CIB1 deficiency results in impaired thrombosis: the potential role of CIB1 in outside-in signaling through integrin alpha IIb beta 3.
CIB1 deficiency results in impaired thrombosis: the potential role of CIB1 in outside-in signaling through integrin alpha IIb beta 3.
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DOI：
10.1111/j.1538-7836.2009.03581.x
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Naik UP
中科院分区：
文献类型：
--
作者：
Naik MU;Nigam A;Manrai P;Millili P;Czymmek K;Sullivan M;Naik UP
激动剂诱导的由内而外信号传导激活血小板整合素αIIbβ3，使其结合血浆纤维蛋白原（Fg）。纤维蛋白结合诱导由外向内的信号传导，最终导致血小板聚集，导致生理性止血和病理性血栓形成。通过αIIbβ3的由外向内信号传导如何调节止血和血栓形成尚不清楚。我们先前已经证明CIB 1参与调节αIIbβ3功能。确定CIB1在止血和血栓形成过程中的体内作用。Cib 1基因切除显著增加小鼠尾部出血时间。超过50%的Cib 1基因敲除小鼠表现出再出血表型。在Cib 1不存在的情况下，10%FeCl 3诱导的损伤后颈动脉完全闭塞所需的时间显著延迟。这也与不稳定血栓形成有关。由内而外的信号传导似乎是正常的，因为ADP、胶原和PAR4肽诱导的聚集和纤维蛋白原结合不受影响。Cib 1的缺乏也影响了血小板在固定化Fg上扩散的能力，但不影响丝状伪足的形成。通过加入外源性ADP可以恢复Cib 1无效血小板的铺展。通过Western印迹分析确定，在不存在Cib 1的情况下，整合素β3亚基的外向内信号传导依赖性酪氨酸磷酸化显著降低。使用基因敲除小鼠，我们首次表明缺乏Cib 1导致血栓形成受损。CIB1通过影响血小板铺展而不是血小板丝状伪足形成来调节这些过程。这些体内和体外结果清楚地表明，CIB1是血栓形成的关键调节因子。
Agonist-induced inside-out signaling activates platelet integrin αIIbβ3, rendering it to bind plasma fibrinogen (Fg). Fg binding induces outside-in signaling that culminates in platelet aggregation, leading to physiological hemostasis and pathological thrombosis. How outside-in signaling through αIIbβ3 regulates hemostasis and thrombosis is not well understood. We have previously shown that CIB1 is involved in regulating αIIbβ3 function. To determine the in vivo role of CIB1 in the process of hemostasis and thrombosis. Genetic ablation of Cib1 significantly increased mouse tail bleeding time. Greater than 50% of the Cib1 null mice showed a rebleeding phenotype. Time taken for complete occlusion of carotid artery upon 10% FeCl3-induced injury was significantly delayed in the absence of Cib1. This was also associated with unstable thrombus formation. The inside-out signaling appears normal as ADP-, collagen-and PAR4 peptide-induced aggregation and fibrinogen binding was unaffected. The absence of Cib1 also affected the ability of platelets to spread on immobilized Fg, but not filopodia formation. Spreading could be restored in Cib1 null platelets by the addition of exogenous ADP. Outside-in signaling-dependent tyrosine phosphorylation of the integrin β3 subunit was significantly reduced in the absence of Cib1 as determined by Western blot analysis. Using gene knockout mice, we show for the first time that lack of Cib1 results in impaired thrombosis. CIB1 regulates these processes by affecting platelet spreading, but not platelet filopodia formation. These in vivo and in vitro results clearly show that CIB1 is a key regulator of thrombosis.
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DOI：
10.1083/jcb.200502090
发表时间：
2005-08-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Leisner TM;Liu M;Jaffer ZM;Chernoff J;Parise LV
通讯作者：
Parise LV
影响因子：
6.7
作者：
DeNofrio, Jan C.;Yuan, Weiping;Parise, Leslie V.
通讯作者：
Parise, Leslie V.
影响因子：
4.1
作者：
Shock, DD;Naik, UP;Parise, LV
通讯作者：
Parise, LV
影响因子：
9.2
作者：
Schwer, HD;Lecine, P;Shivdasani, RA
通讯作者：
Shivdasani, RA
影响因子：
5.3
作者：
Yuan, Weiping;Leisner, Tina M.;Parise, Leslie V.
通讯作者：
Parise, Leslie V.