Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells
Kidins220/ARMS Associates with B-Raf and the TCR, Promoting Sustained Erk Signaling in T Cells
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DOI：
10.4049/jimmunol.1200653
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发表时间：
2013-03-01
影响因子：
4.4
通讯作者：
Schamel, Wolfgang W. A.
中科院分区：
文献类型：
--
作者：
Deswal, Sumit;Meyer, Anja;Schamel, Wolfgang W. A.
MAPK Erk的活化动力学对T细胞的发育和活化至关重要。特别是，持续的Erk信号是T细胞激活和效应功能（如IL-2的产生）所必需的。虽然Raf-1触发短暂的Erk激活，但B-Raf与TCR刺激后持续的Erk信号传导有关。在这项研究中，我们发现B-Raf的抑制丝氨酸365在TCR触发时被去磷酸化。然而，目前尚不清楚B-Raf活化如何与TCR耦合。通过质谱分析，我们确定了220 kDa (Kidins220)/富含锚蛋白重复的膜跨越蛋白的蛋白激酶d相互作用底物，雷帕霉素的哺乳动物靶点，Rictor， Dock2和GM130作为新的B-Raf相互作用伙伴。我们把重点放在了Kidins220上，这是一种在神经细胞中研究过的蛋白质，发现它与前TCR、α -TCR和γ - δ TCR有关。在长时间的TCR刺激后，Kidins220-TCR相互作用减弱，免疫沉淀和近端结扎实验证明了这一点。我们发现，Kidins220是tcr诱导的Erk持续激活所必需的，而不是瞬时激活。因此，直接早期基因产物和转录因子c-Fos和erg1的诱导被阻断，激活标记物CD69、IL-2和ifn - γ的上调被降低。此外，Kidins220是最佳钙信号传导所必需的。总之，我们将Kidins220描述为一种将B-Raf偶联到TCR上的新型TCR相互作用蛋白。Kidins220对于持续的Erk信号传导是必需的；因此，它对tcr介导的T细胞活化至关重要。免疫学杂志，2013,19:1927-1935。
The activation kinetics of MAPK Erk are critical for T cell development and activation. In particular, sustained Erk signaling is required for T cell activation and effector functions, such as IL-2 production. Although Raf-1 triggers transient Erk activation, B-Raf is implicated in sustained Erk signaling after TCR stimulation. In this study, we show that B-Raf is dephosphorylated on its inhibitory serine 365 upon TCR triggering. However, it is unknown how B-Raf activation is coupled to the TCR. Using mass spectrometry, we identified protein kinase D-interacting substrate of 220 kDa (Kidins220)/ankyrin repeat-rich membrane spanning protein, mammalian target of rapamycin, Rictor, Dock2, and GM130 as novel B-Raf interaction partners. We focused on Kidins220, a protein that has been studied in neuronal cells and found that it associated with the pre-TCR, alpha beta TCR, and gamma delta TCR. Upon prolonged TCR stimulation, the Kidins220-TCR interaction was reduced, as demonstrated by immunoprecipitation and proximity ligation assays. We show that Kidins220 is required for TCR-induced sustained, but not transient, Erk activation. Consequently, induction of the immediate early gene products and transcription factors c-Fos and Erg-1 was blocked, and upregulation of the activation markers CD69, IL-2, and IFN-gamma was reduced. Further, Kidins220 was required for optimal calcium signaling. In conclusion, we describe Kidins220 as a novel TCR-interacting protein that couples B-Raf to the TCR. Kidins220 is mandatory for sustained Erk signaling; thus, it is crucial for TCR-mediated T cell activation. The Journal of Immunology, 2013, 190: 1927-1935.