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

Phosphatidic acid‐PKA signaling regulates p38 and ERK1/2 functions in ligand‐independent EGFR endocytosis

“…45 However, the mechanism of recycling arrest under the PA/PDE4/ PKA pathway and the participation of p38 and ERK1/2 remains to be elucidated. Indeed, the complexity of PA and PLD roles in a variety of cellular processes, including cancer progression, 29,32,33 would predict other yet unknown effects of increasing PA levels with drugs such as propranolol.…”

“…[29][30][31] PLD and PA has been involved in a variety of cellular processes and cancer progression. 29,32,33 Among the proteins that bear a PA-binding domain and become stimulated by PA-binding are type 4 phosphodiesterases (PDE4), the main regulators of cAMP levels. 31,34 Drugs such as propranolol that inhibit PAP activity and impede PA hydrolysis has been used as PAP inhibitor in vesicular trafficking studies to assess the role of DAG in the generation of vesicular carriers.…”

Click chemistry and optogenetic approaches to visualize and manipulate phosphatidic acid signaling

“…A key complement to tools for visualizing spatiotemporally distinct pools of PA are approaches for perturbing these pools, with the goal of ascribing specific biological functions to them. Useful tools for loss-of-function studies include PLD knockout and a panel of potent pharmacological inhibitors of PLDs, both pan and isoform-selective (19,47). Such tools allow identification of scenarios where PLD-mediated PA is necessary for downstream events.…”

“…Small-molecule J o u r n a l P r e -p r o o f inhibitors act more rapidly than genetic manipulations such as gene knockdown and knockout, and they can have better orthogonality by separating catalytic functions of target enzymes from noncatalytic roles (e.g., protein-protein interactions). In the realm of PA metabolism, isoformselective PLD inhibitors (19) and protein-based fluorescent PA-binding probes (20)(21)(22) are useful tools to understand loss-of-function effects of specific PA pools and to visualize the total cellular population of PA. However, these tools alone do not have enough specificity to answer several important questions: Where are PLD-derived pools of PA, as opposed to pools made by other routes, synthesized?…”