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

乳腺癌细胞和 T 细胞中 CCR7 介导的事件的调节

• 批准号: 8168395
• 负责人: CHARLOTTE M VINES
• 金额: $ 5.45万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168395
• 关键词: Adhesions; Behavior; Binding; Breast Cancer Cell; CC chemokine receptor 7; CCL19 gene; CCL21 gene; CD18 Antigens; Cell Line; Cells; Chemotaxis; Computer Retrieval of Information on Scientific Projects Database; Data; Event; Family; Fibronectins; Funding; G Protein-Coupled Receptor Genes; Grant; Human; Institution; Integrins; Lead; Ligands; Mediating; PLC gamma1; Phospholipase; Phosphorylation; Regulation; Research; Research Personnel; Resources; Role; Signal Pathway; Signal Transduction; Source; T-Lymphocyte; United States National Institutes of Health; Vascular Cell Adhesion Molecule-1; beta-Chemokines; cell motility; chemokine; lymph nodes; migration; phospholipase C gamma; response; trafficking

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 C-C 趋化因子受体 7 (CCR7) 响应趋化因子配体的梯度，调节细胞向淋巴结的运输（趋化性），这是通过调节整合素的粘附来控制的，尽管 CCR7 对 β2 整合素的调节有作用。尽管已进行过研究，但 CCR7 在调节其他整合素家族中的作用仍知之甚少。CCR7 是一种 GPCR，可以在其两个整合素中的任何一个结合后激活信号传导事件。最初，为了更好地了解 T 细胞中 CCR7 激活的信号通路，我们使用 CCR7+ Hut78 人类 T 细胞系迁移至 CCL19 或 CCL21。 1 整合素配体纤连蛋白和 VCAM-1 揭示了不同的迁移行为 对信号通路的分析表明，CCL19 激活 CCR7 会导致磷脂酶 C γ 1 磷酸化增加，磷脂酶 C γ 1 被认为是 ERK1/2 磷酸化的上游调节因子。在用 CCL19 刺激 CCR7 后，ERK1/2 磷酸化水平增加。相反，CCL21 激活 CCR7 导致 CCL19 磷酸化水平降低 2 倍，从而促进 CCL19 磷酸化，而 CCL21 刺激 CCR7 对磷脂酶 C γ 没有影响。这些数据表明，CCR7 与 CCL19 或 CCL21 结合后，ERK1/2 磷酸化。受磷脂酶 C 的差异调节这可能会导致通过 ¿ 的差异迁移1个整合素。