A putative protein tyrosine phosphatase inhibitor, phenylarsine oxide (PAO),potentiated phospholipase D (PLD) activity concentration-dependently in [H-3] oleic acid-labeled rat basophilic leukemia (RBL-2H3) cells without significant increase in phosphatidylinositol-specific plospholipase C (PI-PLC) activity. Although PAO induced tyrosine phosphorylation of several proteins, both PAO-induced PLD activation and tyrosine phosphorylation were not affected by a protein tyrosine kinase inhibitor, genistein. Another tyrosine kinase inhibitor, herbimycin A, prevented the PAO-induced PLD stimulation but had no effect on protein tyrosine phosphorylation. However, depletion of protein kinase C (PKC) greatly reduced PAO-stimulated PLD activity. These results indicate that PKC but not tyrosine kinase may be involved in PAO-mediated PLD activation. (C) 1994 Academic Press, Inc.