Phospholipase D (PLD) relays various cellular signals by modulating membrane composition and/or producing the second messenger phosphatidic acid. How its activity is regulated has remained unclear, however. Now Sung Ho Ryu and colleagues report that phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) interacts with PLD1 through its Phox homology (PX) domain, which causes PLD1 to localize to the plasma membrane and become activated.
Interactions between PX domains, found in numerous membrane-associated proteins, and phosphoinositides are important for the localization and activity of many PX-domain-containing proteins. On , the authors show that the PX domain of PLD1 interacts specifically with PtdIns(3,4,5)P3 and that mutation of a conserved arginine within the domain disrupts this binding. In addition, they report that the activity of PLD1 is stimulated in vitro by the addition of PtdIns(3,4,5)P3, which is synthesized by phosphoinositide 3-kinase (PI3K) after the activation of cell-surface-receptor kinases. Thus, the PLD1 PX domain may enable PLD1 to mediate signal transduction from PI3K by providing a binding site for PtdIns(3,4,5)P3 and by activating PLD1.
