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首页> 外文期刊>American Journal of Physiology >Pathological shear stress directly regulates platelet alphaIIbbeta3 signaling.
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Pathological shear stress directly regulates platelet alphaIIbbeta3 signaling.

机译：病理切应力直接调节血小板alphaIIbbeta3信号。

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Integrin mechanotransduction is a ubiquitous biological process. Mechanical forces are transduced transmembranously by an integrin's ligand-bound extracellular domain through its beta-subunit's cytoplasmic domain connected to the cytoskeleton. This often culminates in the activation of tyrosine kinases directing cell responses. The delicate balance between hemostasis and thrombosis requires exquisitely fine-tuned integrin function, and balance is maintained in vivo despite that the major platelet integrin alpha(IIb)beta(3) is continuously subjected to frictional or shearing forces generated by laminar blood flow. To test the hypothesis that platelet function is regulated by the direct effects of mechanical forces on alpha(IIb)beta(3), we examined alpha(IIb)beta(3)/cytoskeletal interactions in human platelets exposed to shear stress in a cone-plate viscometer. We observed that alpha-actinin, myosin heavy chain, and Syk coimmunoprecipitate with alpha(IIb)beta(3) in resting platelets and that 120 dyn/cm(2) shear stress leads to their disassociation from alpha(IIb)beta(3). Shear-induced disassociation of alpha-actinin and myosin heavy chain from the beta(3) tail is unaffected by blocking von Willebrand factor (VWF) binding to glycoprotein (Gp) Ib-IX-V but abolished by blocking VWF binding to alpha(IIb)beta(3). Syk's disassociation from beta(3) is inhibited when VWF binding to either GpIb-IX-V or alpha(IIb)beta(3) is blocked. Shear stress-induced phosphorylation of SLP-76 and its association with tyrosine-phosphorylated adhesion and degranulation-promoting adapter protein are inhibited by blocking ligand binding to alpha(IIb)beta(3) but not by blocking ligand binding to GpIb-IX-V. Chinese hamster ovary cells expressing alpha(IIb)beta(3) with beta(3) truncated of its cytoskeletal binding domains demonstrate diminished shear-dependent adhesion and cohesion. These results support the hypothesis that shear stress directly modulates alpha(IIb)beta(3) function and suggest that shear-induced alpha(IIb)beta(3)-mediated signaling contributes to the regulation of platelet aggregation by directing the release of constraining cytoskeletal elements from the beta(3)-tail.
机译：整联蛋白机械转导是普遍存在的生物学过程。整联蛋白的配体结合的胞外域通过连接至细胞骨架的β亚基的胞质域跨膜地传导机械力。这通常最终导致指导细胞反应的酪氨酸激酶的激活。止血和血栓形成之间的微妙平衡需要精细调节整联蛋白功能，尽管主要血小板整联蛋白α（IIb）β（3）不断受到层流血流产生的摩擦力或剪切力，但体内仍保持平衡。为了测试这一假设，即血小板功能受机械力对alpha（IIb）beta（3）的直接影响所调节，我们检查了暴露于剪切应力下的圆锥体中人类血小板中的alpha（IIb）beta（3）/细胞骨架相互作用。平板粘度计。我们观察到α-肌动蛋白，肌球蛋白重链和Syk coimmunoprecipitate与静止血小板中的alpha（IIb）beta（3）和120 dyn / cm（2）剪切应力导致它们与alpha（IIb）beta（3）分离。剪切诱导的α-肌动蛋白和肌球蛋白重链从beta（3）尾部的解离不受阻断von Willebrand因子（VWF）与糖蛋白（Gp）Ib-IX-V结合的影响，但由于阻断VWF与α（IIb）结合而被废除）beta（3）。当VWF与GpIb-IX-V或alpha（IIb）beta（3）的结合被阻止时，Syk从beta（3）的解离被抑制。剪应力诱导的SLP-76磷酸化及其与酪氨酸磷酸化粘附和脱粒促进衔接蛋白的缔合通过阻断配体与alpha（IIb）beta（3）的结合而受到抑制，但不受阻断配体与GpIb-IX-V的结合而被抑制。中国仓鼠卵巢细胞表达的alpha（IIb）beta（3）与其细胞骨架结合域被截断的beta（3）显示减少剪切依赖性粘附和内聚。这些结果支持这样的假设，即剪应力直接调节alpha（IIb）beta（3）的功能，并表明剪切诱导的alpha（IIb）beta（3）介导的信号通过指导约束性细胞骨架的释放而有助于血小板聚集的调节。 beta（3）-tail中的元素。

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