Multiple roles of phosphoinositide-specific phospholipase C isozymes

  • Suh, Pann-Ghill (Division of Molecular and Life Sciences, Pohang University of Science and Technology) ;
  • Park, Jae-Il (Division of Molecular and Life Sciences, Pohang University of Science and Technology) ;
  • Manzoli, Lucia (Cellular Signaling Laboratory, Department of Anatomical Sciences, University of Bologna) ;
  • Cocco, Lucio (Cellular Signaling Laboratory, Department of Anatomical Sciences, University of Bologna) ;
  • Peak, Joanna C. (Cancer Research UK Centre for Cell and Molecular Biology, Chester Beatty Laboratories, The Institute of Cancer Research) ;
  • Katan, Matilda (Cancer Research UK Centre for Cell and Molecular Biology, Chester Beatty Laboratories, The Institute of Cancer Research) ;
  • Fukami, Kiyoko (Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Science) ;
  • Kataoka, Tohru (Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine) ;
  • Yun, Sang-Uk (Division of Molecular and Life Sciences, Pohang University of Science and Technology) ;
  • Ryu, Sung-Ho (Division of Molecular and Life Sciences, Pohang University of Science and Technology)
  • Accepted : 2008.06.03
  • Published : 2008.06.30


Phosphoinositide-specific phospholipase C is an effector molecule in the signal transduction process. It generates two second messengers, inositol-1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. Currently, thirteen mammal PLC isozymes have been identified, and they are divided into six groups: PLC-$\beta$, -$\gamma$, -$\delta$, -$\varepsilon$, -$\zeta$ and -$\eta$. Sequence analysis studies demonstrated that each isozyme has more than one alternative splicing variant. PLC isozymes contain the X and Y domains that are responsible for catalytic activity. Several other domains including the PH domain, the C2 domain and EF hand motifs are involved in various biological functions of PLC isozymes as signaling proteins. The distribution of PLC isozymes is tissue and organ specific. Recent studies on isolated cells and knockout mice depleted of PLC isozymes have revealed their distinct phenotypes. Given the specificity in distribution and cellular localization, it is clear that each PLC isozyme bears a unique function in the modulation of physiological responses. In this review, we discuss the structural organization, enzymatic properties and molecular diversity of PLC splicing variants and study functional and physiological roles of each isozyme.


Alternative splicing variant;Phosphoinositide-specific phospholipase C;Signal transduction


  1. Majerus, P. W., Connolly, T. M., Deckmyn, H., Ross, T. S., Bross, T. E., Ishii, H., Bansal, V. S. and Wilson, D. B. (1986) The metabolism of phosphoinositide-derived messenger molecules. Science 234, 1519-1526.
  2. Singer, W. D., Brown, H. A. and Sternweis, P. C. (1997) Regulation of eukaryotic phosphatidylinositol-specific phospholipase C and phospholipase D. Annu. Rev. Biochem. 66, 475-509.
  3. Rhee, S. G. (2001) Regulation of phosphoinositide-specific phospholipase C. Annu. Rev. Biochem. 70, 281-312.
  4. Hokin, M. R. and Hokin, L. E. (1953) Enzyme secretion and the incorporation of P32 into phospholipides of pancreas slices. J Biol. Chem. 203, 967-977.
  5. Streb, H., Irvine, R. F., Berridge, M. J. and Schulz, I. (1983) Release of $Ca^{2+}$ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature 306, 67-69.
  6. Takenawa, T. and Nagai, Y. (1981) Purification of phosphatidylinositol- specific phospholipase C from rat liver. J. Biol. Chem. 256, 6769-6775.
  7. Suh, P. G., Ryu, S. H., Moon, K. H., Suh, H. W. and Rhee, S. G. (1988) Cloning and sequence of multiple forms of phospholipase C. Cell 54, 161-169.
  8. Essen, L. O., Perisic, O., Cheung, R., Katan, M. and Williams, R. L. (1996) Crystal structure of a mammalian phosphoinositide-specific phospholipase C delta. Nature 380, 595-602.
  9. Ellis, M. V., U, S. and Katan, M. (1995) Mutations within a highly conserved sequence present in the X region of phosphoinositide- specific phospholipase C-delta 1. Biochem. J. 307, 69-75.
  10. Williams, R. L. (1999) Mammalian phosphoinositide-specific phospholipase C. Biochim. Biophys. Acta. 1441, 255-267.
  11. Ellis, M. V., James, S. R., Perisic, O., Downes, C. P., Williams, R. L. and Katan, M. (1998) Catalytic domain of phosphoinositide-specific phospholipase C (PLC). Mutational analysis of residues within the active site and hydrophobic ridge of plcdelta1. J. Biol. Chem. 273, 11650-11659.
  12. Wang, L. P., Lim, C., Kuan, Y., Chen, C. L., Chen, H. F. and King, K. (1996) Positive charge at position 549 is essential for phosphatidylinositol 4,5-bisphosphate-hydrolyzing but not phosphatidylinositol-hydrolyzing activities of human phospholipase C delta1. J. Biol. Chem. 271, 24505-24516.
  13. Paterson, H. F., Savopoulos, J. W., Perisic, O., Cheung, R., Ellis, M. V., Williams, R. L. and Katan, M. (1995) Phospholipase C delta 1 requires a pleckstrin homology domain for interaction with the plasma membrane. Biochem. J. 312, 661-666.
  14. Wang, T., Dowal, L., El-Maghrabi, M. R., Rebecchi, M. and Scarlata, S. (2000) The pleckstrin homology domain of phospholipase C-beta(2) links the binding of gbetagamma to activation of the catalytic core. J. Biol. Chem. 275, 7466-7469.
  15. Falasca, M., Logan, S. K., Lehto, V. P., Baccante, G., Lemmon, M. A. and Schlessinger, J. (1998) Activation of phospholipase C gamma by PI 3-kinase-induced PH domain- mediated membrane targeting. EMBO J. 17, 414-422.
  16. Wen, W., Yan, J. and Zhang, M. (2006) Structural characterization of the split pleckstrin homology domain in phospholipase C-gamma1 and its interaction with TRPC3. J. Biol. Chem. 281, 12060-12068
  17. Nakashima, S., Banno, Y., Watanabe, T., Nakamura, Y., Mizutani, T., Sakai, H., Zhao, Y., Sugimoto, Y. and Nozawa, Y. (1995) Deletion and site-directed mutagenesis of EF-hand domain of phospholipase C-delta 1: effects on its activity. Biochem. Biophys. Res. Commun. 211, 365-369.
  18. Otterhag, L., Sommarin, M. and Pical, C. (2001) N-terminal EF-hand-like domain is required for phosphoinositide- specific phospholipase C activity in Arabidopsis thaliana. FEBS Lett. 497, 165-170.
  19. Homma, Y., Takenawa, T., Emori, Y., Sorimachi, H. and 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, 406-412.
  20. Park, D., Jhon, D. Y., Kriz, R., Knopf, J. and Rhee, S. G. (1992) Cloning, sequencing, expression, and Gq-independent activation of phospholipase C-beta 2. J. Biol. Chem. 267, 16048-16055.
  21. Sun, L., Mao, G., Kunapuli, S. P., Dhanasekaran, D. N. and Rao, A. K. (2007) Alternative splice variants of phospholipase C-beta2 are expressed in platelets: effect on Galphaq-dependent activation and localization. Platelets. 18, 217-223.
  22. Jhon, D. Y., Lee, H. H., Park, D., Lee, C. W., Lee, K. H., Yoo, O. J. and Rhee, S. G. (1993) Cloning, sequencing, purification, and Gq-dependent activation of phospholipase C-beta 3. J. Biol. Chem. 268, 6654-6661.
  23. Adamski, F. M., Timms, K. M. and Shieh, B. H. (1999) A unique isoform of phospholipase Cbeta4 highly expressed in the cerebellum and eye. Biochim. Biophys. Acta. 1444, 55-60.
  24. Min, D. S., Kim, D. M., Lee, Y. H., Seo, J., Suh, P. G. and Ryu, S. H. (1993) Purification of a novel phospholipase C isozyme from bovine cerebellum. J. Biol. Chem. 268, 12207-12212.
  25. Alvarez, R. A., Ghalayini, A. J., Xu, P., Hardcastle, A., Bhattacharya, S., Rao, P. N., Pettenati, M. J., Anderson, R. E. and Baehr, W. (1995) cDNA sequence and gene locus of the human retinal phosphoinositide-specific phospholipase-C beta 4 (PLCB4). Genomics 29, 53-61.
  26. Mizuguchi, M., Yamada, M., Kim, S. U. and Rhee, S. G. (1991) Phospholipase C isozymes in neurons and glial cells in culture: an immunocytochemical and immunochemical study. Brain Res. 548, 35-40.
  27. Tanaka, O. and Kondo, H. (1994) Localization of mRNAs for three novel members (beta 3, beta 4 and gamma 2) of phospholipase C family in mature rat brain. Neurosci. Lett. 182, 17-20.
  28. Ji, Q. S., Ermini, S., Baulida, J., Sun, F. L. and Carpenter, G. (1998) Epidermal growth factor signaling and mitogenesis in Plcg1 null mouse embryonic fibroblasts. Mol. Biol. Cell. 9, 749-757.
  29. Wang, D., Feng, J., Wen, R., Marine, J. C., Sangster, M. Y., Parganas, E., Hoffmeyer, A., Jackson, C. W., Cleveland, J. L., Murray, P. J. and Ihle, J. N. (2000) Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Immunity 13, 25-35.
  30. Hashimoto, A., Takeda, K., Inaba, M., Sekimata, M., Kaisho, T., Ikehara, S., Homma, Y., Akira, S. and Kurosaki, T. (2000) Cutting edge: essential role of phospholipase C-gamma 2 in B cell development and function. J. Immunol. 165, 1738-1742.
  31. Lee, W. K., Kim, J. K., Seo, M. S., Cha, J. H., Lee, K. J., Rha, H. K., Min, D. S., Jo, Y. H. and Lee, K. H. (1999) Molecular cloning and expression analysis of a mouse phospholipase C-delta1. Biochem. Biophys. Res. Commun. 261, 393-399.
  32. Lin, F. G., Cheng, H. F., Lee, I. F., Kao, H. J., Loh, S. H. and Lee, W. H. (2001) Downregulation of phospholipase C delta3 by cAMP and calcium. Biochem. Biophys. Res. Commun. 286, 274-280.
  33. Lee, S. B. and Rhee, S. G. (1996) Molecular cloning, splice variants, expression, and purification of phospholipase C-delta 4. J. Biol. Chem. 271, 25-31.
  34. Lopez, I., Mak, E. C., Ding, J., Hamm, H. E. and Lomasney, J. W. (2001) A novel bifunctional phospholipase c that is regulated by Galpha 12 and stimulates the Ras/mitogenactivated protein kinase pathway. J. Biol. Chem. 276, 2758-2765.
  35. Saunders, C. M., Larman, M. G., Parrington, J., Cox, L. J., Royse, J., Blayney, L. M., Swann, K. and Lai, F. A. (2002) PLC zeta: a sperm-specific trigger of Ca(2+) oscillations in eggs and embryo development. Development 129, 3533-3544.
  36. Hwang, J. I., Oh, Y. S., Shin, K. J., Kim, H., Ryu, S. H. and Suh, P. G. (2005) Molecular cloning and characterization of a novel phospholipase C, PLC-eta. Biochem. J. 389, 181-186.
  37. Zhou, Y., Wing, M. R., Sondek, J. and Harden, T. K. (2005) Molecular cloning and characterization of PLC-eta2. Biochem. J. 391, 667-676.
  38. Nakahara, M., Shimozawa, M., Nakamura, Y., Irino, Y., Morita, M., Kudo, Y. and Fukami, K. (2005) A novel phospholipase C, PLC(eta)2, is a neuron-specific isozyme. J. Biol. Chem. 280, 29128-29134.
  39. Bahk, Y. Y., Song, H., Baek, S. H., Park, B. Y., Kim, H., Ryu, S. H. and Suh, P. G. (1998) Localization of two forms of phospholipase C-beta1, a and b, in C6Bu-1 cells. Biochim. Biophys. Acta. 1389, 76-80.
  40. Mao, G. F., Kunapuli, S. P. and Koneti Rao, A. (2000) Evidence for two alternatively spliced forms of phospholipase C-beta2 in haematopoietic cells. Br. J. Haematol. 110, 402-408.
  41. Kim, M. J., Min, D. S., Ryu, S. H. and Suh, P. G. (1998) A cytosolic, galphaq- and betagamma-insensitive splice variant of phospholipase C-beta4. J. Biol. Chem. 273, 3618-3624.
  42. Sorli, S. C., Bunney, T. D., Sugden, P. H., Paterson, H. F. and Katan, M. (2005) Signaling properties and expression in normal and tumor tissues of two phospholipase C epsilon splice variants. Oncogene 24, 90-100.
  43. Peruzzi, D., Aluigi, M., Manzoli, L., Billi, A. M., Di Giorgio, F. P., Morleo, M., Martelli, A. M. and Cocco, L. (2002) Molecular characterization of the human PLC beta1 gene. Biochim. Biophys. Acta. 1584, 46-54.
  44. Min, D. S., Kim, Y., Lee, Y. H., Suh, P. G. and Ryu, S. H. (1993) A G-protein-coupled 130 kDa phospholipase C isozyme, PLC-beta 4, from the particulate fraction of bovine cerebellum. FEBS Lett. 331, 38-42
  45. Harada, K., Takeuchi, H., Oike, M., Matsuda, M., Kanematsu, T., Yagisawa, H., Nakayama, K. I., Maeda, K., Erneux, C. and Hirata, M. (2005) Role of PRIP-1, a novel Ins(1,4,5)P3 binding protein, in Ins(1,4,5)P3-mediated $Ca^{2+}$ signaling. J. Cell. Physiol. 202, 422-433.
  46. Nagano, K., Fukami, K., Minagawa, T., Watanabe, Y., Ozaki, C. and Takenawa, T. (1999) A novel phospholipase C delta4 (PLCdelta4) splice variant as a negative regulator of PLC. J. Biol. Chem. 274, 2872-2879.
  47. Kouchi, Z., Fukami, K., Shikano, T., Oda, S., Nakamura, Y., Takenawa, T. and Miyazaki, S. (2004) Recombinant phospholipase Czeta has high $Ca^{2+}$ sensitivity and induces $Ca^{2+}$ oscillations in mouse eggs. J. Biol. Chem. 279, 10408-10412.
  48. Rebecchi, M. J. and Pentyala, S. N. (2000) Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol. Rev. 80, 1291-1335.
  49. Faenza, I., Bregoli, L., Ramazzotti, G., Gaboardi, G., Follo, M. Y., Mongiorgi, S., Billi, A. M., Manzoli, L., Martelli, A. M. and Cocco, L. (2008) Nuclear phospholipase C beta1 and cellular differentiation. Front. Biosci. 13, 2452-2463.
  50. Drin, G. and Scarlata, S. (2007) Stimulation of phospholipase Cbeta by membrane interactions, interdomain movement, and G protein binding-how many ways can you activate an enzyme? Cell. Signal. 19, 1383-1392.
  51. Ross, E. M., Mateu, D., Gomes, A. V., Arana, C., Tran, T. and Litosch, I. (2006) Structural determinants for phosphatidic acid regulation of phospholipase C-beta1. J. Biol. Chem. 281, 33087-33094.
  52. Park, D., Jhon, D. Y., Lee, C. W., Ryu, S. H. and Rhee, S. G. (1993) Removal of the carboxyl-terminal region of phospholipase C-beta 1 by calpain abolishes activation by G alpha q. J. Biol. Chem. 268, 3710-3714.
  53. Smrcka, A. V. and Sternweis, P. C. (1993) Regulation of purified subtypes of phosphatidylinositol-specific phospholipase C beta by G protein alpha and beta gamma subunits. J. Biol. Chem. 268, 9667-9674.
  54. Lee, C. W., Lee, K. H., Lee, S. B., Park, D. and Rhee, S. G. (1994) Regulation of phospholipase C-beta 4 by ribonucleotides and the alpha subunit of Gq. J. Biol. Chem. 269, 25335-25338.
  55. Camps, M., Carozzi, A., Schnabel, P., Scheer, A., Parker, P. J. and Gierschik, P. (1992) Isozyme-selective stimulation of phospholipase C-beta 2 by G protein beta gamma- subunits. Nature 360, 684-686.
  56. Runnels, L. W. and Scarlata, S. F. (1999) Determination of the affinities between heterotrimeric G protein subunits and their phospholipase C-beta effectors. Biochemistry 38, 1488-1496.
  57. Offermanns, S., Toombs, C. F., Hu, Y. H. and Simon, M. I. (1997) Defective platelet activation in G alpha(q)-deficient mice. Nature 389, 183-186.
  58. Lee, S. B., Shin, S. H., Hepler, J. R., Gilman, A. G. and Rhee, S. G. (1993) Activation of phospholipase C-beta 2 mutants by G protein alpha q and beta gamma subunits. J. Biol. Chem. 268, 25952-25957.
  59. Wang, T., Pentyala, S., Rebecchi, M. J. and Scarlata, S. (1999) Differential association of the pleckstrin homology domains of phospholipases C-beta 1, C-beta 2, and C-delta 1 with lipid bilayers and the beta gamma subunits of heterotrimeric G proteins. Biochemistry 38, 1517-1524.
  60. Dippel, E., Kalkbrenner, F., Wittig, B. and Schultz, G. (1996) A heterotrimeric G protein complex couples the muscarinic m1 receptor to phospholipase C-beta. Proc. Natl. Acad. Sci. U. S. A. 93, 1391-1396.
  61. Biddlecome, G. H., Berstein, G. and Ross, E. M. (1996) Regulation of phospholipase C-beta1 by Gq and m1 muscarinic cholinergic receptor. Steady-state balance of receptor- mediated activation and GTPase-activating protein- promoted deactivation. J. Biol. Chem. 271, 7999-8007.
  62. Divecha, N. and Irvine, R. F. (1995) Phospholipid signaling. Cell 80, 269-278.
  63. Cocco, L., Capitani, S., Maraldi, N. M., Mazzotti, G., Barnabei, O., Rizzoli, R., Gilmour, R. S., Wirtz, K. W., Rhee, S. G. and Manzoli, F. A. (1998) Inositides in the nucleus: taking stock of PLC beta 1. Adv. Enzyme Regul. 38, 351-363.
  64. Martelli, A. M., Gilmour, R. S., Bertagnolo, V., Neri, L. M., Manzoli, L. and Cocco, L. (1992) Nuclear localization and signalling activity of phosphoinositidase C beta in Swiss 3T3 cells. Nature 358, 242-245.
  65. Divecha, N., Letcher, A. J., Banfic, H. H., Rhee, S. G. and Irvine, R. F. (1995) Changes in the components of a nuclear inositide cycle during differentiation in murine erythroleukaemia cells. Biochem. J. 312(Pt 1), 63-67.
  66. Kim, C. G., Park, D. and Rhee, S. G. (1996) The role of carboxyl-terminal basic amino acids in Gqalpha-dependent activation, particulate association, and nuclear localization of phospholipase C-beta1. J. Biol. Chem. 271, 21187-21192.
  67. Payrastre, B., Nievers, M., Boonstra, J., Breton, M., Verkleij, A. J. and Van Bergen en Henegouwen, P. M. (1992) A differential location of phosphoinositide kinases, diacylglycerol kinase, and phospholipase C in the nuclear matrix. J. Biol. Chem. 267, 5078-5084.
  68. Deleris, P., Bacqueville, D., Gayral, S., Carrez, L., Salles, J. P., Perret, B. and Breton-Douillon, M. (2003) SHIP-2 and PTEN are expressed and active in vascular smooth muscle cell nuclei, but only SHIP-2 is associated with nuclear speckles. J. Biol. Chem. 278, 38884-38891.
  69. Didichenko, S. A. and Thelen, M. (2001) Phosphatidylinositol 3-kinase c2alpha contains a nuclear localization sequence and associates with nuclear speckles. J. Biol. Chem. 276, 48135-48142.
  70. Tabellini, G., Bortul, R., Santi, S., Riccio, M., Baldini, G., Cappellini, A., Billi, A. M., Berezney, R., Ruggeri, A., Cocco, L. and Martelli, A. M. (2003) Diacylglycerol kinase- theta is localized in the speckle domains of the nucleus. Exp. Cell Res. 287, 143-154.
  71. Fiume, R., Faenza, I., Matteucci, A., Astolfi, A., Vitale, M., Martelli, A. M. and Cocco, L. (2005) Nuclear phospholipase C beta1 (PLCbeta1) affects CD24 expression in murine erythroleukemia cells. J. Biol. Chem. 280, 24221-24226.
  72. Lo Vasco, V. R., Calabrese, G., Manzoli, L., Palka, G., Spadano, A., Morizio, E., Guanciali-Franchi, P., Fantasia, D. and Cocco, L. (2004) Inositide-specific phospholipase c beta1 gene deletion in the progression of myelodysplastic syndrome to acute myeloid leukemia. Leukemia 18, 1122-1126.
  73. Follo, M. Y., Mongiorgi, S., Bosi, C., Cappellini, A., Finelli, C., Chiarini, F., Papa, V., Libra, M., Martinelli, G., Cocco, L. and Martelli, A. M. (2007) The Akt/mammalian target of rapamycin signal transduction pathway is activated in high-risk myelodysplastic syndromes and influences cell survival and proliferation. Cancer Res. 67, 4287-4294.
  74. Kaminskas, E., Farrell, A., Abraham, S., Baird, A., Hsieh, L. S., Lee, S. L., Leighton, J. K., Patel, H., Rahman, A., Sridhara, R., Wang, Y. C. and Pazdur, R. (2005) Approval summary: azacitidine for treatment of .myelodysplastic syndrome subtypes. Clin. Cancer Res. 11, 3604-3608
  75. Silverman, L. R., Demakos, E. P., Peterson, B. L., Kornblith, A. B., Holland, J. C., Odchimar-Reissig, R., Stone, R. M., Nelson, D., Powell, B. L., DeCastro, C. M., Ellerton, J., Larson, R. A., Schiffer, C. A. and Holland, J. F. (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J. Clin. Oncol. 20, 2429-2440.
  76. Daskalakis, M., Nguyen, T. T., Nguyen, C., Guldberg, P., Kohler, G., Wijermans, P., Jones, P. A. and Lubbert, M. (2002) Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment. Blood 100, 2957-2964.
  77. Follo, M. Y., Finelli, C., Bosi, C., Martinelli, G., Mongiorgi, S., Baccarani, M., Manzoli, L., Blalock, W. L., Martelli, A. M. and Cocco, L. (2008) PI-PLCbeta-1 and activated Akt levels are linked to azacitidine responsiveness in high-risk myelodysplastic syndromes. Leukemia 22, 198-200.
  78. Cheson, B. D., Greenberg, P. L., Bennett, J. M., Lowenberg, B., Wijermans, P. W., Nimer, S. D., Pinto, A., Beran, M., de Witte, T. M., Stone, R. M., Mittelman, M., Sanz, G. F., Gore, S. D., Schiffer, C. A. and Kantarjian, H. (2006) Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108, 419-425.
  79. Cocco, L., Martelli, A. M., Vitale, M., Falconi, M., Barnabei, O., Stewart Gilmour, R. and Manzoli, F. A. (2002) Inositides in the nucleus: regulation of nuclear PI-PLCbeta1. Adv. Enzyme Regul. 42, 181-193.
  80. Faenza, I., Matteucci, A., Manzoli, L., Billi, A. M., Aluigi, M., Peruzzi, D., Vitale, M., Castorina, S., Suh, P. G. and Cocco, L. (2000) A role for nuclear phospholipase Cbeta 1 in cell cycle control. J. Biol. Chem. 275, 30520-30524.
  81. Faenza, I., Ramazzotti, G., Bavelloni, A., Fiume, R., Gaboardi, G. C., Follo, M. Y., Gilmour, R. S., Martelli, A. M., Ravid, K. and Cocco, L. (2007) Inositide-dependent phospholipase C signaling mimics insulin in skeletal muscle differentiation by affecting specific regions of the cyclin D3 promoter. Endocrinology 148, 1108-1117.
  82. Kim, D., Jun, K. S., Lee, S. B., Kang, N. G., Min, D. S., Kim, Y. H., Ryu, S. H., Suh, P. G. and Shin, H. S. (1997) Phospholipase C isozymes selectively couple to specific neurotransmitter receptors. Nature 389, 290-293.
  83. Jiang, H., Kuang, Y., Wu, Y., Xie, W., Simon, M. I. and Wu, D. (1997) Roles of phospholipase C beta2 in chemoattractant- elicited responses. Proc. Natl. Acad. Sci. U. S. A. 94, 7971-7975.
  84. Xie, W., Samoriski, G. M., McLaughlin, J. P., Romoser, V. A., Smrcka, A., Hinkle, P. M., Bidlack, J. M., Gross, R. A., Jiang, H. and Wu, D. (1999) Genetic alteration of phospholipase C beta3 expression modulates behavioral and cellular responses to mu opioids. Proc. Natl. Acad. Sci. U. S. A. 96, 10385-10390.
  85. Jiang, H., Lyubarsky, A., Dodd, R., Vardi, N., Pugh, E., Baylor, D., Simon, M. I. and Wu, D. (1996) Phospholipase C beta 4 is involved in modulating the visual response in mice. Proc. Natl. Acad. Sci. U. S. A. 93, 14598-14601.
  86. Katan, M. (1998) Families of phosphoinositide-specific phospholipase C: structure and function. Biochim. Biophys. Acta. 1436, 5-17.
  87. Katan, M. and Williams, R. L. (1997) Phosphoinositidespecific phospholipase C: structural basis for catalysis and regulatory interactions. Semin. Cell Dev. Biol. 8, 287-296.
  88. Carpenter, G. and Ji, Q. (1999) Phospholipase C-gamma as a signal-transducing element. Exp. Cell Res. 253, 15-24.
  89. Kamat, A. and Carpenter, G. (1997) Phospholipase C-gamma1: regulation of enzyme function and role in growth factor-dependent signal transduction. Cytokine Growth Factor Rev. 8, 109-117.
  90. Sekiya, F., Poulin, B., Kim, Y. J. and Rhee, S. G. (2004) Mechanism of tyrosine phosphorylation and activation of phospholipase C-gamma 1. Tyrosine 783 phosphorylation is not sufficient for lipase activation. J. Biol. Chem. 279, 32181-32190.
  91. Poulin, B., Sekiya, F. and Rhee, S. G. (2005) Intramolecular interaction between phosphorylated tyrosine-783 and the C-terminal Src homology 2 domain activates phospholipase C-gamma1. Proc. Natl. Acad. Sci. U. S. A. 102, 4276-4281.
  92. Espagnolle, N., Depoil, D., Zaru, R., Demeur, C., Champagne, E., Guiraud, M. and Valitutti, S. (2007) CD2 and TCR synergize for the activation of phospholipase Cgamma1/calcium pathway at the immunological synap se. Int. Immunol. 19, 239-248.
  93. Marrero, M. B., Paxton, W. G., Schieffer, B., Ling, B. N. and Bernstein, K. E. (1996) Angiotensin II signalling events mediated by tyrosine phosphorylation. Cell. Signal. 8, 21-26.
  94. Venema, V. J., Ju, H., Sun, J., Eaton, D. C., Marrero, M. B. and Venema, R. C. (1998) Bradykinin stimulates the tyrosine phosphorylation and bradykinin B2 receptor association of phospholipase C gamma 1 in vascular endothelial cells. Biochem. Biophys. Res. Commun. 246, 70-75.
  95. Sozzani, P., Hasan, L., Seguelas, M. H., Caput, D., Ferrara, P., Pipy, B. and Cambon, C. (1998) IL-13 induces tyrosine phosphorylation of phospholipase C gamma-1 following IRS-2 association in human monocytes: relationship with the inhibitory effect of IL-13 on ROI production. Biochem. Biophys. Res. Commun. 244, 665-670.
  96. Kurosaki, T., Maeda, A., Ishiai, M., Hashimoto, A., Inabe, K. and Takata, M. (2000) Regulation of the phospholipase C-gamma2 pathway in B cells. Immunol. Rev. 176, 19-29.
  97. Watson, S. P., Auger, J. M., McCarty, O. J. and Pearce, A. C. (2005) GPVI and integrin alphaIIb beta3 signaling in platelets. J. Thromb. Haemost. 3, 1752-1762.
  98. Wen, R., Jou, S. T., Chen, Y., Hoffmeyer, A. and Wang, D. (2002) Phospholipase C gamma 2 is essential for specific functions of Fc epsilon R and Fc gamma R. J. Immunol. 169, 6743-6752.
  99. Wilde, J. I., and Watson, S. P. (2001) Regulation of phospholipase C gamma isoforms in haematopoietic cells: why one, not the other?. Cell. Signal. 13, 691-701.
  100. Haendeler, J., Yin, G., Hojo, Y., Saito, Y., Melaragno, M., Yan, C., Sharma, V. K., Heller, M., Aebersold, R. and Berk, B. C. (2003) GIT1 mediates Src-dependent activation of phospholipase Cgamma by angiotensin II and epidermal growth factor. J. Biol. Chem. 278, 49936-49944.
  101. Jones, N. P., Peak, J., Brader, S., Eccles, S. A. and Katan, M. (2005) PLCgamma1 is essential for early events in integrin signalling required for cell motility. J. Cell Sci. 118, 2695-2706.
  102. Jones, N. P. and Katan, M. (2007) Role of Phospholipase C${\gamma}$1 in Cell Spreading Requires Association with a $\beta$-Pix/ GIT1-Containing Complex, Leading to Activation of Cdc42 and Rac1. Mol. Cell. Biol. 27, 5790-5805.
  103. Chang, J. S., Seok, H., Kwon, T. K., Min, D. S., Ahn, B. H., Lee, Y. H., Suh, J. W., Kim, J. W., Iwashita, S., Omori, A., Ichinose, S., Numata, O., Seo, J. K., Oh, Y. S. and Suh, P. G. (2002) Interaction of elongation factor- 1alpha and pleckstrin homology domain of phospholipase C-gamma 1 with activating its activity. J. Biol. Chem. 277, 19697-19702.
  104. Choi, J. H., Bae, S. S., Park, J. B., Ha, S. H., Song, H., Kim, J. H., Cocco, L., Ryu, S. H. and Suh, P. G. (2003) Cbl competitively inhibits epidermal growth factor-induced activation of phospholipase C-gamma1. Mol. Cells 15, 245-255
  105. Choi, J. H., Hong, W. P., Yun, S., Kim, H. S., Lee, J. R., Park, J. B., Bae, Y. S., Ryu, S. H. and Suh, P. G. (2005) Grb2 negatively regulates epidermal growth factor-induced phospholipase C-gamma1 activity through the direct interaction with tyrosine-phosphorylated phospholipase C-gamma1. Cell. Signal. 17, 1289-1299.
  106. Song, M., Kim, M. J., Ha, S., Park, J. B., Ryu, S. H. and Suh, P. G. (2005) Inositol 5'-phosphatase, SHIP1 interacts with phospholipase C-gamma1 and modulates EGF-induced PLC activity. Exp. Mol. Med. 37, 161-168.
  107. Bar-Sagi, D., Rotin, D., Batzer, A., Mandiyan, V. and Schlessinger, J. (1993) SH3 domains direct cellular localization of signaling molecules. Cell 74, 83-91.
  108. Dearden-Badet, M. T. and Mouchiroud, G. (2005) Re-distribution of phospholipase C gamma 2 in macrophage precursors is mediated by the actin cytoskeleton under the control of the Src kinases. Cell. Signal. 17, 1560-1571.
  109. Nojiri, S. and Hoek, J. B. (2000) Suppression of epidermal growth factor-induced phospholipase C activation associated with actin rearrangement in rat hepatocytes in primary culture. Hepatology 32, 947-957.
  110. Suzuki, K. and Takahashi, K. (2001) Actin filament assembly and actin-myosin contractility are necessary for anchorage- and EGF-dependent activation of phospholipase Cgamma. J. Cell. Physiol. 189, 64-71.
  111. Regunathan, J., Chen, Y., Kutlesa, S., Dai, X., Bai, L., Wen, R., Wang, D. and Malarkannan, S. (2006) Differential and nonredundant roles of phospholipase Cgamma2 and phospholipase Cgamma1 in the terminal maturation of NK cells. J. Immunol. 177, 5365-5376.
  112. Marshall, A. J., Niiro, H., Yun, T. J. and Clark, E. A. (2000) Regulation of B-cell activation and differentiation by the phosphatidylinositol 3-kinase and phospholipase Cgamma pathway. Immunol. Rev. 176, 30-46.
  113. Satterthwaite, A. B., Li, Z. and Witte, O. N. (1998) Btk function in B cell development and response. Semin. Immunol. 10, 309-316.
  114. Yu, P., Constien, R., Dear, N., Katan, M., Hanke, P., Bunney, T. D., Kunder, S., Quintanilla-Martinez, L., Huffstadt, U., Schroder, A., Jones, N. P., Peters, T., Fuchs, H., de Angelis, M. H., Nehls, M., Grosse, J., Wabnitz, P., Meyer, T. P., Yasuda, K., Schiemann, M., Schneider-Fresenius, C., Jagla, W., Russ, A., Popp, A., Josephs, M., Marquardt, A., Laufs, J., Schmittwolf, C., Wagner, H., Pfeffer, K. and Mudde, G. C. (2005) Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external $Ca^{2+}$ entry. Immunity 22, 451-465.
  115. Ji, Q. S., Winnier, G. E., Niswender, K. D., Horstman, D., Wisdom, R., Magnuson, M. A. and Carpenter, G. (1997) Essential role of the tyrosine kinase substrate phospholipase C-gamma1 in mammalian growth and development. Proc. Natl. Acad. Sci. U. S. A. 94, 2999-3003.
  116. Smith, M. R., Liu, Y. L., Kim, H., Rhee, S. G. and Kung, H. F. (1990) Inhibition of serum- and ras-stimulated DNA synthesis by antibodies to phospholipase C. Science 247, 1074-1077.
  117. Wang, Z., Gluck, S., Zhang, L. and Moran, M. F. (1998) Requirement for phospholipase C-gamma1 enzymatic activity in growth factor-induced mitogenesis. Mol. Cell. Biol. 18, 590-597.
  118. Mohammadi, M., Dionne, C. A., Li, W., Li, N., Spivak, T., Honegger, A. M., Jaye, M. and Schlessinger, J. (1992) Point mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis. Nature 358, 681-684.
  119. Bai, X. C., Deng, F., Liu, A. L., Zou, Z. P., Wang, Y., Ke, Z. Y., Ji, Q. S. and Luo, S. Q. (2002) Phospholipase C-gamma1 is required for cell survival in oxidative stress by protein kinase C. Biochem. J. 363, 395-401.
  120. Mangat, R., Singal, T., Dhalla, N. S. and Tappia, P. S. (2006) Inhibition of phospholipase C-gamma 1 augments the decrease in cardiomyocyte viability by H2O2. Am. J. Physiol. Heart Circ. Physiol. 291, H854-860.
  121. Oh, J. E., Kook, J. K., Park, K. H., Lee, G., Seo, B. M. and Min, B. M. (2003) Phospholipase C-gamma1 is required for subculture-induced terminal differentiation of normal human oral keratinocytes. Int. J. Mol. Med. 11, 491-498.
  122. Kolsch, V., Charest, P. G. and Firtel, R. A. (2008) The regulation of cell motility and chemotaxis by phospholipid signaling. J. Cell Sci. 121, 551-559.
  123. Kassis, J., Moellinger, J., Lo, H., Greenberg, N. M., Kim, H. G. and Wells, A. (1999) A role for phospholipase C-gamma-mediated signaling in tumor cell invasion. Clin. Cancer Res. 5, 2251-2260.
  124. Shepard, C. R., Kassis, J., Whaley, D. L., Kim, H. G. and Wells, A. (2007) PLC gamma contributes to metastasis of in situ-occurring mammary and prostate tumors. Oncogene 26, 3020-3026.
  125. Irvin, B. J., Williams, B. L., Nilson, A. E., Maynor, H. O. and Abraham, R. T. (2000) Pleiotropic contributions of phospholipase C-gamma1 (PLC-gamma1) to T-cell antigen receptor-mediated signaling: reconstitution studies of a PLC-gamma1-deficient Jurkat T-cell line. Mol. Cell. Biol. 20, 9149-9161.
  126. Tkaczyk, C., Beaven, M. A., Brachman, S. M., Metcalfe, D. D. and Gilfillan, A. M. (2003) The phospholipase C gamma 1-dependent pathway of Fc epsilon RI-mediated mast cell activation is regulated independently of phosphatidylinositol 3-kinase. J. Biol. Chem. 278, 48474-48484.
  127. Wells, A. D., Liu, Q. H., Hondowicz, B., Zhang, J., Turka, L. A. and Freedman, B. D. (2003) Regulation of T cell activation and tolerance by phospholipase C gamma- 1-dependent integrin avidity modulation. J. Immunol. 170, 4127-4133.
  128. Bae, S. S., Lee, Y. H., Chang, J. S., Galadari, S. H., Kim, Y. S., Ryu, S. H. and Suh, P. G. (1998) Src homology domains of phospholipase C gamma1 inhibit nerve growth factor- induced differentiation of PC12 cells. J. Neurochem. 71, 178-185.
  129. Lin, H. Y., Xu, J., Ischenko, I., Ornitz, D. M., Halegoua, S. and Hayman, M. J. (1998) Identification of the cytoplasmic regions of fibroblast growth factor (FGF) receptor 1 which play important roles in induction of neurite outgrowth in PC12 cells by FGF-1. Mol. Cell. Biol. 18, 3762-3770.
  130. Blum, S. and Dash, P. K. (2004) A cell-permeable phospholipase Cgamma1-binding peptide transduces neurons and impairs long-term spatial memory. Learn Mem. 11, 239-243.
  131. Bolanos, C. A., Neve, R. L. and Nestler, E. J. (2005) Phospholipase C gamma in distinct regions of the ventral tegmental area differentially regulates morphine-induced locomotor activity. Synapse 56, 166-169.
  132. Bolanos, C. A., Perrotti, L. I., Edwards, S., Eisch, A. J., Barrot, M., Olson, V. G., Russell, D. S., Neve, R. L. and Nestler, E. J. (2003) Phospholipase Cgamma in distinct regions of the ventral tegmental area differentially modulates mood-related behaviors. J. Neurosci. 23, 7569-7576.
  133. Turecki, G., Grof, P., Cavazzoni, P., Duffy, A., Grof, E., Ahrens, B., Berghofer, A., Muller-Oerlinghausen, B., Dvorakova, M., Libigerova, E., Vojtechovsky, M., Zvolsky, P., Joober, R., Nilsson, A., Prochazka, H., Licht, R. W., Rasmussen, N. A., Schou, M., Vestergaard, P., Holzinger, A., Schumann, C., Thau, K., Rouleau, G. A. and Alda, M. (1998) Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder. Mol. Psychiatry 3, 534-538.
  134. Suh, B. C. and Hille, B. (2005) Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate. Curr. Opin. Neurobiol. 15, 370-378.
  135. Horowitz, L. F., Hirdes, W., Suh, B. C., Hilgemann, D. W., Mackie, K. and Hille, B. (2005) Phospholipase C in living cells: activation, inhibition, $Ca^{2+}$ requirement, and regulation of M current. J. Gen. Physiol. 126, 243-262.
  136. Kobrinsky, E., Mirshahi, T., Zhang, H., Jin, T. and Logothetis, D. E. (2000) Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization. Nat. Cell Biol. 2, 507-514.
  137. Suh, B. C., Inoue, T., Meyer, T. and Hille, B. (2006) Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels. Science 314, 1454-1457.
  138. Clapham, D. E. (2003) TRP channels as cellular sensors. Nature 426, 517-524.
  139. Patterson, R. L., van Rossum, D. B., Ford, D. L., Hurt, K. J., Bae, S. S., Suh, P. G., Kurosaki, T., Snyder, S. H. and Gill, D. L. (2002) Phospholipase C-gamma is required for agonist-induced $Ca^{2+}$ entry. Cell 111, 529-541.
  140. Hofmann, T., Obukhov, A. G., Schaefer, M., Harteneck, C., Gudermann, T. and Schultz, G. (1999) Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397, 259-263.
  141. Venkatachalam, K., Ma, H. T., Ford, D. L. and Gill, D. L. (2001) Expression of functional receptor-coupled TRPC3 channels in DT40 triple receptor InsP3 knockout cells. J. Biol. Chem. 276, 33980-33985.
  142. van Rossum, D. B., Patterson, R. L., Sharma, S., Barrow, R. K., Kornberg, M., Gill, D. L. and Snyder, S. H. (2005) Phospholipase $C{\gamma}1$ controls surface expression of TRPC3 through an intermolecular PH domain. Nature 434, 99-104.
  143. Huang, P. S., Davis, L., Huber, H., Goodhart, P. J., Wegrzyn, R. E., Oliff, A. and Heimbrook, D. C. (1995) An SH3 domain is required for the mitogenic activity of microinjected phospholipase C-gamma 1. FEBS Lett. 358, 287-292.
  144. Smith, M. R., Liu, Y. L., Matthews, N. T., Rhee, S. G., Sung, W. K. and Kung, H. F. (1994) Phospholipase C-gamma 1 can induce DNA synthesis by a mechanism independent of its lipase activity. Proc. Natl. Acad. Sci. U. S. A. 91, 6554-6558.
  145. Paronetto, M. P., Venables, J. P., Elliott, D. J., Geremia, R., Rossi, P. and Sette, C. (2003) Tr-kit promotes the formation of a multimolecular complex composed by Fyn, PLCgamma1 and Sam68. Oncogene 22, 8707-8715.
  146. Tvorogov, D. and Carpenter, G. (2002) EGF-dependent association of phospholipase C-gamma1 with c-Cbl. Exp. Cell Res. 277, 86-94.
  147. Kim, M. J., Chang, J. S., Park, S. K., Hwang, J. I., Ryu, S. H. and Suh, P. G. (2000) Direct interaction of SOS1 Ras exchange protein with the SH3 domain of phospholipase C-gamma1. Biochemistry 39, 8674-8682.
  148. Choi, J. H., Park, J. B., Bae, S. S., Yun, S., Kim, H. S., Hong, W. P., Kim, I. S., Kim, J. H., Han, M. Y., Ryu, S. H., Patterson, R. L., Snyder, S. H. and Suh, P. G. (2004) Phospholipase C-gamma1 is a guanine nucleotide exchange factor for dynamin-1 and enhances dynamin-1-dependent epidermal growth factor receptor endocytosis. J. Cell Sci. 117, 3785-3795.
  149. Ye, K., Aghdasi, B., Luo, H. R., Moriarity, J. L., Wu, F. Y., Hong, J. J., Hurt, K. J., Bae, S. S., Suh, P. G. and Snyder, S. H. (2002) Phospholipase C gamma 1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE. Nature 415, 541-544.
  150. Ye, K. (2005) PIKE/nuclear PI 3-kinase signaling in preventing programmed cell death. J. Cell Biochem. 96, 463-472.
  151. Ye, K. and Snyder, S. H. (2004) PIKE GTPase: a novel mediator of phosphoinositide signaling. J. Cell Sci. 117, 155-161.
  152. Choi, J. H., Yang, Y. R., Lee, S. K., Kim, I. S., Ha, S. H., Kim, E. K., Bae, Y. S., Ryu, S. H. and Suh, P. G. (2007) Phospholipase C-gamma1 potentiates integrin-dependent cell spreading and migration through Pyk2/paxillin activation. Cell. Signal. 19, 1784-1796.
  153. Kanner, S. B., Grosmaire, L. S., Ledbetter, J. A. and Damle, N. K. (1993) Beta 2-integrin LFA-1 signaling through phospholipase C-gamma 1 activation. Proc. Natl. Acad. Sci. U. S. A. 90, 7099-7103.
  154. Nakamura, I., Lipfert, L., Rodan, G. A. and Le, T. D. (2001) Convergence of alpha(v)beta(3) integrin- and macrophage colony stimulating factor-mediated signals on phospholipase Cgamma in prefusion osteoclasts. J. Cell Biol. 152, 361-373.
  155. Tvorogov, D., Wang, X. J., Zent, R. and Carpenter, G. (2005) Integrin-dependent PLC-gamma1 phosphorylation mediates fibronectin-dependent adhesion. J. Cell Sci. 118, 601-610.
  156. Inoue, O., Suzuki-Inoue, K., Dean, W. L., Frampton, J. and Watson, S. P. (2003) Integrin alpha2beta1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCgamma2. J. Cell Biol. 160, 769-780.
  157. Ohmori, T., Yatomi, Y., Wu, Y., Osada, M., Satoh, K. and Ozaki, Y. (2001) Wheat germ agglutinin-induced platelet activation via platelet endothelial cell adhesion molecule-1: involvement of rapid phospholipase C gamma 2 activation by Src family kinases. Biochemistry 40, 12992-13001.
  158. Wonerow, P., Pearce, A. C., Vaux, D. J. and Watson, S. P. (2003) A critical role for phospholipase Cgamma2 in alphaIIbbeta3-mediated platelet spreading. J. Biol. Chem. 278, 37520-37529.
  159. Peak, J. C., Jones, N. P., Hobbs, S., Katan, M. and Eccles, S. A. (2008) Phospholipase Cgamma1 regulates the Rap GEF1-Rap1 signalling axis in the control of human prostate carcinoma cell adhesion. Oncogene 27, 2823-2832.
  160. Irino, Y., Cho, H., Nakamura, Y., Nakahara, M., Furutani, M., Suh, P. G., Takenawa, T. and Fukami, K. (2004) Phospholipase C delta-type consists of three isozymes: bovine PLCdelta2 is a homologue of human/mouse PLCdelta4. Biochem. Biophys. Res. Commun. 320, 537-543.
  161. Lemmon, M. A., Falasca, M., Ferguson, K. M. and Schlessinger, J. (1997) Regulatory requirement of signaling melecules to the cell membrane by pleckstrin-homology domains. Trends Cell Biol. 7, 237-242.
  162. Kim, Y. H., Park, T. J., Lee, Y. H., Baek, K. J., Suh, P. G., Ryu, S. H. and Kim, K. T. (1999) Phospholipase C-delta1 is activated by capacitative calcium entry that follows phospholipase C-beta activation upon bradykinin stimulation. J. Biol. Chem. 274, 26127-26134.
  163. Allen, V., Swigart, P., Cheung, R., Cockcroft, S. and Katan, M. (1997) Regulation of inositol lipid-specific phospholipase cdelta by changes in $Ca^{2+}$ ion concentrations. Biochem. J. 327, 545-552.
  164. Feng, J. F., Rhee, S. G. and Im, M. J. (1996) Evidence that phospholipase delta1 is the effector in the Gh (transglutaminase II)-mediated signaling. J. Biol. Chem. 271, 16451-16454.
  165. Kang, S. K., Kim, D. K., Damron, D. S., Baek, K. J. and Im, M. J. (2002) Modulation of intracellular Ca(2+) via alpha(1B)-adrenoreceptor signaling molecules, G alpha( h) (transglutaminase II) and phospholipase C-delta 1. Biochem. Biophys. Res. Commun. 293, 383-390.
  166. Homma, Y. and Emori, Y. (1995) A dual functional signal mediator showing RhoGAP and phospholipase C-delta stimulating activities. EMBO J. 14, 286-291.
  167. Sekimata, M., Kabuyama, Y., Emori, Y. and Homma, Y. (1999) Morphological changes and detachment of adherent cells induced by p122, a GTPase-activating protein for Rho. J. Biol. Chem. 274, 17757-17762.
  168. Nakamura, Y., Fukami, K., Yu, H., Takenaka, K., Kataoka, Y., Shirakata, Y., Nishikawa, S., Hashimoto, K., Yoshida, N. and Takenawa, T. (2003) Phospholipase Cdelta1 is required for skin stem cell lineage commitment. EMBO J. 22, 2981-2991.
  169. Li, M., Chiba, H., Warot, X., Messaddeq, N., Gerard, C., Chambon, P. and Metzger, D. (2001) RXR-alpha ablation in skin keratinocytes results in alopecia and epidermal alterations. Development 128, 675-688.
  170. Ichinohe, M., Nakamura, Y., Sai, K., Nakahara, M., Yamaguchi, H. and Fukami, K. (2007) Lack of phospholipase C-delta1 induces skin inflammation. Biochem. Biophys. Res. Commun. 356, 912-918.
  171. Nakamura, Y., Ichinohe, M., Hirata, M., Matsuura, H., Fujiwara, T., Igarashi, T., Nakahara, M., Yamaguchi, H., Yasugi, S., Takenawa, T. and Fukami, K. (2008) Phospholipase C-delta1 is an essential molecule downstream of Foxn1, the gene responsible for the nude mutation, in normal hair development. FASEB J. 22, 841-849.
  172. Flanagan, S. P. (1966) 'Nude', a new hairless gene with pleiotropic effects in the mouse. Genet. Res. 8, 295-309.
  173. Meier, N., Dear, T. N. and Boehm, T. (1999) Whn and mHa3 are components of the genetic hierarchy controlling hair follicle differentiation. Mech. Dev. 89, 215-221.
  174. Nakamura, Y., Hamada, Y., Fujiwara, T., Enomoto, H., Hiroe, T., Tanaka, S., Nose, M., Nakahara, M., Yoshida, N., Takenawa, T. and Fukami, K. (2005) Phospholipase C-delta1 and -delta3 are essential in the trophoblast for placental development. Mol. Cell Biol. 25, 10979-10988.
  175. James, R. M., Klerkx, A. H., Keighren, M., Flockhart, J. H. and West, J. D. (1995) Restricted distribution of tetraploid cells in mouse tetraploid<==>diploid chimaeras. Dev. Biol. 167, 213-226.
  176. Fukami, K., Nakao, K., Inoue, T., Kataoka, Y., Kurokawa, M., Fissore, R. A., Nakamura, K., Katsuki, M., Mikoshiba, K., Yoshida, N. and Takenawa, T. (2001) Requirement of phospholipase Cdelta4 for the zona pellucida-induced acrosome reaction. Science 292, 920-923.
  177. Darszon, A., Beltran, C., Felix, R., Nishigaki, T. and Trevino, C. L. (2001) Ion transport in sperm signaling. Dev. Biol. 240, 1-14.
  178. Breitbart, H. (2002) Intracellular calcium regulation in sperm capacitation and acrosomal reaction. Mol. Cell Endocrinol. 187, 139-144.
  179. Fukami, K., Yoshida, M., Inoue, T., Kurokawa, M., Fissore, R. A., Yoshida, N., Mikoshiba, K. and Takenawa, T. (2003) Phospholipase Cdelta4 is required for $Ca^{2+}$ mobilization essential for acrosome reaction in sperm. J. Cell Biol. 161, 79-88.
  180. Fu, L., Qin, Y. R., Xie, D., Hu, L., Kwong, D. L., Srivastava, G., Tsao, S. W. and Guan, X. Y. (2007) Characterization of a novel tumor-suppressor gene PLC delta 1 at 3p22 in esophageal squamous cell carcinoma. Cancer Res. 67, 10720-10726.
  181. Yuan, B. Z., Miller, M. J., Keck, C. L., Zimonjic, D. B., Thorgeirsson, S. S. and Popescu, N. C. (1998) Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP. Cancer Res. 58, 2196-2199
  182. Yamaga, M., Fujii, M., Kamata, H., Hirata, H. and Yagisawa, H. (1999) Phospholipase C-delta1 contains a functional nuclear export signal sequence. J. Biol. Chem. 274, 28537-28541.
  183. Stallings, J. D., Tall, E. G., Pentyala, S. and Rebecchi, M. J. (2005) Nuclear translocation of phospholipase C-delta1 is linked to the cell cycle and nuclear phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. 280, 22060-22069.
  184. Stallings, J. D., Zeng, Y. X., Narvaez, F. and Rebecchi, M. J. (2008) Phospholipase C-delta 1is linked to proliferation, DNA synthesis and cyclin E levels. J. Biol. Chem. 283, 13992-14001.
  185. Zhao, K., Wang, W., Rando, O. J., Xue, Y., Swiderek, K., Kuo, A. and Crabtree, G. R. (1998) Rapid and phosphoinositol- dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 95, 625-636.
  186. Caprini, M., Gomis, A., Cabedo, H., Planells-Cases, R., Belmonte, C., Viana, F. and Ferrer-Montiel, A. (2003) GAP43 stimulates inositol trisphosphate-mediated calcium release in response to hypotonicity. EMBO J. 22, 3004-3014.
  187. Shibatohge, M., Kariya, K., Liao, Y., Hu, C. D., Watari, Y., Goshima, M., Shima, F. and Kataoka, T. (1998) Identification of PLC210, a Caenorhabditis elegans phospholipase C, as a putative effector of Ras. J. Biol. Chem. 273, 6218-6222.
  188. Kelley, G. G., Reks, S. E., Ondrako, J. M. and Smrcka, A. V. (2001) Phospholipase C(epsilon): a novel Ras effector. EMBO J. 20, 743-754.
  189. Song, C., Hu, C. D., Masago, M., Kariyai, K., Yamawaki- Kataoka, Y., Shibatohge, M., Wu, D., Satoh, T. and Kataoka, T. (2001) Regulation of a novel human phospholipase C, PLCepsilon, through membrane targeting by Ras. J. Biol. Chem. 276, 2752-2757.
  190. Bunney, T. D., Harris, R., Gandarillas, N. L., Josephs, M. B., Roe, S. M., Sorli, S. C., Paterson, H. F., Rodrigues-Lima, F., Esposito, D., Ponting, C. P., Gierschik, P., Pearl, L. H., Driscoll, P. C. and Katan, M. (2006) Structural and mechanistic insights into ras association domains of phospholipase C epsilon. Mol. Cell 21, 495-507.
  191. Jin, T. G., Satoh, T., Liao, Y., Song, C., Gao, X., Kariya, K., Hu, C. D. and Kataoka, T. (2001) Role of the CDC25 homology domain of phospholipase Cepsilon in amplification of Rap1-dependent signaling. J. Biol. Chem. 276, 30301-30307.
  192. Schmidt, M., Evellin, S., Weernink, P. A., von Dorp, F., Rehmann, H., Lomasney, J. W. and Jakobs, K. H. (2001) A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nat. Cell Biol. 3, 1020-1024.
  193. Evellin, S., Nolte, J., Tysack, K., vom Dorp, F., Thiel, M., Weernink, P. A., Jakobs, K. H., Webb, E. J., Lomasney, J. W. and Schmidt, M. (2002) Stimulation of phospholipase C-epsilon by the M3 muscarinic acetylcholine receptor mediated by cyclic AMP and the GTPase Rap2B. J. Biol. Chem. 277, 16805-16813.
  194. Hains, M. D., Wing, M. R., Maddileti, S., Siderovski, D. P. and Harden, T. K. (2006) Galpha12/13- and rho-dependent activation of phospholipase C-epsilon by lysophosphatidic acid and thrombin receptors. Mol. Pharmacol. 69, 2068-2075.
  195. Kelley, G. G., Kaproth-Joslin, K. A., Reks, S. E., Smrcka, A. V. and Wojcikiewicz, R. J. (2006) G-protein-coupled receptor agonists activate endogenous phospholipase Cepsilon and phospholipase Cbeta3 in a temporally distinct manner. J. Biol. Chem. 281, 2639-2648.
  196. Seifert, J. P., Wing, M. R., Snyder, J. T., Gershburg, S., Sondek, J. and Harden, T. K. (2004) RhoA activates purified phospholipase C-epsilon by a guanine nucleotide-dependent mechanism. J. Biol. Chem. 279, 47992-47997.
  197. Yun, S., Moller, A., Chae, S. K., Hong, W. P., Bae, Y. J., Bowtell, D. D., Ryu, S. H. and Suh, P. G. (2008) Siah proteins induce the epidermal growth factor-dependent degradation of phospholipase Cepsilon. J. Biol. Chem. 283, 1034-1042.
  198. Song, C., Satoh, T., Edamatsu, H., Wu, D., Tadano, M., Gao, X. and Kataoka, T. (2002) Differential roles of Ras and Rap1 in growth factor-dependent activation of phospholipase C epsilon. Oncogene 21, 8105-8113.
  199. Stope, M. B., Vom Dorp, F., Szatkowski, D., Bohm, A., Keiper, M., Nolte, J., Oude Weernink, P. A., Rosskopf, D., Evellin, S., Jakobs, K. H. and Schmidt, M. (2004) Rap2B-dependent stimulation of phospholipase C-epsilon by epidermal growth factor receptor mediated by c-Src phosphorylation of RasGRP3. Mol. Cell Biol. 24, 4664-4676.
  200. 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. and Kataoka, T. (2005) Congenital semilunar valvulogenesis defect in mice deficient in phospholipase C epsilon. Mol.Cell Biol. 25, 2191-2199.
  201. Wang, H., Oestreich, E. A., Maekawa, N., Bullard, T. A., Vikstrom, K. L., Dirksen, R. T., Kelley, G. G., Blaxall, B. C. and Smrcka, A. V. (2005) Phospholipase C epsilon modulates beta-adrenergic receptor-dependent cardiac contraction and inhibits cardiac hypertrophy. Circ. Res. 97, 1305-1313.
  202. Hinkes, B., Wiggins, R. C., Gbadegesin, R., Vlangos, C. N., Seelow, D., Nurnberg, G., Garg, P., Verma, R., Chaib, H., Hoskins, B. E., Ashraf, S., Becker, C., Hennies, H. C., Goyal, M., Wharram, B. L., Schachter, A. D., Mudumana, S., Drummond, I., Kerjaschki, D., Waldherr, R., Dietrich, A., Ozaltin, F., Bakkaloglu, A., Cleper, R., Basel-Vanagaite, L., Pohl, M., Griebel, M., Tsygin, A. N., Soylu, A., Muller, D., Sorli, C. S., Bunney, T. D., Katan, M., Liu, J., Attanasio, M., O'Toole J, F., Hasselbacher, K., Mucha, B., Otto, E. A., Airik, R., Kispert, A., Kelley, G. G., Smrcka, A. V., Gudermann, T., Holzman, L. B., Nurnberg, P. and Hildebrandt, F. (2006) Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat. Genet. 38, 1397-1405.
  203. Vazquez-Manrique, R. P., Nagy, A. I., Legg, J. C., Bales, O. A., Ly, S. and Baylis, H. A. (2008) Phospholipase C-epsilon regulates epidermal morphogenesis in Caenorhabditis elegans. PLoS Genet. 4, e1000043.
  204. Bai, Y., Edamatsu, H., Maeda, S., Saito, H., Suzuki, N., Satoh, T. and Kataoka, T. (2004) Crucial role of phospholipase Cepsilon in chemical carcinogen-induced skin tumor development. Cancer Res. 64, 8808-8810.
  205. Ikuta, S., Edamatsu, H., Li, M., Hu, L. and Kataoka, T. (2008) Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester. Cancer Res. 68, 64-72.
  206. Yun, S., Hong, W. P., Choi, J. H., Yi, K. S., Chae, S. K., Ryu, S. H. and Suh, P. G. (2008) Phospholipase C-epsilon augments epidermal growth factor-dependent cell growth by inhibiting epidermal growth factor receptor down-regulation. J. Biol. Chem. 283, 341-349.
  207. Citro, S., Malik, S., Oestreich, E. A., Radeff-Huang, J., Kelley, G. G., Smrcka, A. V. and Brown, J. H. (2007) Phospholipase Cepsilon is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation. Proc. Natl. Acad. Sci. U. S. A. 104, 15543-15548.
  208. Swann, K., Saunders, C. M., Rogers, N. T. and Lai, F. A. (2006) PLCzeta(zeta): a sperm protein that triggers $Ca^{2+}$ oscillations and egg activation in mammals. Semin. Cell Dev. Biol. 17, 264-273.
  209. Kouchi, Z., Shikano, T., Nakamura, Y., Shirakawa, H., Fukami, K. and Miyazaki, S. (2005) The role of EF-hand domains and C2 domain in regulation of enzymatic activity of phospholipase Czeta. J. Biol. Chem. 280, 21015-21021.
  210. Nomikos, M., Blayney, L. M., Larman, M. G., Campbell, K., Rossbach, A., Saunders, C. M., Swann, K. and Lai, F. A. (2005) Role of phospholipase C-zeta domains in $Ca^{2+}$-dependent phosphatidylinositol 4,5-bisphosphate hydrolysis and cytoplasmic $Ca^{2+}$ oscillations. J. Biol. Chem. 280, 31011-31018
  211. Flesch, F. M., Yu, J. W., Lemmon, M. A. and Burger, K. N. (2005) Membrane activity of the phospholipase C-delta1 pleckstrin homology (PH) domain. Biochem. J. 389, 435-441.
  212. Razzini, G., Brancaccio, A., Lemmon, M. A., Guarnieri, S. and Falasca, M. (2000) The role of the pleckstrin homology domain in membrane targeting and activation of phospholipase Cbeta(1). J. Biol. Chem. 275, 14873-14881.

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  134. PLC-δ1-Lf, a novel N-terminal extended phospholipase C-δ1 vol.528, pp.2, 2013,
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  154. Expression of Phosphoinositide-specific phospholipase C enzymes in human osteosarcoma cell lines vol.7, pp.2, 2013,
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  159. Phosphoinositide-specific Phospholipase C β 1b (PI-PLCβ1b) Interactome: Affinity Purification-Mass Spectrometry Analysis of PI-PLCβ1b with Nuclear Protein vol.12, pp.8, 2013,
  160. Phosphorylation of Phospholipase C-δ1Regulates its Enzymatic Activity vol.108, pp.3, 2009,
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  165. Oocyte activation and phospholipase C zeta (PLCζ): diagnostic and therapeutic implications for assisted reproductive technology vol.10, pp.1, 2012,
  166. Identification of Ser/Thr phosphorylation sites in the C2-domain of phospholipase C γ2 (PLCγ2) using TRPM7-kinase vol.24, pp.11, 2012,
  167. Phospholipase C-γ1 involved in brain disorders vol.53, pp.1, 2013,
  168. Different expression and subcellular localization of Phosphoinositide-specific Phospholipase C enzymes in differently polarized macrophages vol.10, pp.4, 2016,
  169. 2-Aminohydroxamic acid derivatives as inhibitors of Bacillus cereus phosphatidylcholine preferred phospholipase C PC-PLCBc vol.18, pp.24, 2010,
  170. Pharmacogenetic implications for eight common blood pressure-associated single-nucleotide polymorphisms vol.30, pp.6, 2012,
  171. Membrane-induced Allosteric Control of Phospholipase C-β Isozymes vol.289, pp.43, 2014,
  172. Mammalian Phospholipase C vol.75, pp.1, 2013,
  173. The guanine nucleotide exchange factor Rlf interacts with SH3 domain-containing proteins via a binding site with a preselected conformation vol.183, pp.3, 2013,
  174. Identification of Leptospira interrogans Phospholipase C as a Novel Virulence Factor Responsible for Intracellular Free Calcium Ion Elevation during Macrophage Death vol.8, pp.10, 2013,
  175. Putative roles for phospholipase Cη enzymes in neuronal Ca2+signal modulation vol.40, pp.1, 2012,
  176. Signalling in the genomic era vol.4, pp.3, 2010,
  177. Expression pattern and sub-cellular distribution of phosphoinositide specific phospholipase C enzymes after treatment with U-73122 in rat astrocytoma cells vol.110, pp.4, 2010,
  178. Linking alpha-synuclein properties with oxidation: a hypothesis on a mechanism underling cellular aggregation vol.46, pp.2, 2014,
  179. Diverse cellular and physiological roles of phospholipase C-γ1 vol.52, pp.1, 2012,
  180. UCP2 upregulation promotes PLCγ-1 signaling during skin cell transformation vol.56, pp.10, 2017,
  181. Phospholipase C-β1 and β4 Contribute to Non-Genetic Cell-to-Cell Variability in Histamine-Induced Calcium Signals in HeLa Cells vol.9, pp.1, 2014,
  182. Alopecia in a Viable Phospholipase C Delta 1 and Phospholipase C Delta 3 Double Mutant vol.7, pp.6, 2012,
  183. Tsg101 regulates PI(4,5)P2/Ca2+ signaling for HIV-1 Gag assembly vol.5, 2014,
  184. Expression of phospholipase C β1 in olive flounder (Paralichthys olivaceus) following external stress stimulation vol.19, pp.1, 2016,
  185. PLCζ and its role as a trigger of development in vertebrates vol.78, pp.10-11, 2011,
  186. Cellular neurochemical characterization and subcellular localization of phospholipase C β1 in rat brain vol.222, 2012,
  187. Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS vol.106, pp.39, 2009,
  188. PLCB1 epileptic encephalopathies; Review and expansion of the phenotypic spectrum vol.20, pp.3, 2016,
  189. ESCRT Machinery Potentiates HIV-1 Utilization of the PI(4,5)P2-PLC-IP3R-Ca2+ Signaling Cascade vol.413, pp.2, 2011,
  190. Mutations in PLCδ1 associated with hereditary leukonychia display divergent PIP2 hydrolytic function vol.283, pp.24, 2016,
  191. Phosphoinositide pathway and the signal transduction network in neural development vol.28, pp.6, 2012,
  192. Comparative biology of sperm factors and fertilization-induced calcium signals across the animal kingdom vol.80, pp.10, 2013,
  193. Roles of Phospholipase C Isozymes in Organogenesis and Embryonic Development vol.24, pp.6, 2009,
  194. Membrane Environment Exerts an Important Influence on Rac-Mediated Activation of Phospholipase C 2 vol.31, pp.6, 2011,
  195. Nuclear PLCs affect insulin secretion by targeting PPARγ in pancreatic β cells vol.26, pp.1, 2012,
  196. Phospholipase Cβ1 is linked to RNA interference of specific genes through translin-associated factor X vol.26, pp.12, 2012,
  197. The Phospholipase C Inhibitor U73122 Attenuates trans-10, cis-12 Conjugated Linoleic Acid-Mediated Inflammatory Signaling and Insulin Resistance in Human Adipocytes vol.143, pp.5, 2013,
  198. Molecular Mechanisms of N-Formyl-Methionyl-Leucyl-Phenylalanine-Induced Superoxide Generation and Degranulation in Mouse Neutrophils: Phospholipase D Is Dispensable vol.33, pp.1, 2013,
  199. Distinct Phospholipase C-  Isozymes Mediate Lysophosphatidic Acid Receptor 1 Effects on Intestinal Epithelial Homeostasis and Wound Closure vol.33, pp.10, 2013,
  200. PLC- 1 Signaling Plays a Subtype-Specific Role in Postbinding Cell Entry of Influenza A Virus vol.88, pp.1, 2014,
  201. RNA-induced silencing attenuates G protein–mediated calcium signals vol.30, pp.5, 2016,
  202. -dependent phospholipase C pathway that regulates ∆N TRPV1-mediated currents in rat supraoptic neurons vol.5, pp.8, 2017,
  203. The Role of Phospholipase C Signaling in Macrophage-Mediated Inflammatory Response vol.2018, pp.2314-7156, 2018,
  204. Phosphoinositide-specific phospholipase C in normal human liver and in alcohol abuse pp.07302312, 2018,
  205. –Dependent IL-8 Release in Cystic Fibrosis vol.59, pp.4, 2018,
  206. Activation of formyl peptide receptor 2 by WKYMVm enhances emergency granulopoiesis through phospholipase C activity vol.51, pp.8, 2018,
  207. Whole exome sequencing identifies a novel dominant missense mutation underlying leukonychia in a Pakistani family vol.63, pp.10, 2018,
  208. MARCKS and MARCKS-like proteins in development and regeneration vol.25, pp.1, 2018,
  209. Phospholipase Cβ1 regulates proliferation of neuronal cells vol.32, pp.5, 2018,
  210. Silencing of phospholipase C gamma 2 promotes proliferation of rat hepatocytes in vitro vol.119, pp.5, 2018,