Monovalent and multivalent ligation of the B cell receptor exhibit differential dependence upon Syk and Src family kinases.
Monovalent and multivalent ligation of the B cell receptor exhibit differential dependence upon Syk and Src family kinases.
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B细胞受体的单价和多价连接表现出对SYK和SRC家族激酶的差异依赖性。
DOI：
10.1126/scisignal.2003220
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发表时间：
2013-01-01
影响因子：
7.3
通讯作者：
Weiss A
中科院分区：
文献类型：
--
作者：
Mukherjee S;Zhu J;Zikherman J;Parameswaran R;Kadlecek TA;Wang Q;Au-Yeung B;Ploegh H;Kuriyan J;Das J;Weiss A
Src和Syk激酶家族是在启动近膜B细胞受体（BCR）信号传导中起关键作用的两组不同的激酶。然而，与其他淋巴细胞如T细胞不同，B细胞中Src家族激酶（SFK）和Syk之间的“劳动分工”没有很好地分开，因为Syk和SFK都可以磷酸化存在于包含B细胞受体（BCR）的蛋白质中的基于免疫受体酪氨酸的活化基序（ITAM）。为了理解为什么B细胞需要SFKs和Syk来激活，我们通过计算建模和体外实验研究了这两个激酶家族在BCR信号传导中的作用。我们的计算模型表明，正反馈使Syk能够在多聚体配体诱导BCR空间聚集时基本上补偿SFKs的缺失。我们通过实验证实了这一预测。相反，当B细胞被不能产生BCR簇集的单体配体刺激时，Syk和SFKs都是完全和快速激活BCR所必需的。我们的数据表明，SFKs可以发挥关键作用，在增加BCR敏感性的单体抗原的病原体和介导的快速反应，可溶性多聚体抗原的病原体，可以诱导空间BCR集群。
The Src and Syk families of kinases are two distinct sets of kinases that play critical roles in initiating membrane-proximal B cell receptor (BCR) signaling. However, unlike in other lymphocytes, such as T cells, the “division of labor” between Src family kinases (SFKs) and Syk in B cells is not well separated, because both Syk and SFKs can phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) present in proteins comprising the B cell receptor (BCR). To understand why B cells require both SFKs and Syk for activation, we investigated the roles of both families of kinases in BCR signaling with computational modeling and in vitro experiments. Our computational model suggested that positive feedback enabled Syk to substantially compensate for the absence of SFKs when spatial clustering of BCRs was induced by multimeric ligands. We confirmed this prediction experimentally. In contrast, when B cells were stimulated by monomeric ligands that failed to produce BCR clustering, both Syk and SFKs were required for complete and rapid BCR activation. Our data suggest that SFKs could play a pivotal role in increasing BCR sensitivity to monomeric antigens of pathogens and in mediating a rapid response to soluble multimeric antigens of pathogens that can induce spatial BCR clustering.
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影响因子：
64.5
作者：
Deindl, Sebastian;Kadlecek, Theresa A.;Kuriyan, John
通讯作者：
Kuriyan, John
DOI：
10.1073/pnas.88.20.9166
发表时间：
1991-10-01
影响因子：
11.1
作者：
CHAN, AC;IRVING, BA;WEISS, A
通讯作者：
WEISS, A
影响因子：
8.7
作者：
Hermiston ML;Zikherman J;Zhu JW
通讯作者：
Zhu JW
DOI：
10.1073/pnas.0511315103
发表时间：
2006-02-28
影响因子：
11.1
作者：
Kim, YM;Pan, JYJ;Ploegh, HL
通讯作者：
Ploegh, HL
DOI：
10.1073/pnas.94.5.1919
发表时间：
1997-03-04
影响因子：
11.1
作者：
ElHillal, O;Kurosaki, T;Scharenberg, AM
通讯作者：
Scharenberg, AM