Grandoch Maria, López de Jesús Maider, Oude Weernink Paschal A, Weber Artur-Aron, Jakobs Karl H, Schmidt Martina
Institut für Pharmakologie, Universitätsklinikum Essen, Essen, Germany.
Cell Signal. 2009 Apr;21(4):609-21. doi: 10.1016/j.cellsig.2009.01.002. Epub 2009 Jan 7.
Signaling by the B cell antigen receptor (BCR) is essential for B lymphocyte homeostasis and immune function. In immature B cells, ligation of the BCR promotes growth arrest and apoptosis, and BCR-driven balancing between pro-apoptotic extracellular signal-regulated kinase 1 and 2 (ERK1/2) and anti-apoptotic phosphoinositide 3-kinase-dependent Akt seems to define the final cellular apoptotic response. Dysfunction of these late BCR signaling events can lead to the development of immunological diseases. Here we report on novel cyclic AMP-dependent mechanisms of BCR-induced growth arrest and apoptosis in the immature B lymphoma cell line WEHI-231. BCR signaling to ERK1/2 and Akt requires cyclic AMP-regulated Epac, the latter acting as a guanine nucleotide exchange factor for Rap1 and H-Ras independent of protein kinase A. Importantly, activation of endogenously expressed Epac by a specific cyclic AMP analog enhanced the induction of growth arrest (reduced DNA synthesis) and apoptosis (nuclear condensation, annexin V binding, caspase-3 cleavage and poly-ADP-ribose polymerase processing) by the BCR. Our data indicate that cyclic AMP-dependent Epac signals to ERK1/2 and Akt upon activation of Rap1 and H-Ras, and is involved in BCR-induced growth arrest and apoptosis in WEHI-231 cells.
B细胞抗原受体（BCR）信号传导对于B淋巴细胞的稳态和免疫功能至关重要。在未成熟B细胞中，BCR的连接促进生长停滞和凋亡，而BCR驱动的促凋亡细胞外信号调节激酶1和2（ERK1/2）与抗凋亡磷酸肌醇3激酶依赖性Akt之间的平衡似乎决定了最终的细胞凋亡反应。这些晚期BCR信号事件的功能障碍可导致免疫疾病的发生。在此，我们报告了未成熟B淋巴瘤细胞系WEHI-231中BCR诱导生长停滞和凋亡的新型环磷酸腺苷（cAMP）依赖性机制。BCR向ERK1/2和Akt的信号传导需要cAMP调节的交换蛋白直接激活环磷腺苷（Epac），后者作为Rap1和H-Ras的鸟嘌呤核苷酸交换因子，独立于蛋白激酶A。重要的是，一种特异性cAMP类似物对内源性表达的Epac的激活增强了BCR对生长停滞（DNA合成减少）和凋亡（核浓缩、膜联蛋白V结合、半胱天冬酶-3切割和多聚二磷酸腺苷核糖聚合酶加工）的诱导。我们的数据表明，cAMP依赖性Epac在Rap1和H-Ras激活后向ERK1/2和Akt发出信号，并参与了WEHI-231细胞中BCR诱导的生长停滞和凋亡。
