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Review ArticleReview Article

Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer

Ronald C. Bruntz, Craig W. Lindsley and H. Alex Brown
David R. Sibley, ASSOCIATE EDITOR
Pharmacological Reviews October 2014, 66 (4) 1033-1079; DOI: https://doi.org/10.1124/pr.114.009217
Ronald C. Bruntz
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
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Craig W. Lindsley
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
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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
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David R. Sibley
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
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Abstract

Phospholipase D is a ubiquitous class of enzymes that generates phosphatidic acid as an intracellular signaling species. The phospholipase D superfamily plays a central role in a variety of functions in prokaryotes, viruses, yeast, fungi, plants, and eukaryotic species. In mammalian cells, the pathways modulating catalytic activity involve a variety of cellular signaling components, including G protein–coupled receptors, receptor tyrosine kinases, polyphosphatidylinositol lipids, Ras/Rho/ADP-ribosylation factor GTPases, and conventional isoforms of protein kinase C, among others. Recent findings have shown that phosphatidic acid generated by phospholipase D plays roles in numerous essential cellular functions, such as vesicular trafficking, exocytosis, autophagy, regulation of cellular metabolism, and tumorigenesis. Many of these cellular events are modulated by the actions of phosphatidic acid, and identification of two targets (mammalian target of rapamycin and Akt kinase) has especially highlighted a role for phospholipase D in the regulation of cellular metabolism. Phospholipase D is a regulator of intercellular signaling and metabolic pathways, particularly in cells that are under stress conditions. This review provides a comprehensive overview of the regulation of phospholipase D activity and its modulation of cellular signaling pathways and functions.

Footnotes

  • 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.

  • 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.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 66 (4)
Pharmacological Reviews
Vol. 66, Issue 4
1 Oct 2014
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Review ArticleReview Article

PLD and Phosphatidic Acid in Cancer

Ronald C. Bruntz, Craig W. Lindsley and H. Alex Brown
Pharmacological Reviews October 1, 2014, 66 (4) 1033-1079; DOI: https://doi.org/10.1124/pr.114.009217

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Review ArticleReview Article

PLD and Phosphatidic Acid in Cancer

Ronald C. Bruntz, Craig W. Lindsley and H. Alex Brown
Pharmacological Reviews October 1, 2014, 66 (4) 1033-1079; DOI: https://doi.org/10.1124/pr.114.009217
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  • Article
    • Abstract
    • I. Background
    • II. Regulation of Phospholipase D Activity by Lipids
    • III. Phosphorylation
    • IV. Protein Activators of Phospholipase D
    • V. Phospholipase D Inhibitory Proteins
    • VI. Cell Surface Receptor Regulation of Phospholipase D
    • VII. Functions of Phospholipase D Contributing to Cancer
    • VIII. Phospholipase D Small-Molecule Inhibitors
    • IX. Functions of Phosphatidic Acid
    • X. Closing Points
    • Acknowledgments
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