Submitted June 10, 2008
Accepted September 15, 2008
Group IVA cytosolic phospholipase A2 (cPLA2
) and integrin IIb
3 reinforce each other's functions during IIb3 signaling in platelets
Nicolas Prevost, John V. Mitsios, Hisashi Kato, John E Burke, Edward A Dennis, Takao Shimizu, and Sanford J Shattil*
Department of Medicine, University of California San Diego, La Jolla, CA, United States
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, United States
Department of Pharmacology, University of California San Diego, La Jolla, CA, United States
Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
* Corresponding author; email: sshattil{at}ucsd.edu.
Group IVA cytosolic phospholipase A2 (cPLA2
) catalyzes release of arachidonic acid from glycerophospholipids, leading to thromboxane A2 (TxA2) production. Some platelet agonists stimulate cPLA2, but others require fibrinogen binding to IIb
3 in order to elicit TxA2. Therefore, relationships between cPLA2 and IIb3 were examined. cPLA2 and a cPLA2 binding partner, vimentin, co-immunoprecipitated with IIb3 from platelets, independent of fibrinogen binding. Studies with purified proteins and with recombinant proteins expressed in CHO cells determined that the interaction between cPLA2 and IIb3 was indirect and was dependent on the IIb and 3 cytoplasmic tails. Fibrinogen binding to IIb3 caused an increase in integrin-associated cPLA2 activity in normal platelets, but not in cPLA2-deficient mouse platelets or in human platelets treated with pyrrophenone, a cPLA2 inhibitor. cPLA2 activation downstream of IIb3 had functional consequences for platelets in that it was required for fibrinogen-dependent recruitment of activated protein kinase C to the IIb3 complex and for platelet spreading. Thus, cPLA2 and IIb3 interact to reinforce each other’s functions during IIb3 signaling. This provides a plausible explanation for the role of IIb3 in TxA2 formation and in the defective hemostatic function of mouse or human platelets deficient in cPLA2.
