Emerging Roles of Phospholipase D in Pathophysiological Signaling

Phospholipase D (PLD) is a phospholipid-hydrolyzing enzyme that generates phosphatidic acid (PA) as a lipid second messenger by hydrolyzing phosphatidyl choline (PC). Various extracellular signals have been reported to activate PLD, which acts as a key mediator of many cellular functions through the generation of PA and the interactions of PLD and PA with their binding partners. Currently, about 60 PLD-binding partners, including proteins and phospholipids, are known, and PA has been found to interact with about 50 proteins. Although the interactions of binding molecules with PLD and PA are complex and multilayered, the unique interactions between them are important for their unique intracellular functions. Here, we address the interrelationships between PLD and PA and their binding partners in several key signaling pathways, such as the EGFR–ERK signaling axis, nutrient/growth signaling axis, and cytoskeletal reorganization machinery axis. These interrelationships demonstrate dynamic interactions and cooperative regulation, which mediate special intracellular functions. Furthermore, we describe the regulation and functions of PLD in mediating normal and pathological signaling. Additionally, we summarize the roles of PLD as determined in animal studies (Drosophila, zebrafish, and mice) and changes in the PLD expression level in disease states. These findings provide new insight into the functions of PLD under pathophysiological conditions.