Group IVA cytosolic phospholipase A2 (cPLA2α) and integrin αIIbβ3 reinforce each other's functions during αIIbβ3 signaling in platelets

Abstract

AbstractGroup IVA cytosolic phospholipase A2 (cPLA2α) catalyzes release of arachidonic acid from glycerophospholipids, leading to thromboxane A2 (TxA2) production. Some platelet agonists stimulate cPLA2α, but others require fibrinogen binding to αIIbβ3 to elicit TxA2. Therefore, relationships between cPLA2α and αIIbβ3 were examined. cPLA2α and a cPLA2α binding partner, vimentin, coimmunoprecipitated with αIIbβ3 from platelets, independent of fibrinogen binding. Studies with purified proteins and with recombinant proteins expressed in CHO cells determined that the interaction between cPLA2α and αIIbβ3 was indirect and was dependent on the αIIb and β3 cytoplasmic tails. Fibrinogen binding to αIIbβ3 caused an increase in integrin-associated cPLA2α activity in normal platelets, but not in cPLA2α-deficient mouse platelets or in human platelets treated with pyrrophenone, a cPLA2α inhibitor. cPLA2α activation downstream of αIIbβ3 had functional consequences for platelets in that it was required for fibrinogen-dependent recruitment of activated protein kinase Cβ to the αIIbβ3 complex and for platelet spreading. Thus, cPLA2α and αIIbβ3 interact to reinforce each other's functions during αIIbβ3 signaling. This provides a plausible explanation for the role of αIIbβ3 in TxA2 formation and in the defective hemostatic function of mouse or human platelets deficient in cPLA2α.