Inflammation-Induced CCR7 Oligomers Form Scaffolds to Integrate Distinct Signaling Pathways for Efficient Cell Migration
Inflammation-Induced CCR7 Oligomers Form Scaffolds to Integrate Distinct Signaling Pathways for Efficient Cell Migration
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DOI：
10.1016/j.immuni.2015.12.010
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发表时间：
2016-01-19
期刊：
影响因子：
32.4
通讯作者：
Legler, Daniel F.
中科院分区：
文献类型：
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作者：
Hauser, Mark A.;Schaeuble, Karin;Legler, Daniel F.
宿主防御依赖于由趋化因子引导的协调的细胞迁移，这些趋化因子引起选择性但有偏见的信号通路来控制趋化性。在这里，我们发现，不同的炎症刺激引起趋化因子受体CCR 7的寡聚化，使人类树突状细胞和T细胞亚群不仅通过经典的G蛋白依赖性信号传导，而且通过整合寡聚体依赖性Src激酶信号传导途径来处理指导线索。有效的CCR 7驱动的迁移依赖于G蛋白偶联受体的保守NPXXY基序附近的疏水寡聚化界面，如诱变筛选和CCR 7-SNP所示，其表现出超寡聚体特征，导致增强的Src活性和上级趋化性。此外，Src磷酸化寡聚CCR 7，从而为SH 2结构域承载信号分子创建对接位点。最后，我们确定了CCL 21偏置信号，涉及磷酸酶SHP 2控制有效的细胞迁移。总的来说，我们的数据表明，CCR 7寡聚体作为分子枢纽调节不同的信号通路。
Host defense depends on orchestrated cell migration guided by chemokines that elicit selective but biased signaling pathways to control chemotaxis. Here, we showed that different inflammatory stimuli provoked oligomerization of the chemokine receptor CCR7, enabling human dendritic cells and T cell subpopulations to process guidance cues not only through classical G protein-dependent signaling but also by integrating an oligomer-dependent Src kinase signaling pathway. Efficient CCR7-driven migration depends on a hydrophobic oligomerization interface near the conserved NPXXY motif of G proteincoupled receptors as shown by mutagenesis screen and a CCR7-SNP demonstrating super-oligomer characteristics leading to enhanced Src activity and superior chemotaxis. Furthermore, Src phosphorylates oligomeric CCR7, thereby creating a docking site for SH2-domain-bearing signaling molecules. Finally, we identified CCL21-biased signaling that involved the phosphatase SHP2 to control efficient cell migration. Collectively, our data showed that CCR7 oligomers serve as molecular hubs regulating distinct signaling pathways.