Platelet/endothelial cell adhesion molecule-1 serves as a costimulatory agonist receptor that modulates integrin-dependent adhesion and aggregation of human platelets
Platelet/endothelial cell adhesion molecule-1 serves as a costimulatory agonist receptor that modulates integrin-dependent adhesion and aggregation of human platelets
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DOI：
10.1182/blood.v91.2.500.500_500_507
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发表时间：
1998-01-15
期刊：
影响因子：
20.3
通讯作者：
Newman, PJ
中科院分区：
文献类型：
--
作者：
Varon, D;Jackson, DE;Newman, PJ
血小板/内皮细胞粘附分子-1 (PECAM-1) 是 lg 基因超家族的 130 kD 成员，在循环血小板、单核细胞、中性粒细胞和选择性 T 细胞亚群的表面表达。它也是内皮细胞细胞间连接的主要成分。先前的研究表明，白细胞表面的 PECAM-1 交联会导致 β(1) 和 β(2) 整合素家族粘附分子的激活。此外，白细胞跨内皮迁移的过程似乎至少部分是由白细胞和内皮细胞连接PECAM-1分子之间发生的同质粘附相互作用介导的。然而，人们对这种膜糖蛋白在人类血小板中的功能作用知之甚少。在本研究中，我们检查了 PECAM-1 参与对整合素介导的血小板-细胞外基质或血小板-血小板相互作用的影响。在改良的锥板粘度计中，在振荡或限定的低剪切流条件 (200 s(-1)) 下，对近膜 lg 同源结构域 6 特异的二价而非单价抗 PECAM-1 单克隆抗体 (MoAb) 显着增强血小板沉积（增加表面覆盖）和聚集（增加平均大小）到细胞外基质上。此外，二价抗结构域 6 MoAb 能够作为共刺激激动剂，显着增强二磷酸腺苷 (ADP) 和血小板激活因子 (PAF) 诱导的血小板聚集反应。这些抗体似乎通过 PECAM-1 由外向内的信号转导发挥作用，事实证明，它们的结合 (1) 导致 α(IIb)beta(3) 整联蛋白复合物发生构象变化，(2) 诱导 P-选择素的表面表达，(3) 导致 PECAM-1 的酪氨酸磷酸化。总之，这些数据支持 PECAM-1 在细胞激活中的作用，并表明 PECAM-1 可能作为共刺激激动剂受体，能够在粘附和聚集过程中调节人血小板中的整合素功能。 (C) 1998 年，美国血液学会。
Platelet/endothelial cell adhesion molecule-1 (PECAM-1) is a 130-kD member of the lg gene superfamily that is expressed on the surface of circulating platelets, monocytes, neutrophils, and selective T-cell subsets. It is also a major component of the endothelial cell intercellular junction. Previous studies have shown that cross-linking PECAM-1 on the surface of leukocytes results in the activation of adhesion molecules of both the beta(1) and beta(2) integrin family. In addition, the process of leukocyte transendothelial migration appears to be mediated, at least in part, by homophilic adhesive interactions that take place between leukocyte and endothelial cell junctional PECAM-1 molecules. However, little is known about the functional role of this membrane glycoprotein in human platelets. In the present study, we examined the effects of PECAM-1 engagement on integrin-mediated platelet-extracellular matrix or platelet-platelet interactions. Bivalent, but not monovalent, anti-PECAM-1 monoclonal antibodies (MoAbs) specific for membrane-proximal lg-homology domain 6 significantly augmented platelet deposition (increased surface coverage) and aggregation (increased average size) onto extracellular matrix, under both oscillatory or defined low shear flow conditions (200 s(-1)) in a modified cone and plate viscometer. Moreover, bivalent anti-domain 6 MoAbs were capable of serving as costimulatory agonists to markedly enhance both adenosine diphosphate (ADP)- and platelet activating factor (PAF)-induced platelet aggregation responses. These antibodies appeared to act via outside-in signal transduction through PECAM-1, as evidenced by the fact that their binding (1) led to conformational changes in the alpha(IIb)beta(3) integrin complex, (2) induced surface expression of P-selectin, and (3) resulted in the tyrosine phosphorylation of PECAM-1. Together, these data support a role for PECAM-1 in cellular activation and suggest that PECAM-1 may serve as a costimulatory agonist receptor capable of modulating integrin function in human platelets during adhesion and aggregation. (C) 1998 by The American Society of Hematology.