Group IVA cytosolic phospholipase A2 (cPLA2α) and integrin αIIbβ3 reinforce each other's functions during αIIbβ3 signaling in platelets
Group IVA cytosolic phospholipase A2 (cPLA2α) and integrin αIIbβ3 reinforce each other's functions during αIIbβ3 signaling in platelets
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DOI：
10.1182/blood-2008-06-162032
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发表时间：
2009-01-08
期刊：
影响因子：
20.3
通讯作者：
Shattil, Sanford J.
中科院分区：
文献类型：
--
作者：
Prevost, Nicolas;Mitsios, John V.;Shattil, Sanford J.
IVA族胞质磷脂酶A（2）（cPLA（2）α）催化花生四烯酸从甘油磷脂中释放，导致血栓烷A（2）（TxA（2））产生。一些血小板激动剂刺激cPLA（2）α，但其他人需要纤维蛋白原结合到α IIb β 3，以引发TxA（2）。因此，检查了cPLA（2）α和α IIb β 3之间的关系。cPLA（2）α和cPLA（2）α结合伴侣波形蛋白与血小板α IIb β 3共免疫沉淀，不依赖于纤维蛋白原结合。对纯化蛋白和CHO细胞中表达的重组蛋白的研究确定cPLA（2）α和α IIb β 3之间的相互作用是间接的，并且依赖于α IIb和β 3胞质尾区。在正常血小板中，纤维蛋白原与α IIb β 3的结合引起整合素相关cPLA（2）α活性的增加，但在cPLA（2）α缺陷小鼠血小板或用吡咯苯酮（一种cPLA（2）α抑制剂）处理的人血小板中不引起。α IIb β 3下游的cPLA（2）α激活对血小板具有功能性影响，因为它是活化蛋白激酶C β向α II β b3复合物的纤维蛋白原依赖性募集和血小板扩散所必需的。因此，cPLA（2）α和α IIb β 3相互作用，在α IIb β 3信号传导过程中加强彼此的功能。这为α IIb β 3在TxA（2）形成中的作用以及在缺乏cPLA（2）α的小鼠或人血小板的止血功能缺陷中的作用提供了合理的解释。（血。2009;113：447-457）
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)