匹兹堡大学Mark J. Shlomchik小组在研究中取得进展。他们的研究认为AKT激酶信号通路被PTEN重新排布，以控制生发中心B细胞近端BCR信号。 相关论文于2019年发表在《Nature Immunology》杂志上。

研究团队描述了一个GC特异的，Akt激酶驱动的负反馈回路，它减弱了BCR信号。质谱分析表明，与单纯的B细胞相比，GCBCs的AKT靶活性有所改变。重定目标与不同的Aktt308和S473磷酸化有关，反过来由磷酸肌醇依赖性蛋白激酶PDK1和磷酸酶PTEN的GC特异性上调控制。在GCBCS中，AKT优先针对CSK、SHP1和HPK1，后者是BCR信号的负调节因子。我们发现磷酸化增强了这些蛋白质的酶活性，形成了一个负反馈回路，抑制上游BCR信号。AKT抑制缓解了这种负反馈并增强了BCR近端激酶LYN的激活，以及GCBC中的下游BCR信号分子。

据介绍，B细胞抗原受体(BCR)和CD40信号在生发中心(GC)B细胞(GCBCs)中重新排布，来优化选择高亲和性B细胞。在GCBC中，BCR信号受到限制，但机制尚不清楚。

附：英文原文

Title: The AKT kinase signaling network is rewired by PTEN to control proximal BCR signaling in germinal center B cells

Author: Wei Luo, William Hawse, Laura Conter, Nikita Trivedi, Florian Weisel, Daniel Wikenheiser, Richard T. Cattley, Mark J. Shlomchik

Issue&Volume: Volume 20 Issue 6, June 2019

Abstract: 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.

DOI: 10.1038/s41590-019-0376-3

Source:https://www.nature.com/articles/s41590-019-0376-3