A computational model for early events in B cell antigen receptor signaling: analysis of the roles of Lyn and Fyn.
A computational model for early events in B cell antigen receptor signaling: analysis of the roles of Lyn and Fyn.
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DOI：
10.4049/jimmunol.1102003
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发表时间：
2012-07-15
期刊：
影响因子：
--
通讯作者：
Lipniacki T
中科院分区：
文献类型：
--
作者：
Barua D;Hlavacek WS;Lipniacki T
B细胞抗原受体（BCR）信号传导调节B细胞的活性和命运。BCR信号传导包括源自林恩和Fyn的两个反馈环，它们是Src家族蛋白酪氨酸激酶（SFK）。正反馈来自SFK介导的BCR和受体结合的林恩和Fyn的反式磷酸化，其增加林恩和Fyn的激酶活性。负反馈来自SFK介导的跨膜衔接蛋白PAG 1的顺式磷酸化，其将胞质蛋白酪氨酸激酶Csk募集到质膜，在质膜中其作用是降低林恩和Fyn的激酶活性。为了研究正反馈环和负反馈环对BCR信号传导的动态稳定性的影响以及林恩和Fyn对BCR信号传导的相对贡献，我们在这里考虑了BCR信号传导中早期事件的基于规则的模型，该模型包括六种蛋白质的近膜相互作用：BCR、林恩、Fyn、Csk、PAG 1和Syk，一种由于SFK介导的BCR磷酸化而被激活的胞质蛋白酪氨酸激酶。该模型与林恩和Fyn缺失的已知效应一致。我们发现，BCR信号可以产生一个单一的脉冲或振荡的Syk激活取决于抗原信号的强度和林恩和Fyn的相对水平。我们还表明，双稳态可以出现在林恩或Csk缺陷细胞。
B cell antigen receptor (BCR) signaling regulates the activities and fates of B cells. BCR signaling encompasses two feedback loops emanating from Lyn and Fyn, which are Src-family protein tyrosine kinases (SFKs). Positive feedback arises from SFK-mediated trans phosphorylation of BCR and receptor-bound Lyn and Fyn, which increases the kinase activities of Lyn and Fyn. Negative feedback arises from SFK-mediated cis phosphorylation of the transmembrane adapter protein PAG1, which recruits the cytosolic protein tyrosine kinase Csk to the plasma membrane, where it acts to decrease the kinase activities of Lyn and Fyn. To study the effects of the positive and negative feedback loops on the dynamical stability of BCR signaling and the relative contributions of Lyn and Fyn to BCR signaling, we consider here a rule-based model for early events in BCR signaling that encompasses membrane-proximal interactions of six proteins: BCR, Lyn, Fyn, Csk, PAG1 and Syk, a cytosolic protein tyrosine kinase that is activated as a result of SFK-mediated phosphorylation of BCR. The model is consistent with known effects of Lyn and Fyn deletions. We find that BCR signaling can generate a single pulse or oscillations of Syk activation depending on the strength of antigen signal and the relative levels of Lyn and Fyn. We also show that bistability can arise in Lyn or Csk deficient cells.
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