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PLD and Cancer 1521-0081/66/4/1033–1079$25.00 http://dx.doi.org/10.1124/pr.114.009217 PHARMACOLOGICAL REVIEWS Pharmacol Rev 66:1033–1079, October 2014 Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: DAVID R. SIBLEY Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer Ronald C. Bruntz, Craig W. Lindsley, and H. Alex Brown Department of Pharmacology (R.C.B., C.W.L., H.A.B.) and Vanderbilt Center for Neuroscience Drug Discovery (C.W.L.), Vanderbilt University Medical Center; Department of Chemistry, Vanderbilt Institute of Chemical Biology (C.W.L., H.A.B.); Vanderbilt Specialized Chemistry for Accelerated Probe Development (C.W.L.); and Department of Biochemistry, Vanderbilt-Ingram Cancer Center (H.A.B.), Vanderbilt University, Nashville, Tennessee Abstract ..................................................................................1035 Downloaded from I. Background. .............................................................................1035 A. Structure and Mechanism . ...........................................................1036 B. Localization and Tissue Distribution . ...............................................1037 II. Regulation of Phospholipase D Activity by Lipids . .........................................1037 A. Phosphoinositides .....................................................................1037 pharmrev.aspetjournals.org B. Fatty Acids ...........................................................................1038 C. Lipid Modifications . .................................................................1039 III. Phosphorylation . .......................................................................1039 A. Serine and Threonine Phosphorylation . ...............................................1039 B. Tyrosine Phosphorylation . ...........................................................1040 IV. Protein Activators of Phospholipase D .....................................................1041 A. Protein Kinase C......................................................................1041 B. ADP-Ribosylation Factor GTPases.....................................................1042 at Univ Of North Dakota on January 31, 2015 C. Rho GTPases . .......................................................................1043 D. Ras and Ral GTPases .................................................................1044 E. Rheb GTPases . .......................................................................1044 F. Non–G Protein/Protein Kinase C Regulators of Phospholipase D .......................1044 1. Protein Kinase N.. .................................................................1044 2. Cofilin. ............................................................................1044 3. C-Terminal Binding Protein 1. .....................................................1044 V. Phospholipase D Inhibitory Proteins . .....................................................1045 A. Synaptic Vesicle Proteins . ...........................................................1045 B. Miscellaneous Phospholipase D Inhibitors .............................................1045 VI. Cell Surface Receptor Regulation of Phospholipase D . ....................................1046 A. Receptor Tyrosine Kinases . ...........................................................1046 B. G Protein–Coupled Receptors .........................................................1048 VII. Functions of Phospholipase D Contributing to Cancer. ....................................1049 A. Sustaining Proliferative Signaling .....................................................1050 B. Mitogen-Activated Protein Kinase .....................................................1050 C. Mammalian Target of Rapamycin .....................................................1052 D. Evading Growth Suppression..........................................................1053 This research was supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grant P01- ES013125]; the National Institutes of Health National Institute of Mental Health [Grant U54-MH084659]; the McDonnell Foundation for Brain Cancer Research; Voices Against Brain Cancer; and the Vanderbilt Institute of Chemical Biology [Lai Sulin scholarship (to R.C.B.), Bixler-Johnson-Mayes Endowed Chair (to H.A.B.), and the William K. Warren Jr. Chair in Medicine (to C.W.L.)]. Vanderbilt University is a member of the National Institutes of Health Molecular Libraries Probe Production Centers Network and houses the Vanderbilt Specialized Chemistry Center for Accelerated Probe Development. Address correspondence to: Dr. H. Alex Brown, Vanderbilt University School of Medicine, 2220 Pierce Avenue South, Nashville, TN 37232-6600. E-mail: [email protected] Portions of this review appeared in the following: Bruntz RC (2013) Insights into the Molecular Mechanisms of Phospholipase D–Mediated Cancer Cell Survival. Doctoral dissertation, Vanderbilt University, Nashville, TN. dx.doi.org/10.1124/pr.114.009217. 1033 1034 Bruntz et al. E. Resisting Cell Death . .................................................................1054 1. Apoptosis. .......................................................................1054 2. Autophagy. .......................................................................1055 F. Activating Invasion and Metastasis....................................................1057 G. Inducing Angiogenesis ................................................................1060 H. Deregulating Cellular Energetics . .....................................................1061 VIII. Phospholipase D Small-Molecule Inhibitors. ...............................................1062 IX. Functions of Phosphatidic Acid. ...........................................................1064 A. Kinases. .............................................................................1065 1. Sphingosine Kinase 1. ...........................................................1065 2. Protein Kinase C«..................................................................1066 3. Protein Kinase Cd..................................................................1067 4. Protein Kinase Cz..................................................................1067 5. Protein Kinase Ca. ................................................................1067 6. Akt. .............................................................................1067 B. Phosphatases . .......................................................................1067 1. Src Homology Region 2 Domain-Containing Phosphatase-1.. ........................1067 2. Lipin1b............................................................................1067 C. Phospholipase C ......................................................................1067 1. Phospholipase Cb1.................................................................1067 2. Phospholipase Cg1.................................................................1067 3. Phospholipase C«. .................................................................1067 4. Phospholipase Cd3.................................................................1068 D. G Protein Regulatory Proteins.........................................................1068 1. RA-Rho GTPase Activating Protein. ...............................................1068 2. ADP-Ribosylation Factor GTPase Activating Proteins. ..............................1068 3. n-Chimaerin. ......................................................................1068 4. Regulator of G Protein Signaling 4. ...............................................1068 E. Miscellaneous Proteins ................................................................1068 1. NADPH Oxidase. .................................................................1068 2. Neurogranin. ......................................................................1068 3. Sin1. .............................................................................1069 4. ADP/ATP Translocase. ...........................................................1069 5. b-Coatomer, ADP-Ribosylation Factor, N-Ethylmaleimide–Sensitive Factor, and Kinesin........................................................................1069 ABBREVIATIONS: 4E-BP1, 4E binding protein 1; AC, adenylyl cyclase; AMPK, AMP-activated protein kinase; AP3, assembly protein 3; Arf, ADP- ribosylation factor; ASAP1, Arf-GAP with SH3 domain, ANK repeat and PH domain–containing protein 1; Bcl-2, B-cell lymphoma 2; Cdk5, cyclin- dependent kinase 5; CL, cardiolipin; CNS, central nervous system; CR, conserved region; CRMP-2, collapsin response mediator protein-2; CtBP1, C-terminal binding protein 1; DAG, diacylglycerol; DMPK, drug metabolism and pharmacokinetics; DOCK2, dedicator of cytokinesis 2; ECM, extracellular matrix; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; Egr1, early growth response protein 1; EMT, epithelial– mesenchymal transition; Epac1, exchange protein directly activated by cAMP 1; ERK, extracellular signal-regulated kinase; FIPI, N-(2-(4-(2,3-dihydro-2- oxo-1H-benzimidazol-1-yl)-1-piperidinyl)ethyl)-5-fluoro-1H-indole-2-carboxamide; FGF, fibroblast growth factor; FKBP12, FK506 binding protein 12; FRB, FKBP12-rapamycin binding; GAP, GTPase activating protein; GDI, guanine nucleotide dissociation inhibitor; GEF, guanine nucleotide exchange factor; GPCR, G protein–coupled receptor; GPI, glycosylphosphatidylinositol; GRK, G protein–coupled receptor kinase; GTPgS,
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