Integrin αIIb-mediated PI3K/Akt activation in platelets.
Integrin αIIb-mediated PI3K/Akt activation in platelets.
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整联蛋白αIIB介导的PI3K/AKT在血小板中激活。
DOI：
10.1371/journal.pone.0047356
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Niu H;Chen X;Gruppo RA;Li D;Wang Y;Zhang L;Wang K;Chai W;Sun Y;Ding Z;Gartner TK;Liu J
整合素αIIbβ3介导的双向信号传导在血栓形成和止血中起关键作用。β3亚基介导的信号传导已被广泛研究，但αIIb介导的信号传导尚未表征。以前，我们报道了αIIb介导的由外向内信号转导诱导的血小板颗粒分泌和TxA 2产生受β3胞浆结构域残基R724 KEFAKFEEER 734负调控。在这项研究中，我们确定了αIIb介导的由外向内信号传导所利用的部分信号通路。来自人和基因缺陷小鼠的血小板，和遗传修饰的CHO细胞以及各种激酶抑制剂用于这项工作。我们发现，由αIIb介导的由外向内的信号传导启动的β3Δ724人血小板的TxA 2产生和颗粒分泌的聚集分别被Src家族激酶抑制剂PP 2和PI 3 K抑制剂wortmannin抑制，但不被MAPK抑制剂U 0126抑制。此外，PP 2和渥曼青霉素以及棕榈酰化的β3肽R724 KEFAKFEEER 734均抑制Akt残基Ser 473的磷酸化，并阻止TxA 2的产生和储存颗粒的分泌。类似地，由PAR 4激动剂肽AYPGKF刺激的小鼠血小板中Akt磷酸化是αIIbβ3依赖性的，并且被PP 2、渥曼青霉素和棕榈酰化肽p-RKEFAKFEER阻断。在表达αIIbβ3-Δ724或αIIbβ 3E 724 AERKFERKFE 734的CHO细胞悬浮液中，经mAb D3加Fg处理后，Akt也发生磷酸化，但在表达野生型αIIbβ3的细胞中未发生。总之，α IIb介导的由外向内信号传导利用SFK（s）和PI 3 K/Akt信号传导激活血小板，即使在β3胞质结构域的所有膜近端残基（除8个外）缺失的情况下也是如此。我们的研究结果为血小板中α IIb介导的由外向内信号传导所使用的信号通路提供了新的见解。
Integrin αIIbβ3 mediated bidirectional signaling plays a critical role in thrombosis and haemostasis. Signaling mediated by the β3 subunit has been extensively studied, but αIIb mediated signaling has not been characterized. Previously, we reported that platelet granule secretion and TxA2 production induced by αIIb mediated outside-in signaling is negatively regulated by the β3 cytoplasmic domain residues R724KEFAKFEEER734. In this study, we identified part of the signaling pathway utilized by αIIb mediated outside-in signaling. Platelets from humans and gene deficient mice, and genetically modified CHO cells as well as a variety of kinase inhibitors were used for this work. We found that aggregation of TxA2 production and granule secretion by β3Δ724 human platelets initiated by αIIb mediated outside-in signaling was inhibited by the Src family kinase inhibitor PP2 and the PI3K inhibitor wortmannin, respectively, but not by the MAPK inhibitor U0126. Also, PP2 and wortmannin, and the palmitoylated β3 peptide R724KEFAKFEEER734, each inhibited the phosphorylation of Akt residue Ser473 and prevented TxA2 production and storage granule secretion. Similarly, Akt phosphorylation in mouse platelets stimulated by the PAR4 agonist peptide AYPGKF was αIIbβ3-dependent, and blocked by PP2, wortmannin and the palmitoylated peptide p-RKEFAKFEEER. Akt was also phosphorylated in response to mAb D3 plus Fg treatment of CHO cells in suspension expressing αIIbβ3-Δ724 or αIIbβ3E724AERKFERKFE734, but not in cells expressing wild type αIIbβ3. In summary, SFK(s) and PI3K/Akt signaling is utilized by αIIb-mediated outside-in signaling to activate platelets even in the absence of all but 8 membrane proximal residues of the β3 cytoplasmic domain. Our results provide new insight into the signaling pathway used by αIIb-mediated outside-in signaling in platelets.
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影响因子：
6.7
作者：
Derrick, JM;Shattil, SJ;Gartner, TK
通讯作者：
Gartner, TK
DOI：
10.1083/jcb.200703185
发表时间：
2007-11-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Flevaris P;Stojanovic A;Gong H;Chishti A;Welch E;Du X
通讯作者：
Du X
影响因子：
20.3
作者：
Naik, UP;Naik, MU
通讯作者：
Naik, MU
影响因子：
3.7
作者：
Kahner BN;Kato H;Banno A;Ginsberg MH;Shattil SJ;Ye F
通讯作者：
Ye F
影响因子：
4.8
作者：
Deshmukh, Lalit;Meller, Nahum;Vinogradova, Olga
通讯作者：
Vinogradova, Olga