The hematopoietic-specific adaptor protein Gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors
The hematopoietic-specific adaptor protein Gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors
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DOI：
10.1016/s0960-9822(99)80017-7
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发表时间：
1999-01-28
期刊：
影响因子：
9.2
通讯作者：
McGlade, CJ
中科院分区：
文献类型：
--
作者：
Liu, SK;Fang, N;McGlade, CJ
背景：衔接蛋白Gads是一种grb2相关蛋白，最初是在其与对接蛋白Shc的酪氨酸磷酸化形式相互作用的基础上发现的。Gads蛋白的表达仅限于造血组织和细胞系，Gads含有Src同源2 （SH2）结构域，该结构域先前已被证明具有与Grb2相似的结合特异性。Gads也具有两个SH3结构域，但它们与Grb2的结构域具有明显的结合特异性，因为Gads不与已知的Grb2 SH3结构域靶点结合。在这里，我们研究了Gads是否参与t细胞信号传导。结果：我们发现Gads在T细胞中高表达，SLP-76接头蛋白是体内主要的Gads相关蛋白。Gads与SLP-76的组成性相互作用由Gads的羧基末端SH3结构域和SLP-76中富含脯氨酸的20个氨基酸区域介导。Gads还在T细胞受体交联后，共同免疫沉淀活化T细胞（LAT）接头蛋白连接物的酪氨酸磷酸化形式；这种相互作用是由Gads SH2结构域介导的。Gads和SLP-76的过表达导致T细胞信号的协同增强，通过活化T细胞核因子（NFAT）的激活来测量，这种合作需要一个功能性的Gads SH2结构域。结论：这些结果表明Gads通过与SLP-76和LAT的关联在t细胞信号传导中起重要作用。Gads可能促进LAT和SLP-76信号复合物之间的串扰，从而将膜近端事件耦合到下游信号通路。
Background: The adaptor protein Gads is a Grb2-related protein originally identified on the basis of its interaction with the tyrosine-phosphorylated form of the docking protein Shc. Gads protein expression is restricted to hematopoietic tissues and cell lines, Gads contains a Src homology 2 (SH2) domain, which has previously been shown to have a similar binding specificity to that of Grb2. Gads also possesses two SH3 domains, but these have a distinct binding specificity to those of Grb2, as Gads does not bind to known Grb2 SH3 domain targets. Here, we investigated whether Gads is involved in T-cell signaling.Results: We found that Gads is highly expressed in T cells and that the SLP-76 adaptor protein is a major Gads-associated protein in vivo. The constitutive interaction between Gads and SLP-76 was mediated by the carboxy-terminal SH3 domain of Gads and a 20 amino-acid proline-rich region in SLP-76. Gads also coimmunoprecipitated the tyrosine-phosphorylated form of the linker for activated T cells (LAT) adaptor protein following cross-linking of the T-cell receptor; this interaction was mediated by the Gads SH2 domain. Overexpression of Gads and SLP-76 resulted in a synergistic augmentation of T-cell signaling, as measured by activation of nuclear factor of activated T cells (NFAT), and this cooperation required a functional Gads SH2 domain.Conclusions: These results demonstrate that Gads plays an important role in T-cell signaling via its association with SLP-76 and LAT. Gads may promote cross-talk between the LAT and SLP-76 signaling complexes, thereby coupling membrane-proximal events to downstream signaling pathways.