The small GTPase Rap1b regrulates the cross talk between platelet integrin α2β1 and integrin αIIbβ3
The small GTPase Rap1b regrulates the cross talk between platelet integrin α2β1 and integrin αIIbβ3
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DOI：
10.1182/blood-2005-07-3023
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发表时间：
2006-04-01
期刊：
影响因子：
20.3
通讯作者：
Torti, M
中科院分区：
文献类型：
--
作者：
Bernardi, B;Guidetti, GF;Torti, M
研究了小GT受体Rap 1b在血小板整合素α（2）β（1）依赖性由外向内信号传导中的参与。血小板粘附于整合素α（2）β（1）、单体胶原、核心蛋白聚糖和胶原衍生肽CB 8（II）和CB 11（II）的4种不同的特异性配体，诱导Rap 1b的稳健和快速活化。这一过程不需要分泌ADP或血栓素A（2）的产生，但受磷脂酶C（PLC）衍生的第二信使的关键调节。发现Ca 2+和蛋白激酶C都组织了整合素-α（2）β（1）下游的Rap 1b激活的独立但附加的途径，这些途径被U 73122抑制PLC完全阻断。此外，尽管PLC γ 2的磷酸化和活化正常，但整合素α 2 β 1的结合未能在缺乏CaIDAG-GEFI（一种由Ca 2+和甘油二酯调节的鸟嘌呤核苷酸交换因子）的小鼠血小板中触发Rap 1b活化。此外，CaIDAG-GEFI缺陷型血小板表现出整合素α（2）β（1）依赖性粘附和扩散缺陷。我们发现，通过整合素α（2）β（1）的由外向内的信号传导触发了整合素α（IIb）β（3）的由内而外的激活，并促进了纤维蛋白原的结合。与Rap 1b刺激类似，该过程发生在PLC激活的下游，并且在缺乏Rap 1交换因子CaIDAGGEFI的小鼠血小板中显著受损。这些结果表明，Rap 1b是血小板粘附过程中整合素依赖的外向内信号传导的重要元素，并调节粘附受体之间的串扰。
The involvement of the small GTPase Rap1b in platelet integrin alpha(2)beta(1)-dependent outside-in signaling was investigated. Platelet adhesion to 4 different specific ligands for integrin alpha(2)beta(1), monomeric collagen, decorin, and collagen-derived peptides CB8(II) and CB11(II), induced a robust and rapid activation of Rap1b. This process did not require secreted ADP or thromboxane A(2) production but was critically regulated by phospholipase C (PLC)derived second messengers. Both Ca2+ and protein kinase C were found to organize independent but additive pathways for Rap1b activation downstream of integrin-alpha(2)beta(1), which were completely blocked by inhibition of PLC with U73122. Moreover, integrin alpha(2)beta(1) engagement failed to trigger Rap1b activation in murine platelets lacking CaIDAG-GEFI, a guanine nucleotide exchange factor regulated by Ca2+ and diacylglycerol, despite normal phosphorylation and activation of PLC gamma 2. In addition, CaIDAG-GEFI-deficient platelets showed defective integrin alpha(2)beta(1)-dependent adhesion and spreading. We found that outside-in signaling through integrin alpha(2)beta(1) triggered inside-out activation of integrin alpha(IIb)beta(3) and promoted fibrinogen binding. Similarly to Rap1b stimulation, this process occurred downstream of PLC activation and was dramatically impaired in murine platelets lacking the Rap1 exchange factor CaIDAGGEFI. These results demonstrate that Rap1b is an important element in integrin-dependent outside-in signaling during platelet adhesion and regulates the cross talk between adhesive receptors.