Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo.
Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo.
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DOI：
10.1084/jem.20071827
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发表时间：
2007-12-24
期刊：
影响因子：
--
通讯作者：
Fässler R
中科院分区：
文献类型：
--
作者：
Nieswandt B;Moser M;Pleines I;Varga-Szabo D;Monkley S;Critchley D;Fässler R
血管损伤部位的血小板粘附和聚集对正常止血至关重要，但也可能导致病理性血栓形成，引起心肌梗死或中风等疾病。整合素家族的异二聚体受体在血小板的粘附和聚集中起着核心作用。在静息血小板中，整合素对其配体表现出低亲和力状态，并在血管损伤部位转变为高亲和力状态。有人提出，细胞骨架蛋白talin1与整合素β亚基的细胞质结构域的直接结合是触发整合素激活到这种高亲和力状态的必要和充分条件，但仍然缺乏支持这一假设的直接体内证据。在这里，我们发现缺乏talin1的小鼠的血小板不能激活整合素来响应所有已知的主要血小板激动剂，而其他细胞功能仍然保留。结果，血小板缺乏talin的小鼠表现出严重的止血缺陷，并且完全抵抗动脉血栓形成。总的来说，这些实验表明talin是止血和血栓形成中血小板整合素由内向外激活所必需的。
Platelet adhesion and aggregation at sites of vascular injury are essential for normal hemostasis but may also lead to pathological thrombus formation, causing diseases such as myocardial infarction or stroke. Heterodimeric receptors of the integrin family play a central role in the adhesion and aggregation of platelets. In resting platelets, integrins exhibit a low affinity state for their ligands, and they shift to a high affinity state at sites of vascular injury. It has been proposed that direct binding of the cytoskeletal protein talin1 to the cytoplasmic domain of the integrin β subunits is necessary and sufficient to trigger the activation of integrins to this high affinity state, but direct in vivo evidence in support of this hypothesis is still lacking. Here, we show that platelets from mice lacking talin1 are unable to activate integrins in response to all known major platelet agonists while other cellular functions are still preserved. As a consequence, mice with talin-deficient platelets display a severe hemostatic defect and are completely resistant to arterial thrombosis. Collectively, these experiments demonstrate that talin is required for inside-out activation of platelet integrins in hemostasis and thrombosis.
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影响因子：
15.9
作者：
Hodivala-Dilke, KM;McHugh, KP;Hynes, RO
通讯作者：
Hynes, RO
影响因子：
64.8
作者：
REES, DJG;ADES, SE;HYNES, RO
通讯作者：
HYNES, RO
影响因子：
4.8
作者：
Yan, B;Hu, DD;Smith, JW
通讯作者：
Smith, JW
影响因子：
20.3
作者：
Grüner, S;Prostredna, M;Nieswandt, B
通讯作者：
Nieswandt, B
DOI：
10.1006/bbrc.2001.5497
发表时间：
2001-09-07
影响因子：
3.1
作者：
Monkley, SJ;Pritchard, CA;Critchley, DR
通讯作者：
Critchley, DR