MAPK, Phosphatidylinositol 3-Kinase, and Mammalian Target of Rapamycin Pathways Converge at the Level of Ribosomal Protein S6 Phosphorylation to Control Metabolic Signaling in CD8 T Cells
MAPK, Phosphatidylinositol 3-Kinase, and Mammalian Target of Rapamycin Pathways Converge at the Level of Ribosomal Protein S6 Phosphorylation to Control Metabolic Signaling in CD8 T Cells
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DOI：
10.4049/jimmunol.0902294
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发表时间：
2009-12-01
影响因子：
4.4
通讯作者：
Zamoyska, Rose
中科院分区：
文献类型：
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作者：
Salmond, Robert J.;Emery, Juliet;Zamoyska, Rose
核糖体蛋白S6（rpS 6）是真核细胞翻译机制的关键组成部分，是核糖体生物合成所必需的。rpS 6在进化上保守的丝氨酸残基上被磷酸化，并且数据表明rpS 6磷酸化可能调节细胞生长和蛋白质合成。在细胞系中的研究已经显示了丝氨酸激酶哺乳动物雷帕霉素靶蛋白（mTOR）在rpS 6磷酸化中的重要作用，进一步将rpS 6与细胞代谢的控制联系起来。rpS 6在T细胞中是必不可少的，因为其在小鼠双阳性胸腺细胞中的缺失导致T细胞发育的完全阻断;然而，导致TCR刺激下游的rpS 6磷酸化的信号通路尚未完全表征。我们发现，在CD 8 T细胞中最大的TCR诱导的rpS 6磷酸化需要Lck和Fyn活性以及PI 3 K、mTOR和MEK/ERK MAPK通路的下游激活。我们证明了PI 3 K和MAPK通路以及PI 3 K非依赖性mTOR活性之间存在串扰，这导致特定rpS 6丝氨酸残基的差异磷酸化。这些结果将rpS 6磷酸化作为TCR触发下游的多个关键信号传导途径的汇聚点。免疫学杂志，2009，183：7388-7397.
Ribosomal protein S6 (rpS6) is a key component of the translational machinery in eukaryotic cells and is essential for ribosome biogenesis. rpS6 is phosphorylated on evolutionarily conserved serine residues, and data indicate that rpS6 phosphorylation might regulate cell growth and protein synthesis. Studies in cell lines have shown an important role for the serine kinase mammalian target of rapamycin (mTOR) in rpS6 phosphorylation, further linking rpS6 to control of cellular metabolism. rpS6 is essential in T cells because its deletion in mouse double-positive thymocyte cells results in a complete block in T cell development; however, the signaling pathway leading to rpS6 phosphorylation downstream of TCR stimulation has yet to be fully characterized. We show that maximal TCR-induced rpS6 phosphorylation in CD8 T cells requires both Lck and Fyn activity and downstream activation of PI3K, mTOR, and MEK/ERK MAPK pathways. We demonstrate that there is cross-talk between the PI3K and MAPK pathways as well as PI3K-independent mTOR activity, which result in differential phosphorylation of specific rpS6 serine residues. These results place rpS6 phosphorylation as a point of convergence for multiple crucial signaling pathways downstream of TCR triggering. The Journal of Immunology, 2009, 183: 7388-7397.