Platelets are essential for wound healing and inflammatory processes, but can also play a deleterious role by causing heart attack and stroke. Normal platelet activation is dependent on tetraspanins, a superfamily of glycoproteins that function as 'organisers' of cell membranes by recruiting other receptors and signalling proteins into tetraspanin-enriched microdomains. However, our understanding of how tetraspanin microdomains regulate platelets is hindered by the fact that only four of the 33 mammalian tetraspanins have been identified in platelets. This is because of a lack of antibodies to most tetraspanins and difficulties in measuring mRNA, due to low levels in this anucleate cell. To identify potentially platelet-expressed tetraspanins, mRNA was measured in their nucleated progenitor cell, the megakaryocyte, using serial analysis of gene expression and DNA microarrays. Amongst 19 tetraspanins identified in megakaryocytes, Tspan9, a previously uncharacterized tetraspanin, was relatively specific to these cells. Through generating the first Tspan9 antibodies, Tspan9 expression was found to be tightly regulated in platelets. The relative levels of CD9, CD151, Tspan9 and CD63 were 100, 14, 6 and 2 respectively. Since CD9 was expressed at 49000 cell surface copies per platelet, this suggested a copy number of 2800 Tspan9 molecules. Finally, Tspan9 was shown to be a component of tetraspanin microdomains that included the collagen receptor GPVI (glycoprotein VI) and integrin alpha6beta1, but not the von Willebrand receptor GPIbalpha or the integrins alphaIIbbeta3 or alpha2beta1. These findings suggest a role for Tspan9 in regulating platelet function in concert with other platelet tetraspanins and their associated proteins.

译文

血小板对伤口愈合和炎症过程至关重要,但也可能通过引起心脏病发作和中风而发挥有害作用。正常的血小板活化依赖于tetaspanins,tetaspanins是一种糖蛋白的超家族,通过将其他受体和信号蛋白募集到富含tetaspanin的微域中而充当细胞膜的 “组织者”。但是,由于在血小板中仅鉴定了33种哺乳动物的四氮平蛋白中的四种,因此阻碍了我们对四氮平蛋白微结构域如何调节血小板的理解。这是因为缺乏针对大多数四棘蛋白的抗体,并且由于该无核细胞中的低水平而难以测量mRNA。为了鉴定潜在的血小板表达的四棘蛋白,使用基因表达和DNA微阵列的系列分析来测量其有核祖细胞 (巨核细胞) 中的mRNA。在巨核细胞中鉴定出的19种四棘蛋白中,Tspan9 (以前未鉴定的四棘蛋白) 对这些细胞相对特异。通过产生第一个Tspan9抗体,发现Tspan9表达在血小板中受到严格调节。CD9、CD151、Tspan9和CD63的相对水平分别为100、14、6和2。由于CD9以每血小板49000个细胞表面拷贝表达,这提示了2800个Tspan9分子的拷贝数。最后,Tspan9被证明是四棘蛋白微结构域的组成部分,其中包括胶原蛋白受体GPVI (糖蛋白VI) 和整联蛋白alpha6beta1,但不包括von Willebrand受体GPIbalpha或整联蛋白alphaIIbbeta3或alpha2beta1。这些发现表明Tspan9与其他血小板四aspanins及其相关蛋白协同调节血小板功能。

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