoogle Scholar
  106. Michell RH (1975) Inositol phospholipids and cell surface receptor function. Biochim Biophys Acta 415:81–47PubMedCrossRefGoogle Scholar
  107. Mohammadi M, Honegger AM, Rotin D, Fischer R, Bellot F, Li W, Dionne CA, Jaye M, Rubinstein M, Schlessinger J (1991) A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor is a binding site for the SH2 domain of phospholipase C-γ1. Mol Cell Biol 11:5068–5078PubMedGoogle Scholar
  108. Morris AJ, Waldo GL, Downes CP, Harden TK (1990) A receptor and G-protein-regulated polyphosphoinositide-specific phospholipase C from turkey erythrocytes. II. P2Y-purinergic receptor and G-protein-mediated regulation of the purified enzyme reconstituted with turkey erythrocyte ghosts. J Biol Chem 265:13508–13514PubMedGoogle Scholar
  109. Mueller-Roeber B, Pical C (2002) Inositol phospholipid metabolism in Arabidopsis. Characterized and putative isoforms of inositol phospholipid kinase and phosphoinositide-specific phospholipase C. Plant Physiol 130:22–46PubMedCrossRefGoogle Scholar
  110. Nagasawa K, Nishida K, Nagai K, Shimohama S, Fujimoto S (2004) Differential expression profiles of PLC-β1 and -δ1 in primary cultured rat cortical neurons treated with N-methyl-D-aspartate and peroxynitrite. Neurosci Lett 367:246–249PubMedCrossRefGoogle Scholar
  111. Nakahara M, Shimozawa M, Nakamura Y, Irino Y, Morita M, Kudo Y, Fukami K (2005) A novel phospholipase C, PLC-η2, is a neuron-specific isozyme. J Biol Chem 280:29128–29134PubMedCrossRefGoogle Scholar
  112. Nakamura Y, Hamada Y, Fujiwara T, Enomoto H, Hiroe T, Tanaka S, Nose M, Nakahara M, Yoshida N, Takenawa T, Fukami K (2005) Phospholipase C-δ1 and -δ3 are essential in the trophoblast for placental development. Mol Cell Biol 25:10979–10988PubMedCrossRefGoogle Scholar
  113. Nalefski EA, Falke JJ (1996) The C2 domain calcium-binding motif: structural and functional diversity. Protein Sci 5:2375–2390PubMedCrossRefGoogle Scholar
  114. Nebl T, Oh SW, Luna EJ (2000) Membrane cytoskeleton: PIP2 pulls the strings. Curr Biol 10:R351–R354PubMedCrossRefGoogle Scholar
  115. Nehls M, Pfeifer D, Schorpp M, Hedrich H, Boehm T (1994) New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372:103–107PubMedCrossRefGoogle Scholar
  116. Nishizuka Y (1992) Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258:607–614PubMedCrossRefGoogle Scholar
  117. Nomikos M, Mulgrew-Nesbitt A, Pallavi P, Mihalyne G, Zaitseva I, Swann K, Lai FA, Murray D, McLaughlin S (2007) Binding of phosphoinositide-specific phospholipase C-ζ to phospholipid membranes: potential role of an unstructured cluster of basic residues. J Biol Chem 282:16644–16653PubMedCrossRefGoogle Scholar
  118. Oestreich EA, Wang H, Malik S, Kaproth-Joslin KA, Blaxall BC, Kelley GG, Dirksen RT, Smrcka AV (2007) Epac-mediated activation of phospholipase C-ε plays a critical role in β-adrenergic receptor-dependent enhancement of Ca2+ mobilization in cardiac myocytes. J Biol Chem 282:5488–5495PubMedCrossRefGoogle Scholar
  119. Oestreich EA, Malik S, Goonasekera SA, Blaxall BC, Kelley GG, Dirksen RT, Smrcka AV (2009) Epac and phospholipase C-ε regulate Ca2+ release in the heart by activation of protein kinase C-ε and calcium-calmodulin kinase II. J Biol Chem 284:1514–1522PubMedCrossRefGoogle Scholar
  120. Park DJ, Rho HW, Rhee SG (1991) CD3 stimulation causes phosphorylation of phospholipase C-γ1 on serine and tyrosine residues in a human T-cell line. Proc Natl Acad Sci USA 88:5453–5456PubMedCrossRefGoogle Scholar
  121. Park D, Jhon DY, Kriz R, Knopf J, Rhee SG (1992) Cloning, sequencing, expression, and Gq-independent activation of phospholipase C-β2. J Biol Chem 267:16048–16055PubMedGoogle Scholar
  122. Paterson A, Boyer JL, Watts VJ, Morris AJ, Price EM, Harden TK (1995) Concentration of enzyme-dependent activation of PLC-β1 and PLC-β2 by Gα11 and βγ-subunits. Cell Signal 7:709–720PubMedCrossRefGoogle Scholar
  123. Paulssen RH, Woodson J, Liu Z, Ross EM (1996) Carboxyl-terminal fragments of phospholipase C-β1 with intrinsic Gq GTPase-activating protein (GAP) activity. J Biol Chem 271:26622–26629PubMedCrossRefGoogle Scholar
  124. Payne WE, Fitzgerald-Hayes M (1993) A mutation in PLC1, a candidate phosphoinositide-specific phospholipase C gene from Saccharomyces cerevisiae, causes aberrant mitotic chromosome segregation. Mol Cell Biol 13:4351–4364PubMedGoogle Scholar
  125. Philip F, Kadamur G, Silos RG, Woodson J, Ross EM (2010) Synergistic activation of phospholipase C-β3 by Gαq and Gβγ describes a simple two-state coincidence detector. Curr Biol 20:1327–1335PubMedCrossRefGoogle Scholar
  126. Piechulek T, Rehlen T, Walliser C, Vatter P, Moepps B, Gierschik P (2005) Isozyme-specific stimulation of phospholipase C-γ2 by Rac GTPases. J Biol Chem 280:38923–38931PubMedCrossRefGoogle Scholar
  127. Poulin B, Sekiya F, Rhee SG (2000) Differential roles of the Src homology 2 domains of phospholipase C-γ in platelet-derived growth factor-induced activation of PLC-γ1 in intact cells. J Biol Chem 275:6411–6416PubMedCrossRefGoogle Scholar
  128. Raucher D, Stauffer T, Chen W, Shen K, Guo S, York JD, Sheetz MP, Meyer T (2000) Phosphatidylinositol 4,5-bisphosphate functions as a second messenger that regulates cytoskeleton-plasma membrane adhesion. Cell 100:221–228PubMedCrossRefGoogle Scholar
  129. Rebecchi MJ, Scarlata S (1998) Pleckstrin homology domains: a common fold with diverse functions. Annu Rev Biophys Biomol Struct 27:503–528PubMedCrossRefGoogle Scholar
  130. Rebecchi MJ, Raghubir A, Scarlata S, Hartenstine MJ, Brown T, Stallings JD (2009) Expression and function of phospholipase C in breast carcinoma. Adv Enzyme Regul 49:59–73PubMedCrossRefGoogle Scholar
  131. Rebres RA, Roach TI, Fraser ID, Philip F, Moon C, Lin KM, Liu J, Santat L, Cheadle L, Ross EM, Simon MI, Seaman WE (2011) Synergistic Ca2+ responses by Gαi- and Gαq-coupled G-protein-coupled receptors require a single PLC-β isoform that is sensitive to both Gβγ and Gαq. J Biol Chem 286:942–951PubMedCrossRefGoogle Scholar
  132. Rhee SG (2001) Regulation of phosphoinositide-specific phospholipase C. Annu Rev Biochem 70:281–312PubMedCrossRefGoogle Scholar
  133. Roifman CM, Wang G (1992) Phospholipase C-γ1 and phospholipase C-γ2 are substrates of the B cell antigen receptor associated protein tyrosine kinase. Biochem Biophys Res Commun 183:411–416PubMedCrossRefGoogle Scholar
  134. Ross EM (2008) Coordinating speed and amplitude in G-protein signaling. Curr Biol 18:R777–R783PubMedCrossRefGoogle Scholar
  135. Rotin D, Margolis B, Mohammadi M, Daly RJ, Daum G, Li N, Fischer EH, Burgess WH, Ullrich A, Schlessinger J (1992) SH2 domains prevent tyrosine dephosphorylation of the EGF receptor: identification of Tyr992 as the high-affinity binding site for SH2 domains of phospholipase C-γ. EMBO J 11:559–567PubMedGoogle Scholar
  136. Rottbauer W, Just S, Wessels G, Trano N, Most P, Katus HA, Fishman MC (2005) VEGF-PLCγ1 pathway controls cardiac contractility in the embryonic heart. Genes Dev 19:1624–1634PubMedCrossRefGoogle Scholar
  137. Ryu SH, Cho KS, Lee KY, Suh PG, Rhee SG (1986) Two forms of phosphatidylinositol-specific phospholipase C from bovine brain. Biochem Biophys Res Commun 141:137–144PubMedCrossRefGoogle Scholar
  138. Ryu SH, Cho KS, Lee KY, Suh PG, Rhee SG (1987a) Purification and characterization of two immunologically distinct phosphoinositide-specific phospholipases C from bovine brain. J Biol Chem 262:12511–12518Google Scholar
  139. Ryu SH, Suh PG, Cho KS, Lee KY, Rhee SG (1987b) Bovine brain cytosol contains three immunologically distinct forms of inositolphospholipid-specific phospholipase C. Proc Natl Acad Sci U S A 84:6649–6653CrossRefGoogle Scholar
  140. Satoh T, Edamatsu H, Kataoka T (2006) Phospholipase C-ε guanine nucleotide exchange factor activity and activation of Rap1. Methods Enzymol 407:281–290PubMedCrossRefGoogle Scholar
  141. Saunders CM, Larman MG, Parrington J, Cox LJ, Royse J, Blayney LM, Swann K, Lai FA (2002) PLC-ζ: a sperm-specific trigger of Ca2+ oscillations in eggs and embryo development. Development 129:3533–3544PubMedGoogle Scholar
  142. Schmidt M, Evellin S, Weernink PA, von Dorp F, Rehmann H, Lomasney JW, Jakobs KH (2001) A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nat Cell Biol 3:1020–1024PubMedCrossRefGoogle Scholar
  143. Schnabel P, Camps M (1998) Activation of a phospholipase C-β2 deletion mutant by limited proteolysis. Biochem J 330(Pt 1):461–468PubMedGoogle Scholar
  144. Secrist JP, Karnitz L, Abraham RT (1991) T-cell antigen receptor ligation induces tyrosine phosphorylation of phospholipase C-γ1. J Biol Chem 266:12135–12139PubMedGoogle Scholar
  145. Seifert JP, Wing MR, Snyder JT, Gershburg S, Sondek J, Harden TK (2004) RhoA activates purified phospholipase C-ε by a guanine nucleotide-dependent mechanism. J Biol Chem 279:47992–47997PubMedCrossRefGoogle Scholar
  146. Seifert JP, Zhou Y, Hicks SN, Sondek J, Harden TK (2008) Dual activation of phospholipase C-ε by Rho and Ras GTPases. J Biol Chem 283:29690–29698PubMedCrossRefGoogle Scholar
  147. Shibatohge M, Kariya K, Liao Y, Hu CD, Watari Y, Goshima M, Shima F, Kataoka T (1998) Identification of PLC210, a Caenorhabditis elegans phospholipase C, as a putative effector of Ras. J Biol Chem 273:6218–6222PubMedCrossRefGoogle Scholar
  148. Shimohama S, Homma Y, Suenaga T, Fujimoto S, Taniguchi T, Araki W, Yamaoka Y, Takenawa T, Kimura J (1991) Aberrant accumulation of phospholipase C-δ in Alzheimer brains. Am J Pathol 139:737–742PubMedGoogle Scholar
  149. Shimohama S, Perry G, Richey P, Takenawa T, Whitehouse PJ, Miyoshi K, Suenaga T, Matsumoto S, Nishimura M, Kimura J (1993) Abnormal accumulation of phospholipase C-δ in filamentous inclusions of human neurodegenerative diseases. Neurosci Lett 162:183–186PubMedCrossRefGoogle Scholar
  150. Shiroo M, Goff L, Biffen M, Shivnan E, Alexander D (1992) CD45 tyrosine phosphatase-activated p59fyn couples the T cell antigen receptor to pathways of diacylglycerol production, protein kinase C activation and calcium influx. EMBO J 11:4887–4897PubMedGoogle Scholar
  151. Sidhu RS, Clough RR, Bhullar RP (2005) Regulation of phospholipase C-δ1 through direct interactions with the small GTPase Ral and calmodulin. J Biol Chem 280:21933–21941PubMedCrossRefGoogle Scholar
  152. Singer AU, Waldo GL, Harden TK, Sondek J (2002) A unique fold of phospholipase C-β mediates dimerization and interaction with Gαq. Nat Struct Biol 9:32–36PubMedCrossRefGoogle Scholar
  153. Singh SM, Murray D (2003) Molecular modeling of the membrane targeting of phospholipase C pleckstrin homology domains. Protein Sci 12:1934–1953PubMedCrossRefGoogle Scholar
  154. Smrcka AV, Hepler JR, Brown KO, Sternweis PC (1991) Regulation of polyphosphoinositide-specific phospholipase C activity by purified Gq. Science 251:804–807PubMedCrossRefGoogle Scholar
  155. Smrcka AV, Sternweis PC (1993) Regulation of purified subtypes of phosphatidylinositol-specific phospholipase C-β by G protein α and βγ subunits. J Biol Chem 268:9667–9674PubMedGoogle Scholar
  156. Snyder JT, Singer AU, Wing MR, Harden TK, Sondek J (2003) The pleckstrin homology domain of phospholipase C-β2 as an effector site for Rac. J Biol Chem 278:21099–21104PubMedCrossRefGoogle Scholar
  157. Sone Y, Ito M, Shirakawa H, Shikano T, Takeuchi H, Kinoshita K, Miyazaki S (2005) Nuclear translocation of phospholipase C-ζ, an egg-activating factor, during early embryonic development. Biochem Biophys Res Commun 330:690–694PubMedCrossRefGoogle Scholar
  158. Song C, Hu CD, Masago M, Kariyai K, Yamawaki-Kataoka Y, Shibatohge M, Wu D, Satoh T, Kataoka T (2001) Regulation of a novel human phospholipase C, PLC-ε, through membrane targeting by Ras. J Biol Chem 276:2752–2757PubMedCrossRefGoogle Scholar
  159. Stallings JD, Tall EG, Pentyala S, Rebecchi MJ (2005) Nuclear translocation of phospholipase C-δ1 is linked to the cell cycle and nuclear phosphatidylinositol 4,5-bisphosphate. J Biol Chem 280:22060–22069PubMedCrossRefGoogle Scholar
  160. Stallings JD, Zeng YX, Narvaez F, Rebecchi MJ (2008) Phospholipase C-δ1 expression is linked to proliferation, DNA synthesis, and cyclin E levels. J Biol Chem 283:13992–14001PubMedCrossRefGoogle Scholar
  161. Stauffer TP, Ahn S, Meyer T (1998) Receptor-induced transient reduction in plasma membrane PtdIns(4,5)P2 concentration monitored in living cells. Curr Biol 8:343–346PubMedCrossRefGoogle Scholar
  162. Stewart AJ, Mukherjee J, Roberts SJ, Lester D, Farquharson C (2005) Identification of a novel class of mammalian phosphoinositol-specific phospholipase C enzymes. Int J Mol Med 15:117–121PubMedGoogle Scholar
  163. Stoica B, DeBell KE, Graham L, Rellahan BL, Alava MA, Laborda J, Bonvini E (1998) The amino-terminal Src homology 2 domain of phospholipase C-γ1 is essential for TCR-induced tyrosine phosphorylation of phospholipase C-γ1. J Immunol 160:1059–1066PubMedGoogle Scholar
  164. Suh BC, Hille B (2008) PIP2 is a necessary cofactor for ion channel function: how and why? Annu Rev Biophys 37:175–195PubMedCrossRefGoogle Scholar
  165. Suh PG, Ryu SH, Moon KH, Suh HW, Rhee SG (1988) Cloning and sequence of multiple forms of phospholipase C. Cell 54:161–169PubMedCrossRefGoogle Scholar
  166. Suh PG, Park JI, Manzoli L, Cocco L, Peak JC, Katan M, Fukami K, Kataoka T, Yun S, Ryu SH (2008) Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep 41:415–434PubMedCrossRefGoogle Scholar
  167. Tadano M, Edamatsu H, Minamisawa S, Yokoyama U, Ishikawa Y, Suzuki N, Saito H, Wu D, Masago-Toda M, Yamawaki-Kataoka Y, Setsu T, Terashima T, Maeda S, Satoh T, Kataoka T (2005) Congenital semilunar valvulogenesis defect in mice deficient in phospholipase C-ε. Mol Cell Biol 25:2191–2199PubMedCrossRefGoogle Scholar
  168. Takenawa T, Nagai Y (1981) Purification of phosphatidylinositol-specific phospholipase C from rat liver. J Biol Chem 256:6769–6775PubMedGoogle Scholar
  169. Tasma IM, Brendel V, Whitham SA, Bhattacharyya MK (2008) Expression and evolution of the phosphoinositide-specific phospholipase C gene family in Arabidopsis thaliana. Plant Physiol Biochem 46:627–637PubMedCrossRefGoogle Scholar
  170. Taylor SJ, Chae HZ, Rhee SG, Exton JH (1991) Activation of the β1 isozyme of phospholipase C by α-subunits of the Gq class of G proteins. Nature 350:516–518PubMedCrossRefGoogle Scholar
  171. Tesmer JJ, Berman DM, Gilman AG, Sprang SR (1997) Structure of RGS4 bound to AlF4-activated Gαi1: stabilization of the transition state for GTP hydrolysis. Cell 89:251–261PubMedCrossRefGoogle Scholar
  172. Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJ (2005) Snapshot of activated G proteins at the membrane: the Gαq-GRK2-Gβγ complex. Science 310:1686–1690PubMedCrossRefGoogle Scholar
  173. Todderud G, Wahl MI, Rhee SG, Carpenter G (1990) Stimulation of phospholipase C-γ1 membrane association by epidermal growth factor. Science 249:296–298PubMedCrossRefGoogle Scholar
  174. Venema VJ, Ju H, Sun J, Eaton DC, Marrero MB, Venema RC (1998) Bradykinin stimulates the tyrosine phosphorylation and bradykinin B2 receptor association of phospholipase C-γ1 in vascular endothelial cells. Biochem Biophys Res Commun 246:70–75PubMedCrossRefGoogle Scholar
  175. Wahl MI, Olashaw NE, Nishibe S, Rhee SG, Pledger WJ, Carpenter G (1989) Platelet-derived growth factor induces rapid and sustained tyrosine phosphorylation of phospholipase C-γ in quiescent BALB/c 3T3 cells. Mol Cell Biol 9:2934–2943PubMedGoogle Scholar
  176. Waksman G, Kominos D, Robertson SC, Pant N, Baltimore D, Birge RB, Cowburn D, Hanafusa H, Mayer BJ, Overduin M et al (1992) Crystal structure of the phosphotyrosine recognition domain SH2 of v-src complexed with tyrosine-phosphorylated peptides. Nature 358:646–653PubMedCrossRefGoogle Scholar
  177. Waldo GL, Boyer JL, Morris AJ, Harden TK (1991) Purification of an AlF4- and G-protein βγ-subunit-regulated phospholipase C-activating protein. J Biol Chem 266:14217–14225PubMedGoogle Scholar
  178. Waldo GL, Ricks TK, Hicks SN, Cheever ML, Kawano T, Tsuboi K, Wang X, Montell C, Kozasa T, Sondek J, Harden TK (2010) Kinetic scaffolding mediated by a phospholipase C-β and Gq signaling complex. Science 330:974–980PubMedCrossRefGoogle Scholar
  179. Walliser C, Retlich M, Harris R, Everett KL, Josephs MB, Vatter P, Esposito D, Driscoll PC, Katan M, Gierschik P, Bunney TD (2008) Rac regulates its effector phospholipase C-γ2 through interaction with a split pleckstrin homology domain. J Biol Chem 283:30351–30362PubMedCrossRefGoogle Scholar
  180. Wang D, Feng J, Wen R, Marine JC, Sangster MY, Parganas E, Hoffmeyer A, Jackson CW, Cleveland JL, Murray PJ, Ihle JN (2000a) Phospholipase C γ2 is essential in the functions of B cell and several Fc receptors. Immunity 13:25–35CrossRefGoogle Scholar
  181. Wang T, Dowal L, El-Maghrabi MR, Rebecchi M, Scarlata S (2000b) The pleckstrin homology domain of phospholipase C-β2 links the binding of Gβγ to activation of the catalytic core. J Biol Chem 275:7466–7469CrossRefGoogle Scholar
  182. Wang H, Oestreich EA, Maekawa N, Bullard TA, Vikstrom KL, Dirksen RT, Kelley GG, Blaxall BC, Smrcka AV (2005) Phospholipase C-ε modulates β-adrenergic receptor-dependent cardiac contraction and inhibits cardiac hypertrophy. Circ Res 97:1305–1313PubMedCrossRefGoogle Scholar
  183. Wang X, Zbou C, Qiu G, Fan J, Tang H, Peng Z (2008) Screening of new tumor suppressor genes in sporadic colorectal cancer patients. Hepatogastroenterology 55:2039–2044PubMedGoogle Scholar
  184. Weiss A, Koretzky G, Schatzman RC, Kadlecek T (1991) Functional activation of the T-cell antigen receptor induces tyrosine phosphorylation of phospholipase C-γ1. Proc Natl Acad Sci USA 88:5484–5488PubMedCrossRefGoogle Scholar
  185. Wierenga RK (2001) The TIM-barrel fold: a versatile framework for efficient enzymes. FEBS Lett 492:193–198PubMedCrossRefGoogle Scholar
  186. Wing MR, Houston D, Kelley GG, Der CJ, Siderovski DP, Harden TK (2001) Activation of phospholipase C-ε by heterotrimeric G protein βγ subunits. J Biol Chem 276:48257–48261PubMedGoogle Scholar
  187. Wing MR, Bourdon DM, Harden TK (2003a) PLC-ε: a shared effector protein in Ras-, Rho-, and Gαβγ-mediated signaling. Mol Interv 3:273–280CrossRefGoogle Scholar
  188. Wing MR, Snyder JT, Sondek J, Harden TK (2003b) Direct activation of phospholipase C-ε by Rho. J Biol Chem 278:41253–41258CrossRefGoogle Scholar
  189. Wohlgemuth S, Kiel C, Kramer A, Serrano L, Wittinghofer F, Herrmann C (2005) Recognizing and defining true Ras binding domains I: biochemical analysis. J Mol Biol 348:741–758PubMedCrossRefGoogle Scholar
  190. Xiao W, Hong H, Kawakami Y, Kato Y, Wu D, Yasudo H, Kimura A, Kubagawa H, Bertoli LF, Davis RS, Chau LA, Madrenas J, Hsia CC, Xenocostas A, Kipps TJ, Hennighausen L, Iwama A, Nakauchi H, Kawakami T (2009) Tumor suppression by phospholipase C-β3 via SHP-1-mediated dephosphorylation of Stat5. Cancer Cell 16:161–171PubMedCrossRefGoogle Scholar
  191. Xie W, Samoriski GM, McLaughlin JP, Romoser VA, Smrcka A, Hinkle PM, Bidlack JM, Gross RA, Jiang H, Wu D (1999) Genetic alteration of phospholipase C-β3 expression modulates behavioral and cellular responses to mu opioids. Proc Natl Acad Sci USA 96:10385–10390PubMedCrossRefGoogle Scholar
  192. Yablonski D, Kadlecek T, Weiss A (2001) Identification of a phospholipase C-γ1 SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-γ1 and NFAT. Mol Cell Biol 21:4208–4218PubMedCrossRefGoogle Scholar
  193. Yagisawa H, Sakuma K, Paterson HF, Cheung R, Allen V, Hirata H, Watanabe Y, Hirata M, Williams RL, Katan M (1998) Replacements of single basic amino acids in the pleckstrin homology domain of phospholipase C-δ1 alter the ligand binding, phospholipase activity, and interaction with the plasma membrane. J Biol Chem 273:417–424PubMedCrossRefGoogle Scholar
  194. Yamaga M, Fujii M, Kamata H, Hirata H, Yagisawa H (1999) Phospholipase C-δ1 contains a functional nuclear export signal sequence. J Biol Chem 274:28537–28541PubMedCrossRefGoogle Scholar
  195. Yin HL, Janmey PA (2003) Phosphoinositide regulation of the actin cytoskeleton. Annu Rev Physiol 65:761–789PubMedCrossRefGoogle Scholar
  196. Yoda A, Oda S, Shikano T, Kouchi Z, Awaji T, Shirakawa H, Kinoshita K, Miyazaki S (2004) Ca2+ oscillation-inducing phospholipase C-ζ expressed in mouse eggs is accumulated to the pronucleus during egg activation. Dev Biol 268:245–257PubMedCrossRefGoogle Scholar
  197. Yoko-o T, Matsui Y, Yagisawa H, Nojima H, Uno I, Toh-e A (1993) The putative phosphoinositide-specific phospholipase C gene, PLC1, of the yeast Saccharomyces cerevisiae is important for cell growth. Proc Natl Acad Sci USA 90:1804–1808PubMedCrossRefGoogle Scholar
  198. Yu H, Fukami K, Watanabe Y, Ozaki C, Takenawa T (1998) Phosphatidylinositol 4,5-bisphosphate reverses the inhibition of RNA transcription caused by histone H1. Eur J Biochem 251:281–287PubMedCrossRefGoogle Scholar
  199. Zhang W, Neer EJ (2001) Reassembly of phospholipase C-β2 from separated domains: analysis of basal and G protein-stimulated activities. J Biol Chem 276:2503–2508PubMedCrossRefGoogle Scholar
  200. Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE (1998) LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92:83–92PubMedCrossRefGoogle Scholar
  201. Zhou Y, Wing MR, Sondek J, Harden TK (2005) Molecular cloning and characterization of PLC-η2. Biochem J 391:667–676PubMedCrossRefGoogle Scholar
  202. Zhou Y, Sondek J, Harden TK (2008) Activation of human phospholipase C-η2 by Gβγ. Biochemistry 47:4410–4417PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Aurelie Gresset
    • 1
  • John Sondek
    • 1
  • T. Kendall Harden
    • 1
    Email author
  1. 1.Department of PharmacologyUniversity of North Carolina School of MedicineChapel HillUSA

Personalised recommendations