Differential regulation of NFAT and SRF by the B cell receptor via a PLCγ-Ca2+-dependent pathway
Differential regulation of NFAT and SRF by the B cell receptor via a PLCγ-Ca2+-dependent pathway
复制标题
DOI：
10.1093/emboj/cdg401
复制
发表时间：
2003-08-15
期刊：
影响因子：
11.4
通讯作者：
August, A
中科院分区：
文献类型：
--
作者：
Hao, SL;Kurosaki, T;August, A
NFAT和SRF在淋巴细胞增殖和细胞因子产生的调节中是重要的。NFAT通过B细胞受体（BCR）激活通过PLC γ-Ca 2 +-钙调神经磷酸酶途径发生，但BCR如何激活SRF尚不清楚。我们在这里表明，与NFAT一样，SRF的BCR调节通过Src-Syk-Tec-PLC γ-Ca 2+（Lyn-Syk-Btk-PLC γ-Ca 2+）途径发生。然而，SRF响应于较低的Ca 2+，并且比NFAT更少依赖于IP 3R表达。Ca 2+调节的钙调神经磷酸酶在SRF激活中起部分作用，与二酰基甘油（DAG）组合，而NFAT激活完全需要。SRF和NFAT都需要来自DAG效应蛋白激酶C、Ras和Rap 1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、CDC 42和肌动蛋白。最后，我们表明，Ca 2+是不需要ERK激活，而是为它的协会与细胞的核区域。这些数据表明，从BCR发出的信号通路的组合组装差异调节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-Ca2+-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-Ca2+ (Lyn-Syk-Btk-PLCgamma-Ca2+) pathway. However, SRF responds to lower Ca2+ and is less dependent on IP3R expression than NFAT. Ca2+-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 Ca2+ 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.