Skip to main content
SpringerLink
Log in

Phospholipase D and the Mitogen Phosphatidic Acid in Human Disease: Inhibitors of PLD at the Crossroads of Phospholipid Biology and Cancer

  • Chapter
  • First Online:
Lipid Signaling in Human Diseases

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 259))

Abstract

Lipids are key building blocks of biological membranes and are involved in complex signaling processes such as metabolism, proliferation, migration, and apoptosis. Extracellular signaling by growth factors, stress, and nutrients is transmitted through receptors that activate lipid-modifying enzymes such as the phospholipases, sphingosine kinase, or phosphoinositide 3-kinase, which then modify phospholipids, sphingolipids, and phosphoinositides. One such important enzyme is phospholipase D (PLD), which cleaves phosphatidylcholine to yield phosphatidic acid and choline. PLD isoforms have dual role in cells. The first involves maintaining cell membrane integrity and cell signaling, including cell proliferation, migration, cytoskeletal alterations, and invasion through the PLD product PA, and the second involves protein-protein interactions with a variety of binding partners. Increased evidence of elevated PLD expression and activity linked to many pathological conditions, including cancer, neurological and inflammatory diseases, and infection, has motivated the development of dual- and isoform-specific PLD inhibitors. Many of these inhibitors are reported to be efficacious and safe in cells and mouse disease models, suggesting the potential for PLD inhibitors as therapeutics for cancer and other diseases. Current knowledge and ongoing research of PLD signaling networks will help to evolve inhibitors with increased efficacy and safety for clinical studies.

Gomez-Cambronero was deceased at the time of publication.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahn M et al (2001) Increased expression of phospholipase D1 in the spinal cords of rats with experimental autoimmune encephalomyelitis. Neurosci Lett 316(2):95–98

    CAS  PubMed  Google Scholar 

  • Ahn B-H et al (2002) α-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells. J Biol Chem 277(14):12334–12342

    CAS  PubMed  Google Scholar 

  • Ali WH et al (2013) Deficiencies of the lipid-signaling enzymes phospholipase D1 and D2 alter cytoskeletal organization, macrophage phagocytosis, and cytokine-stimulated neutrophil recruitment. PLoS One 8(1):e55325

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ammar MR et al (2013) The Coffin-Lowry syndrome-associated protein RSK2 regulates neurite outgrowth through phosphorylation of phospholipase D1 (PLD1) and synthesis of phosphatidic acid. J Neurosci 33(50):19470–19479

    CAS  PubMed  PubMed Central  Google Scholar 

  • Arakawa T et al (1998) Rebamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing. Dig Dis Sci 43(9 Suppl):5s–13s

    CAS  PubMed  Google Scholar 

  • Bae EJ et al (2014) Phospholipase D1 regulates autophagic flux and clearance of alpha-synuclein aggregates. Cell Death Differ 21(7):1132–1141

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233

    CAS  PubMed  PubMed Central  Google Scholar 

  • Basiouni S, Fuhrmann H, Schumann J (2013) The influence of polyunsaturated fatty acids on the phospholipase d isoforms trafficking and activity in mast cells. Int J Mol Sci 14(5):9005–9017

    PubMed  PubMed Central  Google Scholar 

  • Bluth M et al (2008) Use of gene expression profiles in cells of peripheral blood to identify new molecular markers of acute pancreatitis. Arch Surg 143(3):227–233

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brown HA et al (1993) ADP-ribosylation factor, a small GTP-dependent regulatory protein, stimulates phospholipase D activity. Cell 75(6):1137–1144

    CAS  PubMed  Google Scholar 

  • Brown HA et al (1995) Partial purification and characterization of Arf-sensitive phospholipase D from porcine brain. J Biol Chem 270(25):14935–14943

    CAS  PubMed  Google Scholar 

  • Bruntz RC et al (2014) Phospholipase D2 mediates survival signaling through direct regulation of Akt in glioblastoma cells. J Biol Chem 289(2):600–616

    CAS  PubMed  Google Scholar 

  • Cacace R et al (2015) Rare variants in PLD3 do not affect risk for early-onset Alzheimer disease in a European consortium cohort. Hum Mutat 36(12):1226–1235

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cai D et al (2006) Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation. Proc Natl Acad Sci U S A 103(6):1941–1946

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chae YC et al (2008) Phospholipase D activity regulates integrin-mediated cell spreading and migration by inducing GTP-Rac translocation to the plasma membrane. Mol Biol Cell 19(7):3111–3123

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chaves-Moreira D et al (2017) Potential implications for designing drugs against the Brown spider venom phospholipase-D. J Cell Biochem 118(4):726–738

    CAS  PubMed  Google Scholar 

  • Chen Y, Zheng Y, Foster DA (2003) Phospholipase D confers rapamycin resistance in human breast cancer cells. Oncogene 22(25):3937–3942

    CAS  PubMed  Google Scholar 

  • Chen Y, Rodrik V, Foster DA (2005) Alternative phospholipase D/mTOR survival signal in human breast cancer cells. Oncogene 24(4):672–679

    CAS  PubMed  Google Scholar 

  • Chen Q et al (2012) Key roles for the lipid signaling enzyme phospholipase D1 in the tumor microenvironment during tumor angiogenesis and metastasis. Sci Signal 5(249):ra79

    PubMed  PubMed Central  Google Scholar 

  • Chen Z et al (2014) MicroRNA-203 inhibits the proliferation and invasion of U251 glioblastoma cells by directly targeting PLD2. Mol Med Rep 9(2):503–508

    CAS  PubMed  Google Scholar 

  • Cho JH et al (2008) Overexpression of phospholipase D suppresses taxotere-induced cell death in stomach cancer cells. Biochim Biophys Acta 1783(5):912–923

    CAS  PubMed  Google Scholar 

  • Choi SY et al (2006) A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis. Nat Cell Biol 8(11):1255–1262

    CAS  PubMed  Google Scholar 

  • Colley WC et al (1997) Phospholipase D2, a distinct phospholipase D isoform with novel regulatory properties that provokes cytoskeletal reorganization. Curr Biol 7(3):191–201

    CAS  PubMed  Google Scholar 

  • Conde MA et al (2018) Phospholipase D1 downregulation by alpha-synuclein: implications for neurodegeneration in Parkinson’s disease. Biochim Biophys Acta Mol Cell Biol Lipids 1863(6):639–650

    CAS  PubMed  Google Scholar 

  • Corrotte M et al (2006) Dynamics and function of phospholipase D and phosphatidic acid during phagocytosis. Traffic 7(3):365–377

    CAS  PubMed  Google Scholar 

  • Cruchaga C et al (2014) Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature 505(7484):550–554

    CAS  PubMed  Google Scholar 

  • Di Fulvio M et al (2006) The elucidation of novel SH2 binding sites on PLD2. Oncogene 25(21):3032–3040

    PubMed  PubMed Central  Google Scholar 

  • Du G et al (2003) Regulation of phospholipase D1 subcellular cycling through coordination of multiple membrane association motifs. J Cell Biol 162(2):305–315

    CAS  PubMed  PubMed Central  Google Scholar 

  • Du GW et al (2004) Phospholipase D2 localizes to the plasma membrane and regulates angiotensin II receptor endocytosis. Mol Biol Cell 15(3):1024–1030

    CAS  PubMed  PubMed Central  Google Scholar 

  • Elvers M et al (2010) Impaired alpha(IIb)beta(3) integrin activation and shear-dependent thrombus formation in mice lacking phospholipase D1. Sci Signal 3(103):ra1

    PubMed  PubMed Central  Google Scholar 

  • Fingar DC et al (2004) mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 24(1):200–216

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fite K, Elkhadragy L, Gomez-Cambronero J (2016) A repertoire of MicroRNAs regulates cancer cell starvation by targeting phospholipase D in a feedback loop that operates maximally in cancer cells. Mol Cell Biol 36(7):1078–1089

    CAS  PubMed  PubMed Central  Google Scholar 

  • Foster DA (2007) Regulation of mTOR by phosphatidic acid? Cancer Res 67(1):1–4

    CAS  PubMed  Google Scholar 

  • Foster DA et al (2014) Phospholipase D and the maintenance of phosphatidic acid levels for regulation of mammalian target of rapamycin (mTOR). J Biol Chem 289(33):22583–22588

    CAS  PubMed  PubMed Central  Google Scholar 

  • Frohman MA (2015) The phospholipase D superfamily as therapeutic targets. Trends Pharmacol Sci 36(3):137–144

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ganesan R et al (2015) Two sites of action for PLD2 inhibitors: the enzyme catalytic center and an allosteric, phosphoinositide biding pocket. Biochim Biophys Acta 1851(3):261–272

    CAS  PubMed  Google Scholar 

  • Ganesan R et al (2018) Oxidized LDL phagocytosis during foam cell formation in atherosclerotic plaques relies on a PLD2-CD36 functional interdependence. J Leukoc Biol 103(5):867–883

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gao Q, Frohman MA (2012) Roles for the lipid-signaling enzyme MitoPLD in mitochondrial dynamics, piRNA biogenesis, and spermatogenesis. BMB Rep 45(1):7–13

    CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia A et al (2008) Honokiol suppresses survival signals mediated by Ras-dependent phospholipase D activity in human cancer cells. Clin Cancer Res 14(13):4267–4274

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gavin AL et al (2018) PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing. Nat Immunol 19(9):942–953

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gobel K et al (2014) Phospholipase D1 mediates lymphocyte adhesion and migration in experimental autoimmune encephalomyelitis. Eur J Immunol 44(8):2295–2305

    PubMed  Google Scholar 

  • Gomez-Cambronero J (2014a) Phosphatidic acid, phospholipase D and tumorigenesis. Adv Biol Regul 54:197–206

    CAS  PubMed  Google Scholar 

  • Gomez-Cambronero J (2014b) Phospholipase D in cell signaling: from a myriad of cell functions to cancer growth and metastasis. J Biol Chem 289(33):22557–22566

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gomez-Cambronero J, di Fulvio M, Knapek K (2007) Understanding phospholipase D (PLD) using leukocytes: PLD involvement in cell adhesion and chemotaxis. J Leukoc Biol 82(2):272–281

    CAS  PubMed  Google Scholar 

  • Gomez-Munoz A, Martens JS, Steinbrecher UP (2000) Stimulation of phospholipase D activity by oxidized LDL in mouse peritoneal macrophages. Arterioscler Thromb Vasc Biol 20(1):135–143

    CAS  PubMed  Google Scholar 

  • Gottlin EB et al (1998) Catalytic mechanism of the phospholipase D superfamily proceeds via a covalent phosphohistidine intermediate. Proc Natl Acad Sci U S A 95(16):9202–9207

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gozgit JM et al (2007) PLD1 is overexpressed in an ER-negative MCF-7 cell line variant and a subset of phospho-Akt-negative breast carcinomas. Br J Cancer 97(6):809–817

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hammond SM et al (1995) Human ADP-ribosylation factor-activated phosphatidylcholine-specific phospholipase D defines a new and highly conserved gene family. J Biol Chem 270(50):29640–29643

    CAS  PubMed  Google Scholar 

  • Hammond SM et al (1997) 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-alpha. J Biol Chem 272:3860–3868. 1997(0021–9258 (Print))

    CAS  PubMed  Google Scholar 

  • Han X et al (2011) beta-1,3-Glucan-induced host phospholipase D activation is involved in Aspergillus fumigatus internalization into type II human pneumocyte A549 cells. PLoS One 6(7):e21468

    CAS  PubMed  PubMed Central  Google Scholar 

  • Harel-Dassa K et al (2017) Phospholipase D messenger RNA expression and clinical role in high-grade serous carcinoma. Hum Pathol 62:115–121

    CAS  PubMed  Google Scholar 

  • Henkels KM et al (2013) Phospholipase D (PLD) drives cell invasion, tumor growth and metastasis in a human breast cancer xenograph model. Oncogene 32(49):5551–5562

    CAS  PubMed  PubMed Central  Google Scholar 

  • Henkels KM, Muppani NR, Gomez-Cambronero J (2016) PLD-specific small-molecule inhibitors decrease tumor-associated macrophages and neutrophils infiltration in breast tumors and lung and liver metastases. PLoS One 11(11):e0166553

    PubMed  PubMed Central  Google Scholar 

  • Hodgkin MN et al (2000a) Phospholipase D regulation and localisation is dependent upon a phosphatidylinositol 4,5-biphosphate-specific PH domain. Curr Biol 10:43–46. (0960–9822 (Print))

    CAS  PubMed  Google Scholar 

  • Hodgkin MN et al (2000b) Phospholipase D regulation and localisation is dependent upon a phosphatidylinositol 4,5-bisphosphate-specific PH domain. Curr Biol 10(1):43–46

    CAS  PubMed  Google Scholar 

  • Huang H et al (2011) piRNA-associated germline nuage formation and spermatogenesis require MitoPLD profusogenic mitochondrial-surface lipid signaling. Dev Cell 20(3):376–387

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hui L et al (2004) Phospholipase D elevates the level of MDM2 and suppresses DNA damage-induced increases in p53. Mol Cell Biol 24(13):5677–5686

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hwang WC et al (2014) Inhibition of phospholipase D2 induces autophagy in colorectal cancer cells. Exp Mol Med 46(12):e124–e124

    CAS  PubMed  PubMed Central  Google Scholar 

  • Iyer SS et al (2004) Phospholipases D1 and D2 coordinately regulate macrophage phagocytosis. J Immunol 173(4):2615–2623

    CAS  PubMed  Google Scholar 

  • Iyer SS et al (2006) Phospholipase D1 regulates phagocyte adhesion. J Immunol 176(6):3686–3696

    CAS  PubMed  Google Scholar 

  • Jiang Y et al (2016) Phosphatidic acid produced by RalA-activated PLD2 stimulates caveolae-mediated endocytosis and trafficking in endothelial cells. J Biol Chem 291(39):20729–20738

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jin J-K et al (2006) Phospholipase D1 is up-regulated in the mitochondrial fraction from the brains of Alzheimer’s disease patients. Neurosci Lett 407(3):263–267

    CAS  PubMed  Google Scholar 

  • Jung K et al (2003) Upregulation of phospholipase D1 in the spinal cords of rats with clip compression injury. Neurosci Lett 336(2):126–130

    CAS  PubMed  Google Scholar 

  • Jung S et al (2014) A nonsense mutation in PLD4 is associated with a zinc deficiency-like syndrome in Fleckvieh cattle. BMC Genomics 15:623

    PubMed  PubMed Central  Google Scholar 

  • Kang DW, Min DS (2010) Positive feedback regulation between phospholipase D and Wnt signaling promotes Wnt-driven anchorage-independent growth of colorectal cancer cells. PLoS One 5(8):e12109

    PubMed  PubMed Central  Google Scholar 

  • Kang DW et al (2009) Triptolide-induced suppression of phospholipase D expression inhibits proliferation of MDA-MB-231 breast cancer cells. Exp Mol Med 41(9):678

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kang DW et al (2011) Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells. Int J Cancer 128(4):805–816

    CAS  PubMed  Google Scholar 

  • Kang DW et al (2015a) Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells. J Exp Med 212(8):1219–1237

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kang YH, Kim D, Jin EJ (2015b) Down-regulation of phospholipase D stimulates death of lung cancer cells involving up-regulation of the long ncRNA ANRIL. Anticancer Res 35(5):2795–2803

    CAS  PubMed  Google Scholar 

  • Kang DW et al (2017) Phospholipase D1 acts through Akt/TopBP1 and RB1 to regulate the E2F1-dependent apoptotic program in cancer cells. Cancer Res 77(1):142–152

    CAS  PubMed  Google Scholar 

  • Kantonen S et al (2011) A novel phospholipase D2-Grb2-WASp heterotrimer regulates leukocyte phagocytosis in a two-step mechanism. Mol Cell Biol 31(22):4524–4537

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kassas N et al (2012) Genetically encoded probes for phosphatidic acid. Methods Cell Biol 108:445–459

    CAS  PubMed  Google Scholar 

  • Kassas N et al (2017) Comparative characterization of phosphatidic acid sensors and their localization during frustrated phagocytosis. J Biol Chem 292(10):4266–4279

    CAS  PubMed  PubMed Central  Google Scholar 

  • Katayama K et al (1998) Cloning, differential regulation and tissue distribution of alternatively spliced isoforms of ADP-ribosylation-factor-dependent phospholipase D from rat liver. Biochem J 329:647–652

    CAS  PubMed  PubMed Central  Google Scholar 

  • Knoepp SM et al (2008) Effects of active and inactive phospholipase D2 on signal transduction, adhesion, migration, invasion, and metastasis in EL4 lymphoma cells. Mol Pharmacol 74(3):574–584

    CAS  PubMed  Google Scholar 

  • Koch T et al (2009) Mu-opioid receptor-stimulated synthesis of reactive oxygen species is mediated via phospholipase D2. J Neurochem 110(4):1288–1296

    CAS  PubMed  Google Scholar 

  • Koo JB, Han J-S (2016) Cigarette smoke extract-induced interleukin-6 expression is regulated by phospholipase D1 in human bronchial epithelial cells. J Toxicol Sci 41(1):77–89

    CAS  PubMed  Google Scholar 

  • Korin YD, Zack JA (1999) Nonproductive human immunodeficiency virus type 1 infection in nucleoside-treated G0 lymphocytes. J Virol 73(8):6526–6532

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lavieri R et al (2009) Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part II. Identification of the 1,3,8-triazaspiro[4,5]decan-4-one privileged structure that engenders PLD2 selectivity. Bioorg Med Chem Lett 19(8):2240–2243

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lavieri RR et al (2010) Design, synthesis, and biological evaluation of halogenated N-(2-(4-oxo-1-phenyl-1, 3, 8-triazaspiro [4.5] decan-8-yl) ethyl) benzamides: discovery of an isoform-selective small molecule phospholipase D2 inhibitor. J Med Chem 53(18):6706–6719

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JS et al (2005) Phosphatidylinositol (3,4,5)-trisphosphate specifically interacts with the phox homology domain of phospholipase D1 and stimulates its activity. J Cell Sci 118(19):4405–4413

    CAS  PubMed  Google Scholar 

  • Lee CS et al (2006) The phox homology domain of phospholipase D activates dynamin GTPase activity and accelerates EGFR endocytosis. Nat Cell Biol 8(5):477–484

    CAS  PubMed  Google Scholar 

  • Lee SK et al (2015) Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2. J Exp Med 212(9):1381–1390

    CAS  PubMed  PubMed Central  Google Scholar 

  • Leiros I, McSweeney S, Hough E (2004) The reaction mechanism of phospholipase D from Streptomyces sp strain PMF. Snapshots along the reaction pathway reveal a pentacoordinate reaction intermediate and an unexpected final product. J Mol Biol 339(4):805–820

    CAS  PubMed  Google Scholar 

  • Lerchner A et al (2006) Probing conserved amino acids in phospholipase D (Brassica oleracea var. capitata) for their importance in hydrolysis and transphosphatidylation activity. Protein Eng Des Sel 19(10):443–452

    CAS  PubMed  Google Scholar 

  • Levin WJ et al (1995) Expression patterns of immediate early transcription factors in human non-small cell lung cancer. The Lung Cancer Study Group. Oncogene 11(7):1261–1269

    CAS  PubMed  Google Scholar 

  • Lewis JA et al (2009) Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: impact of alternative halogenated privileged structures for PLD1 specificity. Bioorg Med Chem Lett 19(7):1916–1920

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li G, Lin F, Xue HW (2007) Genome-wide analysis of the phospholipase D family in Oryza sativa and functional characterization of PLD beta 1 in seed germination. Cell Res 17(10):881–894

    CAS  PubMed  Google Scholar 

  • Mancini F, Ciervo A (2015) Enzymatic characterization of Chlamydophila pneumoniae phospholipase D. New Microbiol 38(1):59–66

    CAS  PubMed  Google Scholar 

  • Monovich L et al (2007) Optimization of halopemide for phospholipase D2 inhibition. Bioorg Med Chem Lett 17(8):2310–2311

    CAS  PubMed  Google Scholar 

  • Motes CM et al (2005) Differential effects of two phospholipase D inhibitors, 1-butanol and N-acylethanolamine, on in vivo cytoskeletal organization and Arabidopsis seedling growth. Protoplasma 226(3–4):109–123

    CAS  PubMed  Google Scholar 

  • Murphy E, Steenbergen C (2008) Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 88(2):581–609

    CAS  PubMed  PubMed Central  Google Scholar 

  • Natarajan V et al (1995) Oxidized low density lipoprotein-mediated activation of phospholipase D in smooth muscle cells: a possible role in cell proliferation and atherogenesis. J Lipid Res 36(9):2005–2016

    CAS  PubMed  Google Scholar 

  • Nelson RK et al (2017) Phospholipase D2 loss results in increased blood pressure via inhibition of the endothelial nitric oxide synthase pathway. Sci Rep 7(1):9112

    PubMed  PubMed Central  Google Scholar 

  • Nishikimi A et al (2009) Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis. Science 324(5925):384–387

    CAS  PubMed  PubMed Central  Google Scholar 

  • Noh JY et al (2010) Procoagulant and prothrombotic activation of human erythrocytes by phosphatidic acid. Am J Phys Heart Circ Phys 299(2):H347–H355

    CAS  Google Scholar 

  • Nureki O (2014) Is zucchini a phosphodiesterase or a ribonuclease? Biom J 37(6):369–374

    Google Scholar 

  • O’Reilly MC et al (2013) Development of dual PLD1/2 and PLD2 selective inhibitors from a common 1,3,8-Triazaspiro[4.5]decane core: discovery of ML298 and ML299 that decrease invasive migration in U87-MG glioblastoma cells. J Med Chem 56(6):2695–2699

    PubMed  PubMed Central  Google Scholar 

  • Oguin TH et al (2014) Phospholipase D facilitates efficient entry of influenza virus, allowing escape from innate immune inhibition. J Biol Chem 289(37):25405–25417

    CAS  PubMed  PubMed Central  Google Scholar 

  • Olala LO et al (2013) A role for phospholipase D in angiotensin II-induced protein kinase D activation in adrenal glomerulosa cell models. Mol Cell Endocrinol 366(1):31–37

    CAS  PubMed  Google Scholar 

  • Oliveira TG et al (2010) Phospholipase D2 ablation ameliorates Alzheimer’s disease-linked synaptic dysfunction and cognitive deficits. J Neurosci 30(49):16419–16428

    CAS  PubMed  PubMed Central  Google Scholar 

  • O’Reilly MC et al (2014) Discovery of a highly selective PLD2 inhibitor (ML395): a new probe with improved physiochemical properties and broad-Spectrum antiviral activity against influenza strains. ChemMedChem 9(12):2633–2637

    PubMed  PubMed Central  Google Scholar 

  • Orth JD, McNiven MA (2006) Get off my back! Rapid receptor internalization through circular dorsal ruffles. Cancer Res 66(23):11094–11096

    CAS  PubMed  Google Scholar 

  • Oshimoto H et al (2003) Increased activity and expression of phospholipase D2 in human colorectal cancer. Oncol Res 14(1):31–37

    CAS  PubMed  Google Scholar 

  • Osisami M, Ali W, Frohman MA (2012) A role for phospholipase D3 in myotube formation. PLoS One 7(3):e33341

    CAS  PubMed  PubMed Central  Google Scholar 

  • Otani Y et al (2011) PLD4 is involved in phagocytosis of microglia: expression and localization changes of PLD4 are correlated with activation state of microglia. PLoS One 6(11):e27544

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pan X et al (2013) Restrictions to HIV-1 replication in resting CD4+ T lymphocytes. Cell Res 23(7):876–885

    CAS  PubMed  PubMed Central  Google Scholar 

  • Park MH, do Min S (2011) Quercetin-induced downregulation of phospholipase D1 inhibits proliferation and invasion in U87 glioma cells. Biochem Biophys Res Commun 412(4):710–715

    CAS  PubMed  Google Scholar 

  • Park SH et al (1998a) Assignment of human PLD1 to human chromosome band 3q26 by fluorescence in situ hybridization. Cytogenet Cell Genet 82(3–4):224–224

    CAS  PubMed  Google Scholar 

  • Park SH et al (1998b) Assignment of human PLD2 to chromosome band 17p13.1 by fluorescence in situ hybridization. Cytogenet Cell Genet 82(3–4):225

    CAS  PubMed  Google Scholar 

  • Park MH et al (2013a) Caffeic acid phenethyl ester downregulates phospholipase D1 via direct binding and inhibition of NFκB transactivation. Biochem Biophys Res Commun 442(1–2):1–7

    CAS  PubMed  Google Scholar 

  • Park DW et al (2013b) TLR2 stimulates ABCA1 expression via PKC-eta and PLD2 pathway. Biochem Biophys Res Commun 430(3):933–937

    CAS  PubMed  Google Scholar 

  • Plesa G et al (2007) Addition of deoxynucleosides enhances human immunodeficiency virus type 1 integration and 2LTR formation in resting CD4+ T cells. J Virol 81(24):13938–13942

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ponting CP, Kerr ID (1996) A novel family of phospholipase D homologues that includes phospholipid synthases and putative endonucleases: identification of duplicated repeats and potential active site residues. Protein Sci 5(5):914–922

    CAS  PubMed  PubMed Central  Google Scholar 

  • Puar MS et al (2000) Sch 420789. A novel fungal metabolite with phospholipase D inhibitory activity. J Antibiot 53(8):837–838

    CAS  PubMed  Google Scholar 

  • Qiu D, Kao PN (2003) Immunosuppressive and anti-inflammatory mechanisms of triptolide, the principal active diterpenoid from the Chinese medicinal herb Tripterygium wilfordii Hook. F. Drugs R D 4(1):1–18

    CAS  PubMed  Google Scholar 

  • Rappley I et al (2009) Evidence that α-synuclein does not inhibit phospholipase D. Biochemistry 48(5):1077–1083

    CAS  PubMed  PubMed Central  Google Scholar 

  • Redina OE, Frohman MA (1998a) Genomic analysis of murine phospholipase D1 and comparison to phospholipase D2 reveals an unusual difference in gene size. Gene 222(1):53–60

    CAS  PubMed  Google Scholar 

  • Redina OE, Frohman MA (1998b) Organization and alternative splicing of the murine phospholipase D2 gene. Biochem J 331(Pt 3):845–851

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saito M et al (2007) Expression of phospholipase D2 in human colorectal carcinoma. Oncol Rep 18:1329–1334

    CAS  PubMed  Google Scholar 

  • Sanematsu F et al (2013) Phosphatidic acid-dependent recruitment and function of the Rac activator DOCK1 during dorsal ruffle formation. J Biol Chem 288(12):8092–8100

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saqcena M et al (2013) Amino acids and mTOR mediate distinct metabolic checkpoints in mammalian G1 cell cycle. PLoS One 8(8):e74157

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saqib KM, Wakelam MJ (1997) Differential expression of human phospholipase D genes. Biochem Soc Trans 25(4):S586

    CAS  PubMed  Google Scholar 

  • Satoh J-i et al (2014) PLD3 is accumulated on neuritic plaques in Alzheimer’s disease brains. Alzheimer’s Res Ther 6(5–8):70

    Google Scholar 

  • Schonberger T et al (2014) Pivotal role of phospholipase D1 in tumor necrosis factor-alpha-mediated inflammation and scar formation after myocardial ischemia and reperfusion in mice. Am J Pathol 184(9):2450–2464

    PubMed  Google Scholar 

  • Sciorra VA et al (1999) Identification of a phosphoinositide binding motif that mediates activation of mammalian and yeast phospholipase D isoenzymes. EMBO J 18(21):5911–5921

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sciorra VA, Hammond SM, Morris AJ (2001) Potent direct inhibition of mammalian phospholipase D isoenzymes by calphostin-c. Biochemistry 40(8):2640–2646

    CAS  PubMed  Google Scholar 

  • Sciorra VA et al (2002) Dual role for phosphoinositides in regulation of yeast and mammalian phospholipase D enzymes. J Cell Biol 159(6):1039–1049

    CAS  PubMed  PubMed Central  Google Scholar 

  • Scott SA et al (2009) Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness. Nat Chem Biol 5(2):108–117

    CAS  PubMed  PubMed Central  Google Scholar 

  • Secor JD et al (2011) Novel lipid-soluble thiol-redox antioxidant and heavy metal chelator, N,N-bis(2-mercaptoethyl)isophthalamide (NBMI) and phospholipase D-specific inhibitor, 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) attenuate mercury-induced lipid signaling leading to protection against cytotoxicity in aortic endothelial cells. Int J Toxicol 30(6):619–638

    CAS  PubMed  PubMed Central  Google Scholar 

  • Selvy PE et al (2011) Phospholipase D: enzymology, functionality, and chemical modulation. Chem Rev 111(10):6064–6119

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sethu S, Pushparaj PN, Melendez AJ (2010) Phospholipase D1 mediates TNFalpha-induced inflammation in a murine model of TNFalpha-induced peritonitis. PLoS One 5(5):e10506

    PubMed  PubMed Central  Google Scholar 

  • Shi M et al (2007) Phospholipase D provides a survival signal in human cancer cells with activated H-Ras or K-Ras. Cancer Lett 258(2):268–275

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sorkin A et al (2000) Interaction of EGF receptor and grb2 in living cells visualized by fluorescence resonance energy transfer (FRET) microscopy. Curr Biol 10(21):1395–1398

    CAS  PubMed  Google Scholar 

  • Speranza F et al (2014) The molecular basis of leukocyte adhesion involving phosphatidic acid and phospholipase D. J Biol Chem 289(42):28885–28897

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stahelin RV et al (2004) Mechanism of membrane binding of the phospholipase D1 PX domain. J Biol Chem 279(52):54918–54926

    CAS  PubMed  Google Scholar 

  • Steed PM et al (1998) Characterization of human PLD2 and the analysis of PLD isoform splice variants. FASEB J 12(13):1309–1317

    CAS  PubMed  Google Scholar 

  • Stegner D et al (2013) Pharmacological inhibition of phospholipase D protects mice from occlusive Thrombus formation and ischemic stroke-brief report. Arterioscler Thromb Vasc Biol 33(9):2212–2217

    CAS  PubMed  Google Scholar 

  • Su W et al (2009) 5-Fluoro-2-indolyl des-chlorohalopemide (FIPI), a phospholipase D pharmacological inhibitor that alters cell spreading and inhibits chemotaxis. Mol Pharmacol 75(3):437–446

    CAS  PubMed  Google Scholar 

  • Sugars JM et al (1999) Fatty acylation of phospholipase D1 on cysteine residues 240 and 241 determines localization on intracellular membranes. J Biol Chem 274(42):30023–30027

    CAS  PubMed  Google Scholar 

  • Sulzmaier FJ et al (2012) PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D. Oncogene 31(30):3547–3560

    CAS  PubMed  Google Scholar 

  • Sung TC et al (1997) Mutagenesis of phospholipase D defines a superfamily including a trans-Golgi viral protein required for poxvirus pathogenicity. EMBO J 16(15):4519–4530

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sung TC et al (1999) Structural analysis of human phospholipase D1. J Biol Chem 274(6):3659–3666

    CAS  PubMed  Google Scholar 

  • Sung JY et al (2001) Differential activation of phospholipases by mitogenic EGF and neurogenic PDGF in immortalized hippocampal stem cell lines: activation of phospholipase C and D during neuronal differentiation. J Neurochem 78(5):1044–1053

    CAS  PubMed  Google Scholar 

  • Taylor HE et al (2015) Phospholipase D1 couples CD4+ T cell activation to c-Myc-dependent deoxyribonucleotide Pool expansion and HIV-1 replication. PLoS Pathog 11(5):e1004864

    PubMed  PubMed Central  Google Scholar 

  • Terao C et al (2013) PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population. Arthritis Rheum 65(2):472–480

    CAS  PubMed  Google Scholar 

  • Thielmann I et al (2012) Redundant functions of phospholipases D1 and D2 in platelet alpha-granule release. J Thromb Haemost 10(11):2361–2372

    CAS  PubMed  Google Scholar 

  • Tou J-S, Urbizo C (2001) Resveratrol inhibits the formation of phosphatidic acid and diglyceride in chemotactic peptide- or phorbol ester-stimulated human neutrophils. Cell Signal 13(3):191–197

    CAS  PubMed  Google Scholar 

  • Uchida N et al (1997) Increased phospholipase D activity in human breast cancer. J Cancer Res Clin Oncol 123(5):280–285

    CAS  PubMed  Google Scholar 

  • Uchida N, Okamura S, Kuwano H (1999) Phospholipase D activity in human gastric carcinoma. Anticancer Res 19(1B):671–675

    CAS  PubMed  Google Scholar 

  • Usatyuk PV et al (2009) Phospholipase D-mediated activation of IQGAP1 through Rac1 regulates hyperoxia-induced p47phox translocation and reactive oxygen species generation in lung endothelial cells. J Biol Chem 284(22):15339–15352

    CAS  PubMed  PubMed Central  Google Scholar 

  • Usatyuk PV et al (2013) Phospholipase D signaling mediates reactive oxygen species-induced lung endothelial barrier dysfunction. Pulm Circ 3(1):108–115

    CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe H et al (2004) Phospholipase D2 functions as a downstream signaling molecule of MAP kinase pathway in L1-stimulated neurite outgrowth of cerebellar granule neurons. J Neurochem 89(1):142–151

    CAS  PubMed  Google Scholar 

  • Xie Z, Ho WT, Exton JH (2001) Requirements and effects of palmitoylation of rat PLD1. J Biol Chem 276(12):9383–9391

    CAS  PubMed  Google Scholar 

  • Xu LM et al (2011) Phospholipase D mediates nutrient input to mammalian target of rapamycin complex 1 (mTORC1). J Biol Chem 286(29):25477–25486

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yamada Y et al (2003) Association of a polymorphism of the phospholipase D2 gene with the prevalence of colorectal cancer. J Mol Med 81(2):126–131

    CAS  PubMed  Google Scholar 

  • Yoon MS et al (2011) Class III PI-3-kinase activates phospholipase D in an amino acid-sensing mTORC1 pathway. J Cell Biol 195(3):435–447

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshikawa F et al (2010) Phospholipase D family member 4, a transmembrane glycoprotein with no phospholipase D activity, expression in spleen and early postnatal microglia. PLoS One 5(11):e13932

    PubMed  PubMed Central  Google Scholar 

  • Zeniou-Meyer M et al (2008) The Coffin-Lowry syndrome-associated protein RSK2 is implicated in calcium-regulated exocytosis through the regulation of PLD1. Proc Natl Acad Sci U S A 105(24):8434–8439

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y et al (2004) Increased expression of two phospholipase D isoforms during experimentally induced hippocampal mossy fiber outgrowth. Glia 46(1):74–83

    PubMed  Google Scholar 

  • Zhao C et al (2007) Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos. Nat Cell Biol 9(6):707

    Google Scholar 

  • Zheng Y et al (2006) Phospholipase D couples survival and migration signals in stress response of human cancer cells. J Biol Chem 281(23):15862–15868

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA

    Julian Gomez-Cambronero & Krushangi N. Shah

Authors
  1. Julian Gomez-Cambronero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Krushangi N. Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Krushangi N. Shah .

Editor information

Editors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, USA

    Julian Gomez-Cambronero

  2. Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA

    Michael A. Frohman

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gomez-Cambronero, J., Shah, K.N. (2019). Phospholipase D and the Mitogen Phosphatidic Acid in Human Disease: Inhibitors of PLD at the Crossroads of Phospholipid Biology and Cancer. In: Gomez-Cambronero, J., Frohman, M. (eds) Lipid Signaling in Human Diseases. Handbook of Experimental Pharmacology, vol 259. Springer, Cham. https://doi.org/10.1007/164_2019_216

Download citation

Publish with us

Policies and ethics

Search

Navigation