title: Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer.
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.
authors.affiliation: 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.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Bruntz
authors.affiliation: 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.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: 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 alex.brown@Vanderbilt.edu.
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
mesh_terms: D000818:Animals; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000473:pathology* / Q000628:therapy; D010712:Phosphatidic Acids / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D010712:Phosphatidic Acids; D010739:Phospholipase D