A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2
A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2
复制标题
DOI：
10.1182/blood-2005-05-1994
复制
发表时间：
2006-01-15
期刊：
影响因子：
20.3
通讯作者：
Watson, SP
中科院分区：
文献类型：
--
作者：
Suzuki-Inoue, K;Fuller, GLJ;Watson, SP
据报道，蛇毒红细胞素与血小板上的整合素α 2 β 1和糖蛋白（GP）Ib α结合，但它也能够诱导不依赖于2种受体和GPVI的活化。使用红细胞素亲和层析，我们已经确定了一种新的C型凝集素受体，CLEC-2，在血小板中赋予红细胞素在细胞系中表达时的信号应答。CLEC-2在其胞质tall中的YXXL基序中具有单个酪氨酸残基，其在通过红细胞素或CLEC-2的抗体而不是胶原蛋白、凝血酶受体激动剂肽（TRAP）或惊厥素活化血小板时经历酪氨酸磷酸化。CLEC-2和其他信号蛋白的酪氨酸磷酸化被红细胞素抑制Src家族激酶抑制剂PP 2。此外，在Syk和PLC γ 2不存在的情况下，红细胞素对鼠血小板的活化被消除，并且在LAT、SLP-76和Vav 2/Vav 3不存在的情况下部分减少。这些发现定义了血小板中的一种新的信号传导途径，其中通过红细胞素激活CLEC-2导致其胞质tall的酪氨酸磷酸化，Sylk的结合和下游酪氨酸磷酸化事件的启动，以及PLC γ 2的激活。CLEC-2是在血小板上发现的第一个C型凝集素受体，其通过这种新途径发出信号。
The snake venom rhodocytin has been reported to bind to integrin alpha 2 beta 1 and glycoprotein (GP) Ib alpha on platelets, but it is also able to induce activation independent of the 2 receptors and of GPVI. Using rhodocytin affinity chromatography, we have identified a novel C-type lectin receptor, CLEC-2, in platelets that confers signaling responses to rhodocytin when expressed in a cell line. CLEC-2 has a single tyrosine residue in a YXXL motif in its cytosolic tall, which undergoes tyrosine phosphorylation upon platelet activation by rhodocytin or an antibody to CLEC-2, but not to collagen, thrombin receptor agonist peptide (TRAP), or convulxin. Tyrosine phosphorylation of CLEC-2 and other signaling proteins by rhodocytin is inhibited by the Src family kinase inhibitor PP2. Further, activation of murine platelets by rhodocytin is abolished in the absence of Syk and PLC gamma 2, and partially reduced in the absence of LAT, SLP-76, and Vav2/Vav3. These findings define a novel signaling pathway in platelets whereby activation of CLEC-2 by rhodocytin leads to tyrosine phosphorylation of its cytosolic tall, binding of Sylk and initiation of downstream tyrosine phosphorylation events, and activation of PLCy2. CLEC-2 is the first C-type lectin receptor to be found on platelets which signals through this novel pathway.