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: 6181527
• 负责人: KAREN E. HEDIN
• 金额: $ 24.67万
• 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 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6181527
• 关键词: CD3 molecule; CD4 molecule; G protein; T cell receptor; T lymphocyte; biological signal transduction; chemokine; cytokine receptors; guanine nucleotide binding protein; guanosinetriphosphatases; human subject; mitogen activated protein kinase; phosphatidylinositol 3 kinase; receptor coupling; tissue /cell culture

Our long-term goal is to characterize the molecular mechanisms and biological impact of chemokine receptor signaling in T lymphocytes. Toward this end, we are studying the role and mechanisms of function of the CXCR4 chemokine receptor in T cells. CXCR4 stimulates the proliferation and/or apoptosis of several cell types, and mutant mice lacking either CXCR4 or its ligand, SDF-1, die from developmental defects. In addition, CXCR4 binds directly to the gp120 glycoprotein of Human Immunodeficiency Virus-1 (HIV-1) and, together with HIV-1 binding to CD4, permits viral infection of T lymphocytes. The molecular mechanisms by which CXCR4 mediates these effects are poorly understood. Our preliminary results indicate that CXCR4 signaling uses a Gi protein to activate the ERK mitogen-activated protein (MAP) kinases in T lymphocytes. ERK and other MAP kinases phosphorylate transcription factors in response to signaling by cell-surface receptors, thereby allowing growth factors and hormones to regulate cell growth and differentiation. Our central hypothesis is that chemokine receptors use distinct G proteins, small GTP-binding proteins and kinases to activate ERK in T lymphocytes. Therefore, our specific aims are to: 1) characterize CXCR4-mediated stimulation of MEK-1 and ERK, 2) characterize CXCR4 coupling to G proteins that mediate ERK activation, and 3) characterize the role(s) of lck and CD4 in CXCR4 activation of ERK. We propose to use state-of-the-art molecular techniques in combination with normal human T cells and T cell model cell lines to characterize the molecular mechanisms of CXCR4-mediated ERK activation. We are optimistic that the successful completion of this proposal will characterize in detail the molecular mechanism(s) used by CXCR4 to activate ERK in an important cell type where CXCR4 is abundantly expressed: T lymphocytes. Since ERK participates in T lymphocyte differentiation and immune activation, the results of these studies will form a basis for understanding chemokine control of the immune system's development and function. In addition, understanding T lymphocyte CXCR4 signaling will provide the theoretical framework for future studies aimed at understanding the pathophysiology of AIDS.

我们的长期目标是表征 T 淋巴细胞中趋化因子受体信号传导的分子机制和生物学影响。 为此，我们正在研究CXCR4趋化因子受体在T细胞中的作用和功能机制。 CXCR4 刺激多种细胞类型的增殖和/或凋亡，缺乏 CXCR4 或其配体 SDF-1 的突变小鼠会因发育缺陷而死亡。 此外，CXCR4 直接与人类免疫缺陷病毒-1 (HIV-1) 的 gp120 糖蛋白结合，并与 HIV-1 与 CD4 结合一起，允许病毒感染 T 淋巴细胞。 CXCR4 介导这些作用的分子机制尚不清楚。 我们的初步结果表明，CXCR4 信号传导使用 Gi 蛋白激活 T 淋巴细胞中的 ERK 丝裂原激活蛋白 (MAP) 激酶。 ERK 和其他 MAP 激酶响应细胞表面受体的信号传导而磷酸化转录因子，从而使生长因子和激素能够调节细胞生长和分化。我们的中心假设是趋化因子受体使用不同的 G 蛋白、小 GTP 结合蛋白和激酶来激活 T 淋巴细胞中的 ERK。 因此，我们的具体目标是：1）表征CXCR4介导的MEK-1和ERK刺激，2）表征CXCR4与介导ERK激活的G蛋白的偶联，3）表征lck和CD4在CXCR4激活ERK中的作用。 我们建议使用最先进的分子技术结合正常人类 T 细胞和 T 细胞模型细胞系来表征 CXCR4 介导的 ERK 激活的分子机制。 我们乐观地认为，该提案的成功完成将详细描述 CXCR4 在 CXCR4 大量表达的重要细胞类型（T 淋巴细胞）中激活 ERK 的分子机制。 由于ERK参与T淋巴细胞分化和免疫激活，这些研究结果将为了解趋化因子控制免疫系统的发育和功能奠定基础。 此外，了解T淋巴细胞CXCR4信号传导将为未来旨在了解艾滋病病理生理学的研究提供理论框架。