RT Journal Article
SR Electronic
T1 Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer
JF Pharmacological Reviews
JO Pharmacol Rev
FD American Society for Pharmacology and Experimental Therapeutics
SP 1033
OP 1079
DO 10.1124/pr.114.009217
VO 66
IS 4
A1 Ronald C. Bruntz
A1 Craig W. Lindsley
A1 H. Alex Brown
A2 David R. Sibley
YR 2014
UL http://pharmrev.aspetjournals.org/content/66/4/1033.abstract
AB 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.