Hematopoietic lineage cell-specific protein 1 (HS1) is a functionally important signaling molecule in platelet activation
Hematopoietic lineage cell-specific protein 1 (HS1) is a functionally important signaling molecule in platelet activation
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DOI：
10.1182/blood-2006-11-056069
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发表时间：
2007-10-01
期刊：
影响因子：
20.3
通讯作者：
Kunapuli, Satya P.
中科院分区：
文献类型：
--
作者：
Kahner, Bryan N.;Dorsam, Robert T.;Kunapuli, Satya P.
胶原蛋白通过糖蛋白VI（GPVI）下游的细胞内信号级联激活血小板。我们研究了造血谱系细胞特异性蛋白1（HS1）下游的GPVI在血小板活化的贡献。GPVI的刺激导致HS1的酪氨酸磷酸化，其被Src家族激酶抑制剂阻断。免疫共沉淀实验表明，HS1与Syk和磷脂酰肌醇3-激酶。与野生型同窝小鼠相比，HS1基因敲除小鼠在FeCl3体内血栓形成模型中显示出血时间延长和闭塞时间延长。此外，与野生型同窝小鼠血小板相比，GPVI和蛋白酶激活受体4（PAR-4）激动剂刺激后，HS1-null小鼠血小板的聚集和分泌反应减少。最后，与野生型同窝小鼠相比，HS1基因敲除小鼠血小板中GPVI或PAR-4刺激后Akt磷酸化减少。这些结果表明，HS1蛋白的磷酸化发生在GPVI刺激的下游，并且HS1在GPVI和PAR下游的血小板活化中起重要的功能作用。
Collagen activates platelets through an intracellular signaling cascade downstream of glycoprotein VI (GPVI). We have investigated the contribution of hematopoietic lineage cell-specific protein 1 (HS1) downstream of GPVI in platelet activation. Stimulation of GPVI leads to tyrosine phosphorylation of HS1, which is blocked by Src-famlly kinase inhibitors. Colimmunoprecipitation experiments revealed that HS1 associates with Syk and phosphatidlylinositol 3-kinases. HS1-null mice displayed increased bleeding times and increased time to occlusion in the FeCl3 in vivo thrombosis model compared with their wild-type littermates. In addition, aggregation and secretion responses were diminished in HS1-null mouse platelets after stimulation of GPVI and protease-activated receptor 4 (PAR-4) agonists compared with wild-type littermate mouse platelets. Finally, Akt phosphorylation was diminished after GPVI or PAR-4 stimulation in platelets from HS1-null mice compared with their wild-type littermates. These results demonstrate that phosphorylation of the HS1 protein occurs downstream of GPVI stimulation and that HS1 plays a significant functional role in platelet activation downstream of GPVI and PARs.