Calmodulin-dependent phosphatase, kinases, and transcriptional corepressors involved in T-cell activation.
Calmodulin-dependent phosphatase, kinases, and transcriptional corepressors involved in T-cell activation.
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DOI：
10.1111/j.1600-065x.2008.00756.x
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发表时间：
2009-03
影响因子：
8.7
通讯作者：
Liu JO
中科院分区：
文献类型：
--
作者：
Liu JO
第二信使钙在介导导致细胞因子产生和T细胞克隆扩增的TCR信号传导途径中起重要作用。免疫抑制药物环孢素A（CsA）和FK506既作为治疗剂，又作为分子探针，用于解开蛋白磷酸酶钙调神经磷酸酶作为一种限速酶，参与钙信号从细胞质传递到细胞核中，以重新编程基因表达。小鼠基因敲除模型的使用有助于验证和进一步阐明钙调神经磷酸酶不同亚型在辅助T细胞活化和胸腺细胞发育中的功能。除了钙调磷酸酶之外，其他三种钙调蛋白结合蛋白也已被证明在T细胞的钙信号传导中发挥重要作用。因此，已经发现Cabin1和II类HDAC与转录因子肌细胞增强因子家族和转录共激活因子p300一起构成新的钙信号传导模块，以钙依赖性方式抑制和激活细胞因子基因转录。钙调蛋白依赖性蛋白激酶（CaMK）II和IV也显示出发挥负和正的调节功能，分别在TCR介导的细胞因子的产生。T细胞中这些和其他信号转导子之间的串扰形成了广泛的非线性信号传导网络，决定了TCR信号传导途径的最终结果。
The second messenger calcium plays an essential role in mediating the TCR signaling pathway leading to cytokine production and T cell clonal expansion. The immunosuppressive drugs cyclosproin A (CsA) and FK506 have served both as therapeutic agents and as molecular probes for unraveling the protein phosphatase calcineurin as a rate-limiting enzyme involved in the transmission of calcium signal from the cytosol into the nucleus to reprogram gene expression. The use of mouse knockout models has helped to verify and further elucidate the functions of different isoforms of calcineurin in both helper T cell activation and thymocyte development. In addition to calcineurin, three other classes of calmodulin-binding proteins have also been shown to play important roles in calcium signaling in T cells. Thus, Cabin1 and class II HDACs have been found to constitute a novel calcium-signaling module in conjunction with the transcription factor myocyte enhance factor family and the transcriptional coactivator p300 to suppress and activate cytokine gene transcription in a calcium-dependent manner. The calmodulin-dependent protein kinases (CaMK) II and IV were also shown to play negative and positive regulatory functions, respectively, in TCR-mediated cytokine production. The crosstalks among these and other signal transducers in T cells form an extensive non-linear signaling network that dictates the final outcome of the TCR signaling pathway.