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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 C-C趋化因子受体7（CCR 7）响应于趋化因子配体的梯度调节细胞向淋巴结的运输。 T细胞向趋化因子的迁移（趋化性）通过调节整合素的粘附来控制。尽管已经研究了CCR 7对β 2整联蛋白的调节，但CCR 7在调节其他整联蛋白家族中的作用仍然知之甚少。CCR 7是一种GPCR，可以在结合其两种配体CCL 19或CCL 21后激活信号传导事件。最初，为了更好地理解由CCR 7在T细胞中激活的信号通路，我们使用了CCR 7 + Hut 78人T细胞系。 Hut 78细胞向CCL 19或CCL 21的迁移在μ 1整联蛋白配体纤连蛋白和VCAM-1上显示不同的迁移行为。 信号通路的分析显示，CCL 19对CCR 7的激活导致磷脂酶C γ 1的磷酸化增加，磷脂酶C γ 1被认为是ERK 1/2磷酸化的上游调节因子，并且在β 1整联蛋白信号传导中很重要。 在用CCL 19刺激CCR 7后，ERK 1/2磷酸化水平比基础水平增加3倍。 相反，CCL 21激活CCR 7导致ERK 1/2磷酸化水平降低2倍。CCL 19促进CCL 19的磷酸化，而用CCL 21刺激CCR 7对磷脂酶C γ磷酸化没有影响。这些数据表明，CCR 7与CCL 19或CCL 21结合后，ERK 1/2磷酸化受到磷脂酶C的差异调节，这可能导致通过整合素的差异迁移。

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.