Differential regulation of NFAT and SRF by the B cell receptor via a PLCgamma-Ca(2+)-dependent pathway.
Differential regulation of NFAT and SRF by the B cell receptor via a PLCgamma-Ca(2+)-dependent pathway.
复制标题
B 细胞受体通过 PLCgamma-Ca(2 ) 依赖性途径对 NFAT 和 SRF 进行差异调节。
作者：
Shengli Hao;T. Kurosaki;A. August
NFAT 和 SRF 对于淋巴细胞增殖和细胞因子产生的调节很重要。 B 细胞受体 (BCR) 通过 PLCgamma-Ca(2+)-钙调磷酸酶途径激活 NFAT，但 BCR 如何激活 SRF 尚不清楚。我们在此表明，与 NFAT 一样，SRF 的 BCR 调节通过 Src-Syk-Tec-PLCgamma-Ca(2+) (Lyn-Syk-Btk-PLCgamma-Ca(2+)) 途径发生。然而，与 NFAT 相比，SRF 对较低的 Ca(2+) 有反应，并且对 IP(3)R 表达的依赖性较小。 Ca(2+) 调节的钙调神经磷酸酶与二酰基甘油 (DAG) 结合在 SRF 激活中发挥部分作用，同时是 NFAT 激活所必需的。 SRF 和 NFAT 都需要来自 DAG 效应蛋白激酶 C、Ras 和 Rap1 以及下游 MEK-ERK 通路的信号；然而，NFAT 而不是 SRF 依赖于 JNK 信号。 SRF 和 NFAT 也依赖于 Rac、Rho、CDC42 和肌动蛋白。最后，我们表明Ca(2+) 不是ERK 激活所必需的，而是其与细胞核区域的关联所必需的。这些数据表明，BCR 发出的信号通路的组合组装有差异地调节 NFAT 和 SRF，以激活基因表达。
NFAT and SRF are important in the regulation of proliferation and cytokine production in lymphocytes. NFAT activation by the B cell receptor (BCR) occurs via the PLCgamma-Ca(2+)-calcineurin pathway, however how the BCR activates SRF is unclear. We show here that like NFAT, BCR regulation of SRF occurs via an Src-Syk-Tec-PLCgamma-Ca(2+) (Lyn-Syk-Btk-PLCgamma-Ca(2+)) pathway. However, SRF responds to lower Ca(2+) and is less dependent on IP(3)R expression than NFAT. Ca(2+)-regulated calcineurin plays a partial role in SRF activation, in combination with diacylglycerol (DAG), while is fully required for NFAT activation. Signals from the DAG effectors protein kinase C, Ras and Rap1, and the downstream MEK-ERK pathway are required for both SRF and NFAT; however, NFAT but not SRF is dependent on JNK signals. Both SRF and NFAT were also dependent on Rac, Rho, CDC42 and actin. Finally, we show that Ca(2+) is not required for ERK activation, but instead for its association with nuclear areas of the cell. These data suggest that combinatorial assembly of signaling pathways emanating from the BCR differentially regulate NFAT and SRF, to activate gene expression.