Regulation of phospholipase D by phosphorylation-dependent mechanisms

The rapid production of phosphatidic acid following receptor stimulation ha s been demonstrated in a wide range of mammalian cells. Virtually every cel l uses phosphatidylcholine as substrate to produce phosphatidic acid in a c ontrolled reaction catalyzed by specific PLD isoforms. Considerable effort has been directed at studying the regulation of PLD activities and subseque nt work has characterized a family of proteins including PLD1 and PLD2. Whe reas both PLD enzymes are dependent on phosphatidylinositol 4,5-bisphosphat e for activity only the PLD1 isoform was strongly stimulated by the small G TPases ARF and RhoA and by protein kinase Ca as well. A role for tyrosine k inase activities in the membrane recruitment of small GTPases, in the synth esis of phosphatidylinositol 4,5-bisphosphate and tyrosine phosphorylation of PLD1 and PLD2 has been uncovered. However, it still not clear exactly ho w tyrosine phosphorylation of proteins contributes to PLD activation in cel ls. Here we review the data linking tyrosine phosphorylation of proteins to the activation of PLD and describe recent finding on the sites and possibl e mechanisms of action of tyrosine kinases in receptor-mediated PLD activat ion. Finally, a model illustrating the potential complex interplay linking these signaling events with the activation of PLD is presented. (C) 1999 El sevier Science B.V. All rights reserved.