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 known to have growth factor-like activities and to cause platelet aggregation. Activated phosphoinositide 3-kinase has been suggested to be involved in cytoskeletal reorganization and mitogenesis. We report that lysophosphatidic acid causes platelet phosphoinositide 3-kinase activation, leading to accumulation of phosphatidylinositol (3, 4, 5) P3 and phosphatidylinositol (3, 4) P2, and stimulates phospholipase C. Worthmannin, a potent inhibitor of phosphoinositide 3-kinase, blocks platelet aggregation induced by lysophosphatidic acid without impairing phospholipase C activation. Eristostatin, an antagonist of fibrinogen binding to platelet integrin, completely blocks platelet aggregation without inhibiting phosphoinositide 3-kinase or phospholipase C. We suggest that lysophosphatidic acid, in activating phosphoinositide 3-kinase, promotes platelet aggregation, but that platelet aggregation in response to lysophosphatidic acid does not significantly enhance phosphoinositide 3-kinase activation.
Zhang
J
J
Department of Pharmacology/Jefferson Cancer Institute, Philadelphia, PA, USA.
Rittenhouse
S E
SE
D000730:Androstadienes / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008246:Lysophospholipids / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000097:blood*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D010738:Type C Phospholipases / Q000097:blood*; D014757:Viper Venoms / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D014757:Viper Venoms; C084060:eristostatin; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D010738:Type C Phospholipases; D000077191:Wortmannin