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

Group IVA cytosolic phospholipase A(2) (cPLA(2)alpha) catalyzes release of arachidonic acid from glycerophospholipids, leading to thromboxane A(2) (TxA(2)) production. Some platelet agonists stimulate cPLA(2)alpha, but others require fibrinogen binding to alpha IIb beta 3 to elicit TxA(2). Therefore, relationships between cPLA(2)alpha and alpha IIb beta 3 were examined. cPLA(2)alpha and a cPLA(2)alpha binding partner, vimentin, coimmunoprecipitated with alpha IIb beta 3 from platelets, independent of fibrinogen binding. Studies with purified proteins and with recombinant proteins expressed in CHO cells determined that the interaction between cPLA(2)alpha and alpha IIb beta 3 was indirect and was dependent on the alpha IIb and beta 3 cytoplasmic tails. Fibrinogen binding to alpha IIb beta 3 caused an increase in integrin-associated cPLA(2)alpha activity in normal platelets, but not in cPLA(2)alpha-deficient mouse platelets or in human platelets treated with pyrrophenone, a cPLA(2)alpha inhibitor. cPLA(2)alpha activation down-stream of alpha IIb beta 3 had functional consequences for platelets in that it was required for fibrinogen-dependent recruitment of activated protein kinase C beta to the alpha II beta b3 complex and for platelet spreading. Thus, cPLA(2)alpha and alpha IIb beta 3 interact to reinforce each other's functions during alpha IIb beta 3 signaling. This provides a plausible explanation for the role of alpha IIb beta 3 in TxA(2) formation and in the defective hemostatic function of mouse or humanplatelets deficient in cPLA(2)alpha. (Blood. 2009;113:447-457)