Phosphatidylinositol 3-kinase activation is required to form the NKG2D immunological synapse
Phosphatidylinositol 3-kinase activation is required to form the NKG2D immunological synapse
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DOI：
10.1128/mcb.01477-07
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发表时间：
2007-12-01
影响因子：
5.3
通讯作者：
Shaw, Andrey S.
中科院分区：
文献类型：
--
作者：
Giurisato, Emanuele;Cella, Marina;Shaw, Andrey S.
NKG2D 受体允许自然杀伤 (NK) 细胞检测病毒感染、应激和肿瘤细胞。在人类细胞中，NKG2D 信号传导是通过相关的 DAP10 接头介导的。在这里，我们表明，NKG2D 本身的参与足以刺激 NK 免疫突触 (NKIS) 的形成，并将 NKG2D 招募到中心突触。 DAP10 的诱变研究表明，磷脂酰肌醇 3 激酶结合位点（而不是 Grb2 结合位点）对于将 DAP10 招募到 NKIS 是必需的且足够的。令人惊讶的是，我们发现在没有 Grb2 结合位点的情况下，Grb2 仍然被招募到 NKIS 中。由于 Grb2 的募集依赖于磷脂酰肌醇-(3,4,5)-三磷酸 WIN，因此我们探讨了向 NKIS 募集是由 Grb2 的包含 pleckstrin 同源 (PH) 结构域的结合伴侣介导的可能性。我们发现 PIP3 能够招募 SOS1 的 PH 结构域，但 Vav1 的 PH 结构域不行。这些结果为免疫突触形成机制提供了新的见解，并证明了如何使用多种机制将相同的信号蛋白招募到质膜上。
The receptor NKG2D allows natural killer (NK) cells to detect virally infected, stressed, and tumor cells. In human cells, NKG2D signaling is mediated through the associated DAP10 adapter. Here we show that engagement of NKG2D by itself is sufficient to stimulate the formation of the NK immunological synapse (NKIS), with recruitment of NKG2D to the center synapse. Mutagenesis studies of DAP10 revealed that the phosphatidylinositol 3-kinase binding site, but not the Grb2 binding site, was required and sufficient for recruitment of DAP10 to the NKIS. Surprisingly, we found that in the absence of the Grb2 binding site, Grb2 was still recruited to the NKIS. Since the recruitment of Grb2 was dependent on phosphatidylinositol-(3,4,5)-trisphosphate WIN, we explored the possibility that recruitment to the NKIS is mediated by a pleckstrin homology (PH) domain-containing binding partner for Grb2. We found that the PH domain of SOS1, but not that of Vav1, was able to be recruited by PIP3. These results provide new insights into the mechanism of immunological synapse formation and also demonstrate how multiple mechanisms can be used to recruit the same signaling proteins to the plasma membrane.