LYSOPHOSPHATIDIC ACID ACTIVATES PHOSPHOINOSITIDE 3-KINASE AND PHOSPHOLIPASE-C IN HUMAN PLATELETS - INHIBITORY EFFECTS OF WORTMANNIN ON PHOSPHOINOSITIDE 3-KINASE AND AGGREGATION

Lysophosphatidic acid is a biologically active serum phospholipid know n to have growth factor-like activities and to cause platelet aggregat ion. Activated phosphoinositide 3-kinase has been suggested to be invo lved in cytoskeletal reorganization and mitogenesis. We report that ly sophosphatidic acid causes platelet phosphoinositide 3-kinase activati on, leading to accumulation of phosphatidylinositol (3.4,5)P-3 and pho sphatidylinositol (3,4)P-2 and stimulates phospholipase C. Wortmannin, a potent inhibitor of phosphoinositide 3-kinase, blocks platelet aggr egation induced by lysophosphatidic acid without impairing phospholipa se C activation. Eristostatin, an antagonist of fibrinogen binding to platelet integrin, completely blocks platelet aggregation without inhi biting phosphoinositide 3-kinase or phospholipase C. We suggest that l ysophosphatidic acid, in activating phosphoinositide 3-kinase, promote s platelet aggregation, but that platelet aggregation in response to l ysophosphatidic acid does not significantly enhance phosphoinositide 3 -kinase activation. (C) 1995 Academic Press, Inc.