REGULATION OF CCR7 MEDIATED EVENTS IN BREAST CANCER CELLS AND IN T CELLS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 C-C趋化因子受体7(CCR7)调节细胞向淋巴结的运输，以响应趋化因子配体的梯度。T细胞向趋化因子的迁移(趋化)是通过调节整合素的黏附来控制的。虽然CCR7对β2整合素的调节已经被研究，但CCR7在调节其他整合素家族中的作用仍然知之甚少。CCR7是一种GPCR，可以在其两个配体CCL19或CCL21结合后激活信号事件。最初，为了更好地了解CCR7在T细胞中激活的信号通路，我们使用了CCR7+Hut78人T细胞系。Hut78细胞在整合素配体FN和VCAM-1上向CCL19或CCL21的迁移表现出不同的迁移行为。对信号通路的分析表明，CCL19激活CCR7导致磷脂酶C-Gamma 1的磷酸化增加，磷脂酶C-Gamma 1被认为是ERK1/2磷酸化的上游调节因子，在β1整合素信号转导中起重要作用。CCL19刺激CCR7后，ERK1/2磷酸化水平较基础水平升高3倍。相反，CCL21激活CCR7导致ERK1/2磷酸化水平降低2倍。CCL19促进CCL19的磷酸化，而CCL21刺激CCR7对磷脂酶C-γ的磷酸化无影响。这些数据表明，CCR7与CCL19或CCL21结合后，ERK1/2的磷酸化受磷脂酶C的差异调节，这可能导致通过1整合素的差异迁移。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The C-C chemokine receptor 7 (CCR7) regulates trafficking of cells to the lymph nodes in response to a gradient of chemokine ligands. T cell migration to chemokines (chemotaxis) is controlled by regulating the adhesion of integrins. Although CCR7 regulation of beta 2 integrins have been studied, the role of CCR7 in regulating other families of integrins remains poorly understood. CCR7 is a GPCR that can activate signaling events following binding of either of its two ligands, CCL19 or CCL21. Initially, to better understand the signaling pathways activated by CCR7 in T cells, we used the CCR7+ Hut78 human T cell line. Migration of Hut78 cells to CCL19 or CCL21 on ¿1 integrin ligands Fibronectin and VCAM-1 revealed different migration behaviors. Analysis of the signaling pathways revealed that activation of CCR7 by CCL19 leads to increased phosphorylation of phospholipase C gamma 1, which is thought to be an upstream regulator of ERK1/2 phosphorylation and is important in beta 1 integrin signaling. Following stimulation of CCR7 with CCL19, levels of ERK1/2 phosphorylation were increased 3-fold over basal levels. In contrast, activation of CCR7 with CCL21 led to a 2-fold reduction in the level of ERK1/2 phosphorylation. CCL19 promoted phosphorylation of CCL19 , while stimulation of CCR7 with CCL21 had no effect on phospholipase C gamma phosphorylation. These data suggest that following CCR7 binding to CCL19 or CCL21 ERK1/2 phosphorylation is differentially regulated by phospholipase C¿ which may lead to differential migration through ¿1 integrins.