Grb2 functions at the top of the T-cell antigen receptor-induced tyrosine kinase cascade to control thymic selection
Grb2 functions at the top of the T-cell antigen receptor-induced tyrosine kinase cascade to control thymic selection
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DOI：
10.1073/pnas.0905039107
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发表时间：
2010-06-08
影响因子：
11.1
通讯作者：
Gu, Hua
中科院分区：
文献类型：
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作者：
Jang, Ihn Kyung;Zhang, Jinping;Gu, Hua
Grb 2是介导由各种受体诱导的Ras-MAPK活化的衔接分子。在这里，我们表明，条件性消融Grb 2在胸腺细胞严重损害胸腺阳性和阴性选择。引人注目的是，该突变减弱了T细胞抗原受体（TCR）近端信号传导，包括多种信号传导蛋白的酪氨酸磷酸化和Ca（2+）内流。缺陷性TCR信号传导可归因于Lck活化的显著损伤。由中央SH 2和C-末端SH 3结构域组成的突变型Grb 2在Grb 2（-/-）胸腺细胞中的异位表达完全恢复胸腺细胞发育。因此，Grb 2在胸腺正选择和负选择中起着关键作用。它通过支架功能在酪氨酸磷酸化级联的顶端放大TCR信号传导。
Grb2 is an adaptor molecule that mediates Ras-MAPK activation induced by various receptors. Here we show that conditional ablation of Grb2 in thymocytes severely impairs both thymic positive and negative selections. Strikingly, the mutation attenuates T-cell antigen receptor (TCR) proximal signaling, including tyrosine phosphorylation of multiple signaling proteins and Ca(2+) influx. The defective TCR signaling can be attributed to a marked impairment in Lck activation. Ectopic expression of a mutant Grb2 composed of the central SH2 and the C-terminal SH3 domains in Grb2(-/-) thymocytes fully restores thymocyte development. Thus, Grb2 plays a pivotal role in both thymic positive and negative selection. It amplifies TCR signaling at the top end of the tyrosine phosphorylation cascade via a scaffolding function.