CalDAG-GEFI and protein kinase C represent alternative pathways leading to activation of integrin αIIbβ3 in platelets

被引:105
作者
Cifuni, Stephen M. [1 ]
Wagner, Denisa D. [1 ,2 ]
Bergmeier, Wolfgang [1 ,3 ,4 ]
机构
[1] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[3] Thomas Jefferson Univ, Cardeza Fdn, Philadelphia, PA 19107 USA
[4] Thomas Jefferson Univ, Dept Med, Philadelphia, PA 19107 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1182/blood-2008-02-139733
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Second messenger-mediated inside-out activation of integrin (alpha IIb beta 3) is a key step in platelet aggregation. We recently showed strongly impaired but not absent (alpha IIb beta 3-mediated aggregation of CalDAG-GEFI-deficient platelets activated with various agonists. Here we further evaluated the roles of CalDAG-GEFI and protein kinase C (PKC) for alpha IIb beta 3 activation in platelets activated with a PAR4 receptor-specific agonist, GYPGKF (PAR4p). Compared with wild-type controls, platelets treated with the PKC inhibitor Ro31-8220 or CalDAG-GEFI-deficient platelets showed a marked defect in aggregation at low (< 1mM PAR4p) but not high PAR4p concentrations. Blocking of PKC function in CalDAG-GEFI-deficient platelets, however, strongly decreased aggregation at all PAR4p concentrations, demonstrating that CaIDAG-GEF1 and PKC represent separate, but synergizing, pathways important for alpha IIb beta 3 activation. PAR4p-induced aggregation in the absence of CalDAG-GEFI required cosignaling through the G(xi-coupled receptor for ADP, P2Y12. Independent roles for CalDAG-GEFI and PKC/G alpha i signaling were also observed for PAR4p-induced activation of the small GTPase Rap1, with CalDAG-GEFI mediating the rapid but reversible activation of this small GTPase. In summary, our study identifies CalDAG-GEFI and PKC as independent pathways leading to Rap1 and alpha IIb beta 3 activation in mouse platelets activated through the PAR4 receptor.
引用
收藏
页码:1696 / 1703
页数:8
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