Abstract
Phospholipases (PLC, PLD and PLA) are essential mediators of intracellular and intercellular signalling. They can function as phospholipid-hydrolysing enzymes that can generate many bioactive lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid and arachidonic acid. Lipid mediators generated by phospholipases regulate multiple cellular processes that can promote tumorigenesis, including proliferation, migration, invasion and angiogenesis. Although many individual phospholipases have been extensively studied, how phospholipases regulate diverse cancer-associated cellular processes and the interplay between different phospholipases have yet to be fully elucidated. A thorough understanding of the cancer-associated signalling networks of phospholipases is necessary to determine whether these enzymes can be targeted therapeutically.
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References
van Meer, G., Voelker, D. R. & Feigenson, G. W. Membrane lipids: where they are and how they behave. Nature Rev. Mol. Cell Biol. 9, 112–124 (2008).
Boesze-Battaglia, K. & Schimmel, R. Cell membrane lipid composition and distribution: implications for cell function and lessons learned from photoreceptors and platelets. J. Exp. Biol. 200, 2927–2936 (1997).
Eyster, K. M. The membrane and lipids as integral participants in signal transduction: lipid signal transduction for the non-lipid biochemist. Adv. Physiol. Educ. 31, 5–16 (2007).
Fisher, A. B. & Jain, M. Phospholipases: Degradation of Phospholipids in Membranes and Emulsions (Wiley, 2009).
Spiegel, S., Foster, D. & Kolesnick, R. Signal transduction through lipid second messengers. Curr. Opin. Cell Biol. 8, 159–167 (1996).
Wymann, M. P. & Schneiter, R. Lipid signalling in disease. Nature Rev. Mol. Cell Biol. 9, 162–176 (2008).
De Maria, L., Vind, J., Oxenboll, K. M., Svendsen, A. & Patkar, S. Phospholipases and their industrial applications. Appl. Microbiol. Biotechnol. 74, 290–300 (2007).
Ramrakhiani, L. & Chand, S. Recent progress on phospholipases: different sources, assay methods, industrial potential and pathogenicity. Appl. Biochem. Biotechnol. 164, 991–1022 (2011).
Aoki, J., Inoue, A., Makide, K., Saiki, N. & Arai, H. Structure and function of extracellular phospholipase A1 belonging to the pancreatic lipase gene family. Biochimie 89, 197–204 (2007).
Murakami, M. et al. Recent progress in phospholipase A2 research: from cells to animals to humans. Prog. Lipid Res. 50, 152–192 (2011).
Suh, P.-G. et al. Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep. 41, 415–434 (2008).
Wang, X., Devaiah, S. P., Zhang, W. & Welti, R. Signaling functions of phosphatidic acid. Prog. Lipid Res. 45, 250–278 (2006).
Hirabayashi, T., Murayama, T. & Shimizu, T. Regulatory mechanism and physiological role of cytosolic phospholipase A2. Biol. Pharm. Bull. 27, 1168–1173 (2004).
Wang, T. et al. Selective interaction of the C2 domains of phospholipase C-β1 and -β2 with activated Gαq subunits: an alternative function for C2-signaling modules. Proc. Natl Acad. Sci. USA 96, 7843–7846 (1999).
Wang, T., Dowal, L., El-Maghrabi, M. R., Rebecchi, M. & Scarlata, S. The pleckstrin homology domain of phospholipase C-β2 links the binding of gβγ to activation of the catalytic core. J. Biol. Chem. 275, 7466–7469 (2000).
Falasca, M. et al. Activation of phospholipase C γ by PI 3-kinase-induced PH domain-mediated membrane targeting. EMBO J. 17, 414–422 (1998).
Hodgkin, M. N. et al. Phospholipase D regulation and localisation is dependent upon a phosphatidylinositol 4,5-biphosphate-specific PH domain. Curr. Biol. 10, 43–46 (2000).
Sugars, J. M., Cellek, S., Manifava, M., Coadwell, J. & Ktistakis, N. T. Hierarchy of membrane-targeting signals of phospholipase D1 involving lipid modification of a pleckstrin homology domain. J. Biol. Chem. 277, 29152–29161 (2002).
Sung, T. C., Zhang, Y., Morris, A. J. & Frohman, M. A. Structural analysis of human phospholipase D1. J. Biol. Chem. 274, 3659–3666 (1999).
Sung, T. C., Altshuller, Y. M., Morris, A. J. & Frohman, M. A. Molecular analysis of mammalian phospholipase D2. J. Biol. Chem. 274, 494–502 (1999).
Du, G. et al. Regulation of phospholipase D1 subcellular cycling through coordination of multiple membrane association motifs. J. Cell Biol. 162, 305–315 (2003).
Stahelin, R. V. et al. Mechanism of membrane binding of the phospholipase D1 PX domain. J. Biol. Chem. 279, 54918–54926 (2004).
Lee, J. S. et al. Phosphatidylinositol (3,4,5)-trisphosphate specifically interacts with the phox homology domain of phospholipase D1 and stimulates its activity. J. Cell Sci. 118, 4405–4413 (2005).
Lee, C. S. et al. The phox homology domain of phospholipase D activates dynamin GTPase activity and accelerates EGFR endocytosis. Nature Cell Biol. 8, 477–484 (2006).
Jeon, H. et al. Phospholipase D2 induces stress fiber formation through mediating nucleotide exchange for RhoA. Cell. Signal. 23, 1320–1326 (2011).
Gomez-Cambronero, J. The exquisite regulation of PLD2 by a wealth of interacting proteins: S6K, Grb2, Sos, WASp and Rac2 (And a surprise discovery: PLD2 is a GEF). Cell. Signal. 23, 1885–1895 (2011).
Oude Weernink, P. A., Lopez de Jesus, M. & Schmidt, M. Phospholipase D signaling: orchestration by PIP2 and small GTPases. Naunyn-Schmiedeberg' Arch. Pharmacol. 374, 399–411 (2007).
Cho, C. H. et al. Localization of VEGFR-2 and PLD2 in endothelial caveolae is involved in VEGF-induced phosphorylation of MEK and ERK. Am. J. Physiol. Heart Circ. Physiol. 286, H1881–H1888 (2004).
Alberghina, M. Phospholipase A2: new lessons from endothelial cells. Microvasc. Res. 80, 280–285 (2010).
Rhee, S. G. Regulation of phosphoinositide-specific phospholipase C. Annu. Rev. Biochem. 70, 281–312 (2001).
Lee, C. S. et al. The roles of phospholipase D in EGFR signaling. Biochim. Biophys. Acta 1791, 862–868 (2009).
Wells, A. & Grandis, J. R. Phospholipase C-γ1 in tumor progression. Clin. Exp. Metastasis 20, 285–290 (2003).
Ji, Q. S. et al. Essential role of the tyrosine kinase substrate phospholipase C-γ1 in mammalian growth and development. Proc. Natl Acad. Sci. USA 94, 2999–3003 (1997).
Kim, M. J. et al. Direct interaction of SOS1 Ras exchange protein with the SH3 domain of phospholipase C-γ1. Biochemistry 39, 8674–8682 (2000).
Kelley, G. G., Reks, S. E., Ondrako, J. M. & Smrcka, A. V. Phospholipase Cɛ: a novel Ras effector. EMBO J. 20, 743–754 (2001).
Bunney, T. D. et al. Structural and mechanistic insights into ras association domains of phospholipase C epsilon. Mol. Cell 21, 495–507 (2006).
Lopez, I., Mak, E. C., Ding, J., Hamm, H. E. & Lomasney, J. W. A novel bifunctional phospholipase c that is regulated by Gα 12 and stimulates the Ras/mitogen-activated protein kinase pathway. J. Biol. Chem. 276, 2758–2765 (2001).
Bai, Y. et al. Crucial role of phospholipase Cepsilon in chemical carcinogen-induced skin tumor development. Cancer Res. 64, 8808–8810 (2004).
Ise, K. et al. Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis. Oncogene 19, 2951–2956 (2000).
Xiao, W. et al. Tumor suppression by phospholipase C-β3 via SHP-1-mediated dephosphorylation of Stat5. Cancer Cell 16, 161–171 (2009).
Follo, M. Y. et al. Phosphoinositide-phospholipase C β1 mono-allelic deletion is associated with myelodysplastic syndromes evolution into acute myeloid leukemia. J. Clin. Oncol. 27, 782–790 (2009).
Fu, L. et al. Characterization of a novel tumor-suppressor gene PLC δ 1 at 3p22 in esophageal squamous cell carcinoma. Cancer Res. 67, 10720–10726 (2007).
Nakamura, Y. et al. Phospholipase Cδ1 is required for skin stem cell lineage commitment. EMBO J. 22, 2981–2991 (2003).
Song, J., Jiang, Y. W. & Foster, D. A. Epidermal growth factor induces the production of biologically distinguishable diglyceride species from phosphatidylinositol and phosphatidylcholine via the independent activation of type C and type D phospholipases. Cell Growth Differ. 5, 79–85 (1994).
Plevin, R., Cook, S. J., Palmer, S. & Wakelam, M. J. Multiple sources of sn-1,2-diacylglycerol in platelet-derived-growth-factor-stimulated Swiss 3T3 fibroblasts. Evidence for activation of phosphoinositidase C and phosphatidylcholine-specific phospholipase D. Biochem. J. 279, 559–565 (1991).
Motoike, T., Bieger, S., Wiegandt, H. & Unsicker, K. Induction of phosphatidic acid by fibroblast growth factor in cultured baby hamster kidney fibroblasts. FEBS Lett. 332, 164–168 (1993).
Carnero, A., Cuadrado, A., del Peso, L. & Lacal, J. C. Activation of type D phospholipase by serum stimulation and ras-induced transformation in NIH3T3 cells. Oncogene 9, 1387–1395 (1994).
Frankel, P. et al. Ral and Rho-dependent activation of phospholipase D in v-Raf-transformed cells. Biochem. Biophys. Res. Commun. 255, 502–507 (1999).
Song, J. G., Pfeffer, L. M. & Foster, D. A. v-Src increases diacylglycerol levels via a type D phospholipase-mediated hydrolysis of phosphatidylcholine. Mol. Cell. Biol. 11, 4903–4908 (1991).
Lu, Z. et al. Phospholipase D and RalA cooperate with the epidermal growth factor receptor to transform 3Y1 rat fibroblasts. Mol. Cell. Biol. 20, 462–467 (2000).
Joseph, T. et al. Transformation of cells overexpressing a tyrosine kinase by phospholipase D1 and D2. Biochem. Biophys. Res. Commun. 289, 1019–1024 (2001).
Rizzo, M. A. et al. Phospholipase D and its product, phosphatidic acid, mediate agonist-dependent raf-1 translocation to the plasma membrane and the activation of the mitogen-activated protein kinase pathway. J. Biol. Chem. 274, 1131–1139 (1999).
Zhao, C., Du, G., Skowronek, K., Frohman, M. A. & Bar-Sagi, D. Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos. Nature Cell Biol. 9, 706–712 (2007).
Fang, Y., Vilella-Bach, M., Bachmann, R., Flanigan, A. & Chen, J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 294, 1942–1945 (2001).
Toschi, A. et al. Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: competition with rapamycin. Mol. Cell. Biol. 29, 1411–1420 (2009).
Mamane, Y., Petroulakis, E., LeBacquer, O. & Sonenberg, N. mTOR, translation initiation and cancer. Oncogene 25, 6416–6422 (2006).
Saito, M. et al. Expression of phospholipase D2 in human colorectal carcinoma. Oncol. Rep. 18, 1329–1334 (2007).
Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007).
Buczynski, M. W., Dumlao, D. S. & Dennis, E. A. Thematic review series: proteomics. An integrated omics analysis of eicosanoid biology. J. Lipid Res. 50, 1015–1038 (2009).
Funk, C. D. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1871–1875 (2001).
Hong, K. H., Bonventre, J. C., O'Leary, E., Bonventre, J. V. & Lander, E. S. Deletion of cytosolic phospholipase A2 suppresses ApcMin-induced tumorigenesis. Proc. Natl Acad. Sci. USA 98, 3935–3939 (2001).
Oshima, M. et al. Suppression of intestinal polyposis in Apc δ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87, 803–809 (1996).
Meyer, A. M. et al. Decreased lung tumorigenesis in mice genetically deficient in cytosolic phospholipase A2. Carcinogenesis 25, 1517–1524 (2004).
MacPhee, M. et al. The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 81, 957–966 (1995).
Papanikolaou, A., Wang, Q. S., Mulherkar, R., Bolt, A. & Rosenberg, D. W. Expression analysis of the group IIA secretory phospholipase A2 in mice with differential susceptibility to azoxymethane-induced colon tumorigenesis. Carcinogenesis 21, 133–138 (2000).
Mills, G. B. & Moolenaar, W. H. The emerging role of lysophosphatidic acid in cancer. Nature Rev. Cancer 3, 582–591 (2003).
Wang, D. & Dubois, R. N. Prostaglandins and cancer. Gut 55, 115–122 (2006).
Xu, Y., Fang, X. J., Casey, G. & Mills, G. B. Lysophospholipids activate ovarian and breast cancer cells. Biochem. J. 309, 933–940 (1995).
Fang, X. et al. Lysophospholipid growth factors in the initiation, progression, metastases, and management of ovarian cancer. Ann. NY Acad. Sci. 905, 188–208 (2000).
Sasagawa, T., Okita, M., Murakami, J., Kato, T. & Watanabe, A. Abnormal serum lysophospholipids in multiple myeloma patients. Lipids 34, 17–21 (1999).
Goetzl, E. J. et al. Distinctive expression and functions of the type 4 endothelial differentiation gene-encoded G protein-coupled receptor for lysophosphatidic acid in ovarian cancer. Cancer Res. 59, 5370–5375 (1999).
Pustilnik, T. B. et al. Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells. Clin. Cancer Res. 5, 3704–3710 (1999).
Schulte, K. M., Beyer, A., Kohrer, K., Oberhauser, S. & Roher, H. D. Lysophosphatidic acid, a novel lipid growth factor for human thyroid cells: over-expression of the high-affinity receptor edg4 in differentiated thyroid cancer. Int. J. Cancer 92, 249–256 (2001).
Van Leeuwen, F. N. et al. Rac activation by lysophosphatidic acid LPA1 receptors through the guanine nucleotide exchange factor Tiam1. J. Biol. Chem. 278, 400–406 (2003).
Karmali, R. A. Eicosanoids and cancer. Prog. Clin. Biol. Res. 222, 687–697 (1986).
Wang, D. & Dubois, R. N. Eicosanoids and cancer. Nature Rev. Cancer 10, 181–193 (2010).
Ben-Neriah, Y. & Karin, M. Inflammation meets cancer, with NF-κB as the matchmaker. Nature Immunol. 12, 715–723 (2011).
Aggarwal, B. B. et al. Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann. NY Acad. Sci. 1171, 59–76 (2009).
Ozanne, B. W., Spence, H. J., McGarry, L. C. & Hennigan, R. F. Transcription factors control invasion: AP-1 the first among equals. Oncogene 26, 1–10 (2007).
Reuter, S., Gupta, S. C., Chaturvedi, M. M. & Aggarwal, B. B. Oxidative stress, inflammation, and cancer: how are they linked? Free Rad. Biol. Med. 49, 1603–1616 (2010).
Mouneimne, G. et al. Phospholipase C and cofilin are required for carcinoma cell directionality in response to EGF stimulation. J. Cell Biol. 166, 697–708 (2004).
Wang, W., Eddy, R. & Condeelis, J. The cofilin pathway in breast cancer invasion and metastasis. Nature Rev. Cancer 7, 429–440 (2007).
Jones, N. P. & Katan, M. Role of phospholipase Cγ1 in cell spreading requires association with a β-Pix/GIT1-containing complex, leading to activation of Cdc42 and Rac1. Mol. Cell. Biol. 27, 5790–5805 (2007).
Sala, G. et al. Phospholipase Cγ1 is required for metastasis development and progression. Cancer Res. 68, 10187–10196 (2008).
Thomas, S. M. et al. Epidermal growth factor receptor-stimulated activation of phospholipase Cγ-1 promotes invasion of head and neck squamous cell carcinoma. Cancer Res. 63, 5629–5635 (2003).
Bertagnolo, V. et al. Phospholipase C-β 2 promotes mitosis and migration of human breast cancer-derived cells. Carcinogenesis 28, 1638–1645 (2007).
Bertagnolo, V. et al. PLC-β2 is highly expressed in breast cancer and is associated with a poor outcome: a study on tissue microarrays. Int. J. Oncol. 28, 863–872 (2006).
Shen, Y., Zheng, Y. & Foster, D. A. Phospholipase D2 stimulates cell protrusion in v-Src-transformed cells. Biochem. Biophys. Res. Commun. 293, 201–206 (2002).
Chae, Y. C. et al. Phospholipase D activity regulates integrin-mediated cell spreading and migration by inducing GTP-Rac translocation to the plasma membrane. Mol. Biol. Cell 19, 3111–3123 (2008).
Honda, A. et al. Phosphatidylinositol 4-phosphate 5-kinase α is a downstream effector of the small G protein ARF6 in membrane ruffle formation. Cell 99, 521–532 (1999).
Kang, D. W. et al. Phorbol ester up-regulates phospholipase D1 but not phospholipase D2 expression through a PKC/Ras/ERK/NFκB-dependent pathway and enhances matrix metalloproteinase-9 secretion in colon cancer cells. J. Biol. Chem. 283, 4094–4104 (2008).
Park, M. H., Ahn, B. H., Hong, Y. K. & Min do, S. Overexpression of phospholipase D enhances matrix metalloproteinase-2 expression and glioma cell invasion via protein kinase C and protein kinase A/NF-κB/Sp1-mediated signaling pathways. Carcinogenesis 30, 356–365 (2009).
Zheng, Y. et al. Phospholipase D couples survival and migration signals in stress response of human cancer cells. J. Biol. Chem. 281, 15862–15868 (2006).
Knoepp, S. M. et al. Effects of active and inactive phospholipase D2 on signal transduction, adhesion, migration, invasion, and metastasis in EL4 lymphoma cells. Mol. Pharmacol. 74, 574–584 (2008).
Shibuya, M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J. Biochem. Mol. Biol. 39, 469–478 (2006).
Lawson, N. D., Mugford, J. W., Diamond, B. A. & Weinstein, B. M. phospholipase Cγ-1 is required downstream of vascular endothelial growth factor during arterial development. Genes Dev. 17, 1346–1351 (2003).
Liao, H. J. et al. Absence of erythrogenesis and vasculogenesis in Plcg1-deficient mice. J. Biol. Chem. 277, 9335–9341 (2002).
Takahashi, T., Yamaguchi, S., Chida, K. & Shibuya, M. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-γ and DNA synthesis in vascular endothelial cells. EMBO J. 20, 2768–2778 (2001).
Sakurai, Y., Ohgimoto, K., Kataoka, Y., Yoshida, N. & Shibuya, M. Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc. Natl Acad. Sci. USA 102, 1076–1081 (2005).
Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).
Bhattacharya, R. et al. Distinct role of PLCβ3 in VEGF-mediated directional migration and vascular sprouting. J. Cell Sci. 122, 1025–1034 (2009).
Nakamura, Y. et al. Phospholipase C-δ1 and -δ3 are essential in the trophoblast for placental development. Mol. Cell. Biol. 25, 10979–10988 (2005).
Zeng, X. X. et al. Phospholipase D1 is required for angiogenesis of intersegmental blood vessels in zebrafish. Dev. Biol. 328, 363–376 (2009).
Kono, M. et al. The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J. Biol. Chem. 279, 29367–29373 (2004).
Delon, C. et al. Sphingosine kinase 1 is an intracellular effector of phosphatidic acid. J. Biol. Chem. 279, 44763–44774 (2004).
Seymour, L. W. et al. Vascular endothelial growth factor stimulates protein kinase C-dependent phospholipase D activity in endothelial cells . Lab. Invest. 75, 427–437 (1996).
Cheng, T., Cao, W., Wen, R., Steinberg, R. H. & LaVail, M. M. Prostaglandin E2 induces vascular endothelial growth factor and basic fibroblast growth factor mRNA expression in cultured rat Muller cells. Invest. Ophthalmol. Vis. Sci. 39, 581–591 (1998).
Wang, D. et al. CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer. J. Exp. Med. 203, 941–951 (2006).
Herbert, S. P., Ponnambalam, S. & Walker, J. H. Cytosolic phospholipase A2-α mediates endothelial cell proliferation and is inactivated by association with the Golgi apparatus. Mol. Biol. Cell 16, 3800–3809 (2005).
Herbert, S. P., Odell, A. F., Ponnambalam, S. & Walker, J. H. Activation of cytosolic phospholipase A2−α as a novel mechanism regulating endothelial cell cycle progression and angiogenesis. J. Biol. Chem. 284, 5784–5796 (2009).
Yazlovitskaya, E. M., Linkous, A. G., Thotala, D. K., Cuneo, K. C. & Hallahan, D. E. Cytosolic phospholipase A2 regulates viability of irradiated vascular endothelium. Cell Death Differ. 15, 1641–1653 (2008).
Tosato, G., Segarra, M. & Salvucci, O. Cytosolic phospholipase A2α and cancer: a role in tumor angiogenesis. J. Natl Cancer Inst. 102, 1377–1379 (2010).
Linkous, A. G., Yazlovitskaya, E. M. & Hallahan, D. E. Cytosolic phospholipase A2 and lysophospholipids in tumor angiogenesis. J. Natl Cancer Inst. 102, 1398–1412 (2010).
Akiba, S. & Sato, T. Cellular function of calcium-independent phospholipase A2. Biol. Pharm. Bull. 27, 1174–1178 (2004).
Ong, W. Y., Farooqui, T. & Farooqui, A. A. Involvement of cytosolic phospholipase A2, calcium independent phospholipase A2 and plasmalogen selective phospholipase A2 in neurodegenerative and neuropsychiatric conditions. Curr. Med. Chem. 17, 2746–2763 (2010).
Samoha, S. & Arber, N. Cyclooxygenase-2 inhibition prevents colorectal cancer: from the bench to the bed side. Oncology 69, 33–37 (2005).
Chakraborti, A. K., Garg, S. K., Kumar, R., Motiwala, H. F. & Jadhavar, P. S. Progress in COX-2 inhibitors: a journey so far. Curr. Med. Chem. 17, 1563–1593 (2010).
Fraser, H. et al. Varespladib (A-002), a secretory phospholipase A2 inhibitor, reduces atherosclerosis and aneurysm formation in ApoE−/− mice. J. Cardiovasc. Pharmacol. 53, 60–65 (2009).
Su, W. et al. 5-Fluoro-2-indolyl des-chlorohalopemide (FIPI), a phospholipase D pharmacological inhibitor that alters cell spreading and inhibits chemotaxis. Mol. Pharmacol. 75, 437–446 (2009).
Scott, S. A. et al. Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness. Nature Chem. Biol. 5, 108–117 (2009).
Fukami, K., Inanobe, S., Kanemaru, K. & Nakamura, Y. Phospholipase C is a key enzyme regulating intracellular calcium and modulating the phosphoinositide balance. Prog. Lipid Res. 49, 429–437 (2010).
Jin, T. G. et al. Role of the CDC25 homology domain of phospholipase Cepsilon in amplification of Rap1-dependent signaling. J. Biol. Chem. 276, 30301–30307 (2001).
Jenkins, G. M. & Frohman, M. A. Phospholipase D: a lipid centric review. Cell. Mol. Life Sci. 62, 2305–2316 (2005).
Pedersen, K. M., Finsen, B., Celis, J. E. & Jensen, N. A. Expression of a novel murine phospholipase D homolog coincides with late neuronal development in the forebrain. J. Biol. Chem. 273, 31494–31504 (1998).
Yoshikawa, F. et al. Phospholipase D family member 4, a transmembrane glycoprotein with no phospholipase D activity, expression in spleen and early postnatal microglia. PLoS ONE 5, e13932 (2010).
Choi, S. Y. et al. A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis. Nature Cell Biol. 8, 1255–1262 (2006).
Otani, Y. et al. PLD4 is involved in phagocytosis of microglia: expression and localization changes of PLD4 are correlated with activation state of microglia. PLoS ONE 6, e27544 (2011).
Kim, Y. et al. Phosphorylation and activation of phospholipase D1 by protein kinase C in vivo: determination of multiple phosphorylation sites. Biochemistry 38, 10344–10351 (1999).
Hammond, S. M. et al. Characterization of two alternately spliced forms of phospholipase D1. Activation of the purified enzymes by phosphatidylinositol 4,5-bisphosphate, ADP-ribosylation factor, and Rho family monomeric GTP-binding proteins and protein kinase C-α. J. Biol. Chem. 272, 3860–3868 (1997).
Aoki, J., Inoue, A. & Okudaira, S. Two pathways for lysophosphatidic acid production. Biochim. Biophys. Acta 1781, 513–518 (2008).
Cormier, R. T. et al. The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64. Oncogene 19, 3182–3192 (2000).
Ilsley, J. N. et al. Cytoplasmic phospholipase A2 deletion enhances colon tumorigenesis. Cancer Res. 65, 2636–2643 (2005).
McHowat, J. et al. Platelet-activating factor and metastasis: calcium-independent phospholipase A2β deficiency protects against breast cancer metastasis to the lung. Am. J. Physiol. Cell Physiol. 300, C825–C832 (2011).
Li, H. et al. Group VIA phospholipase A2 in both host and tumor cells is involved in ovarian cancer development. FASEB J. 24, 4103–4116 (2010).
Shepard, C. R., Kassis, J., Whaley, D. L., Kim, H. G. & Wells, A. PLC γ contributes to metastasis of in situ-occurring mammary and prostate tumors. Oncogene 26, 3020–3026 (2007).
Wen, R. et al. Essential role of phospholipase C γ 2 in early B-cell development and Myc-mediated lymphomagenesis. Mol. Cell. Biol. 26, 9364–9376 (2006).
Oka, M. et al. Enhancement of ultraviolet B-induced skin tumor development in phospholipase Cepsilon-knockout mice is associated with decreased cell death. Carcinogenesis 31, 1897–1902 (2010).
Yoshida, N. et al. Broad, ectopic expression of the sperm protein PLCZ1 induces parthenogenesis and ovarian tumours in mice. Development 134, 3941–3952 (2007).
Murata, K. et al. Expression of group-II phospholipase A2 in malignant and non-malignant human gastric mucosa. Br. J. Cancer 68, 103–111 (1993).
Yamashita, S., Yamashita, J. & Ogawa, M. Overexpression of group II phospholipase A2 in human breast cancer tissues is closely associated with their malignant potency. Br. J. Cancer 69, 1166–1170 (1994).
Buhmeida, A. et al. PLA2 (group IIA phospholipase A2) as a prognostic determinant in stage II colorectal carcinoma. Ann. Oncol. 20, 1230–1235 (2009).
Ganesan, K. et al. Inhibition of gastric cancer invasion and metastasis by PLA2G2A, a novel β-catenin/TCF target gene. Cancer Res. 68, 4277–4286 (2008).
Jiang, J. et al. Expression of group IIA secretory phospholipase A2 is elevated in prostatic intraepithelial neoplasia and adenocarcinoma. Am. J. Pathol. 160, 667–671 (2002).
Graff, J. R. et al. Expression of group IIa secretory phospholipase A2 increases with prostate tumor grade. Clin. Cancer Res. 7, 3857–3861 (2001).
Dong, M. et al. Cytoplasmic phospholipase A2 levels correlate with apoptosis in human colon tumorigenesis. Clin. Cancer Res. 11, 2265–2271 (2005).
Tews, B. et al. Identification of novel oligodendroglioma-associated candidate tumor suppressor genes in 1p36 and 19q13 using microarray-based expression profiling. Int. J. Cancer 119, 792–800 (2006).
Noh, D. Y. et al. Elevated content of phospholipase C-γ 1 in colorectal cancer tissues. Cancer 73, 36–41 (1994).
Arteaga, C. L. et al. Elevated content of the tyrosine kinase substrate phospholipase C-γ 1 in primary human breast carcinomas. Proc. Natl Acad. Sci. USA 88, 10435–10439 (1991).
Noh, D. Y. et al. Expression of phospholipase C-γ 1 and its transcriptional regulators in breast cancer tissues. Anticancer Res. 18, 2643–2648 (1998).
Hu, X. T. et al. Phospholipase C δ 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer. Oncogene 28, 2466–2475 (2009).
Noh, D. Y. et al. Overexpression of phospholipase D1 in human breast cancer tissues. Cancer Lett. 161, 207–214 (2000).
Zhao, Y. et al. Increased activity and intranuclear expression of phospholipase D2 in human renal cancer. Biochem. Biophys. Res. Commun. 278, 140–143 (2000).
Acknowledgements
The authors thank S.-H. Lee, K. Choi, S. K. Jang and H. M. Kwon for many useful discussions and suggestions for this article. They apologize to colleagues whose work could not be cited owing to space limitations. This work was supported by the grants (NRF-M1AXA002-2010-0029764, No.2010-0029434 and No.2012R1A2A1A03010110) of National Research Foundation and the grant (1210041-1) of National Cancer Center in Korea.
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FURTHER INFORMATION
Supplementary information
Supplementary information Table S1
Phenotypes of phospholipase transgenic and knockout mice (XLSX 20 kb)
Supplementary information S2
Network analysis of phospholipases in cancer (PDF 161 kb)
Supplementary information S3
GOBP and GOCC of phospholipases and PLNs. (PDF 152 kb)
Supplementary information Table S4
Interactors and interactions of phospholipases and lipid meidators. (a) Interactors (XLS 238 kb)
Supplementary information S5
Expression profiles of phospholipases in cancer. (PDF 146 kb)
Supplementary information S6
Correlation of expression profiles across cancer types between phospholipases and PLNs. (PDF 341 kb)
Supplementary information S7
A hypothetical network delineating the relationships between phospholipases and their associated processes. (PDF 1149 kb)
Glossary
- ApcMin mice
-
Mice that carry the multiple intestinal neoplasia (Min) point mutation at one Apc allele and that develop intestinal adenomas spontaneously. Commonly used model of human familial adenomatous polyposis and human sporadic colorectal cancer.
- C2 domain
-
A structural domain that is involved in membrane targeting. The C2-like domain of calpain is superficially similar to the C2 domain of other enzymes.
- Caveolae
-
Cholesterol-rich membrane microdomains that are stabilized by the caveolin proteins.
- EF-hand domain
-
A structural domain responsible for calcium binding, found in calcium-binding proteins.
- Intersegmental vessel
-
(ISV). A vessel that carries blood from the dorsal aorta between somites to the dorsal side of the neural tube.
- Matrigel
-
The trade name for a gelatinous protein mixture that is secreted by mouse tumour cells. It resembles the complex extracellular environment found in many tissues and is commonly used as a three-dimensional matrix substrate for cell culture-based in vitro migration and invasion assays.
- Phox homology (PX) domain
-
A phosphoinositide-binding domain that was found in the p40phox and p47phox domains of NADPH oxidase.
- Pleckstrin homology (PH) domains
-
Sequences of approximately 100 amino acids that are present in many signalling molecules and that commonly bind to phospholipids and proteins.
- Signal sequence
-
A short peptide chain that targets a protein to a specific location (for example, the extracellular region, mitochondria and nucleus).
- sn-1 and sn-2 positions
-
To designate the configuration of glycerol derivatives, the carbon atoms of glycerol are numbered stereospecifically. Most fatty acids at the sn-1 position are saturated (palmitate or stearate), and the sn-2 acyl chain is a saturated fatty acid (oleic acids, linoleic acid, and arachidonic acid).
- SH2 domain
-
SRC homology 2 domain. A protein–protein interaction domain capable of binding tyrosine phosphorylated sites.
- SH3 domain
-
SRC homology 3 domain. A protein–protein interaction domain capable of binding proline-rich motifs.
- Stress fibre
-
A contractile actin filament bundle that contains myosin II, which serves both as an F-actin bundling protein and as a force generator.
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Park, J., Lee, C., Jang, JH. et al. Phospholipase signalling networks in cancer. Nat Rev Cancer 12, 782–792 (2012). https://doi.org/10.1038/nrc3379
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DOI: https://doi.org/10.1038/nrc3379
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