CXCR4 Chemokine Receptor regulation of ERK MAP Kinase

CXCR4 趋化因子受体对 ERK MAP 激酶的调节

• 批准号: 6942985
• 负责人: KAREN E. HEDIN
• 金额: $ 27.46万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6942985
• 关键词: CD3 molecule; T cell receptor; T lymphocyte; biological signal transduction; cell migration; chemokine receptor; clinical research; clone cells; enzyme activity; fluorescence resonance energy transfer; human tissue; leukocyte activation /transformation; mitogen activated protein kinase; protein protein interaction

DESCRIPTION (provided by the applicant): T lymphocyte activation and migration are critical for normal immune functions, and signaling by the T lymphocyte antigen receptor-CD3 complex (TCR) and chemokine receptors such as CXCR4 are extensively cross regulated. For example, CXCR4 costimulates the immune activation of TCR-stimulated T lymphocytes, while TCR signaling abrogates CXCR4-mediated migration and participates in CXCR4-mediated infection of T lymphocytes with the Human Immunodeficiency Virus-1 (HIV-1). Despite evidence that TCR and CXCR4 signaling pathways cross-regulate in important ways, CXCR4 signaling pathways in T lymphocytes are incompletely characterized. Moreover, to our knowledge, no detailed studies on the molecular mechanisms of chemokine or CXCR4 and TCR cross-regulation have been reported. Our recent results demonstrate that CXCR4 signaling regulates a close association between CXCR4 and TCR on the surface of T lymphocytes, and activates the ERK MAP kinase via a mechanism requiring the TCR and TCR associated signaling molecules. Our proposed experiments will therefore fill this gap in the current knowledge, by testing the central hypothesis that CXCR4 signals in T cells via a novel mechanism that involves CXCR4 associating with the TCR and using the TCR for signal transduction. Our specific aims are to (1) ask if the interaction between CXCR4 and the TCR is specific, (2) ask how CXCR4 signaling regulates the CXCR4/TCR complex and its movement into subcellular compartments where signaling takes place, and (3) ask if CXCR4 uses the TCR and other signaling proteins for ERK activation and costimulation of TCR signaling. The results of these studies will characterize novel mechanisms of CXCR4 signaling in T cells that are important for CXCA4-mediated gene expression, and that probably also contribute to CXCR4-mediated costimulation of T cell activation and HIV-1 pathobiology. In addition, whether or not the CXCR4/TCR complex is eventually found to have biological relevance, these experiments will address basic questions of how receptors oligomerize, and signal from within, subcellular compartments. Finally, these experiments will identify reagents that can be used to rigorously test the idea that CXCR4/TCR complexes regulate T lymphocyte biological functions. The results of these studies will therefore serve as a theoretical framework for better understanding and manipulating the interplay between T cell immune activation and T cell migration.

描述（由申请人提供）：T 淋巴细胞激活和迁移对于正常免疫功能至关重要，并且 T 淋巴细胞抗原受体-CD3 复合物 (TCR) 和趋化因子受体（例如 CXCR4）的信号传导受到广泛的交叉调节。 例如，CXCR4 共刺激 TCR 刺激的 T 淋巴细胞的免疫激活，而 TCR 信号传导消除 CXCR4 介导的迁移并参与 CXCR4 介导的 T 淋巴细胞感染人类免疫缺陷病毒-1 (HIV-1)。 尽管有证据表明 TCR 和 CXCR4 信号通路以重要方式交叉调节，但 T 淋巴细胞中 CXCR4 信号通路的特征还不完全。 此外，据我们所知，目前还没有关于趋化因子或CXCR4与TCR交叉调节的分子机制的详细研究报道。 我们最近的结果表明，CXCR4 信号传导调节 T 淋巴细胞表面上 CXCR4 和 TCR 之间的密切关联，并通过需要 TCR 和 TCR 相关信号分子的机制激活 ERK MAP 激酶。 因此，我们提出的实验将通过测试中心假设，即 CXCR4 通过一种新机制在 T 细胞中发出信号，该机制涉及 CXCR4 与 TCR 结合并使用 TCR 进行信号转导，来填补当前知识中的这一空白。 我们的具体目标是（1）询问 CXCR4 和 TCR 之间的相互作用是否具有特异性，（2）询问 CXCR4 信号传导如何调节 CXCR4/TCR 复合物及其运动到发生信号传导的亚细胞区室中，以及（3）询问 CXCR4 是否使用 TCR 和其他信号传导蛋白来激活 ERK 和 TCR 信号传导的共刺激。这些研究的结果将描述 T 细胞中 CXCR4 信号传导的新机制，这些机制对于 CXCA4 介导的基因表达很重要，并且可能也有助于 CXCR4 介导的 T 细胞激活和 HIV-1 病理学的共刺激。 此外，无论 CXCR4/TCR 复合物最终是否被发现具有生物学相关性，这些实验都将解决受体如何寡聚以及亚细胞区室内部信号的基本问题。 最后，这些实验将确定可用于严格测试 CXCR4/TCR 复合物调节 T 淋巴细胞生物学功能这一观点的试剂。因此，这些研究的结果将作为更好地理解和操纵 T 细胞免疫激活和 T 细胞迁移之间相互作用的理论框架。