The AKT kinase signaling network is rewired by PTEN to control proximal BCR signaling in germinal center B cells
The AKT kinase signaling network is rewired by PTEN to control proximal BCR signaling in germinal center B cells
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DOI：
10.1038/s41590-019-0376-3
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发表时间：
2019-06-01
影响因子：
30.5
通讯作者：
Shlomchik, Mark J.
中科院分区：
文献类型：
--
作者：
Luo, Wei;Hawse, William;Shlomchik, Mark J.
B细胞抗原受体（BCR）和CD 40信号传导在生发中心（GC）B细胞（GCBC）中重新连接以优化对高亲和力B细胞的选择。在GCBC中，BCR信号受到限制，但其机制尚不清楚。在这里，我们描述了一个GC特异性，AKT激酶驱动的负反馈回路，减弱BCR信号。质谱分析显示，与初始B细胞相比，GCBCs中的AKT靶活性发生了改变。重定向与AKT T308和S473磷酸化差异有关，而磷酸肌醇依赖性蛋白激酶PDK 1和磷酸酶PTEN的GC特异性上调反过来控制。在GCBCs中，AKT优先靶向CSK、SHP-1和HPK 1，它们是BCR信号传导的负调节因子。我们发现磷酸化增强了这些蛋白质的酶活性，产生了一个负反馈回路，抑制了上游BCR信号传导。AKT抑制缓解了这种负反馈，并增强了GCBCs中BCR近端激酶林恩以及下游BCR信号分子的激活。
B cell antigen receptor (BCR) and CD40 signaling are rewired in germinal center (GC) B cells (GCBCs) to optimize selection for high-affinity B cells. In GCBC, BCR signals are constrained, but the mechanisms are not well understood. Here we describe a GC-specific, AKT-kinase-driven negative feedback loop that attenuates BCR signaling. Mass spectrometry revealed that AKT target activity was altered in GCBCs compared with naive B cells. Retargeting was linked to differential AKT T308 and S473 phosphorylation, in turn controlled by GC-specific upregulation of phosphoinositide-dependent protein kinase PDK1 and the phosphatase PTEN. In GCBCs, AKT preferentially targeted CSK, SHP-1 and HPK1, which are negative regulators of BCR signaling. We found that phosphorylation enhances enzymatic activity of these proteins, creating a negative feedback loop that dampens upstream BCR signaling. AKT inhibition relieved this negative feedback and enhanced activation of BCR-proximal kinase LYN, as well as downstream BCR signaling molecules in GCBCs.