Dual specificity phosphatases and MAP kinase signaling

双特异性磷酸酶和 MAP 激酶信号传导

• 批准号: 7263200
• 负责人: NICHOLAS K TONKS
• 金额: $ 28.91万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-21 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7263200
• 关键词: Ablation; Active Sites; Apoptosis; Attenuated; Cell model; Cell physiology; Cells; Chemosensitization; Complex; Data; Disruption; Down-Regulation; Drug Design; Elements; Enzymes; Family; Gene Targeting; Generations; Goals; Health; Inflammation; Inflammatory; Knockout Mice; Lipopolysaccharides; Location; MAPK8 gene; Malignant Neoplasms; Metabolic Diseases; Mitogen-Activated Protein Kinases; Mus; Myristic Acylation Site; Nerve Degeneration; Neurotoxins; Numbers; Pathway interactions; Personal Satisfaction; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Protein Isoforms; Protein Kinase; Protein phosphatase; Proteins; RNA Interference; Range; Receptor Signaling; Regulation; Relative (related person); Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Specificity; Staging; Stimulus; Stress; Structure; Subgroup; Substrate Specificity; System; Testing; Therapeutic; Tissues; cytokine; genetic regulatory protein; human disease; inhibitor/antagonist; insight; mutant; novel; programs; response; therapeutic target

DESCRIPTION (provided by applicant): The broad, long-term objectives of this revised proposal are to characterize a novel aspect of the regulation of MAP kinase-dependent signal transduction by dual specificity phosphatases (DSPs). The JNKs are a subgroup of the MAP kinases that are activated in response to pro-inflammatory cytokines and environmental stresses and are implicated in the regulation of proliferation and apoptosis. They are recognized as therapeutic targets for treatment of several major human diseases including cancer, inflammation, as well as neurodegenerative and metabolic diseases. In contrast to studies to date that have focused on the downregulation of JNK signaling by DSPs, extensive preliminary data are presented showing that 2 DSPs, JSP1 (Jnk Stimulatory Phosphatase 1) and the closely related enzyme DSP18/JSP2, have the potential to augment the activation of JNK. The objective of the proposed studies is to define the role of these DSPs in regulation of the JNK pathway, testing the hypothesis that they may function as determinants of specificity in JNK signaling responses. The Specific Aims are: (1) To analyze the effects on cell signaling of altering expression of JSP1 in cell models, including the use of RNA interference. (2) To conduct a structure-function analysis of JSP1, focusing on the identification of its physiological substrates. (3) To characterize DSP18, the closest relative of JSP1, to determine whether it also functions as a regulator of JNK signaling. (4) To characterize the function of JSP1 through analysis of the phenotype of JSP1 knockout mice and analysis of JNK signaling in tissues and cells derived from these mice. The health relatedness of this research lies in the potential therapeutic implications. The JNKs are recognized as therapeutic targets for several major human diseases. The large number of JNK isoforms, together with their importance in a wide variety of cell functions, suggests that drugs designed to inhibit the JNKs directly at the active site may exert broad-ranging effects thereby limiting their utility. In contrast, if JSP1 or DSP18/JSP2 are shown to regulate the activation of specific JNK isoforms or to activate JNK in response to specific stimuli, an inhibitor of these DSPs may attenuate JNK signaling in a more restricted context, possibly enhancing its therapeutic potential.

描述(由申请人提供)：这项修订提案的广泛的、长期的目标是描述通过双特异性磷酸酶(DSP)调节MAP依赖的信号转导的一个新方面。JNKs是MAP激活酶的一个亚类，可被促炎细胞因子和环境应激激活，参与细胞增殖和细胞凋亡的调节。它们被认为是治疗几种主要人类疾病的靶点，包括癌症、炎症以及神经退行性和代谢性疾病。与迄今集中于DSPs下调JNK信号的研究不同，大量的初步数据表明，两个DSPs，JSP1(JNK刺激性磷酸酶1)和密切相关的酶DSP18/JSP2，具有增强JNK激活的潜力。本研究的目的是明确这些DSP在JNK信号通路调控中的作用，验证它们可能在JNK信号反应中作为特异性决定因素的假设。具体目的是：(1)在细胞模型中分析改变JSP1表达对细胞信号的影响，包括使用RNA干扰。(2)对JSP1的结构和功能进行分析，重点对其生理底物进行鉴定。(3)鉴定与JSP1最接近的同源基因DSP18，以确定其是否也是JNK信号的调节因子。(4)通过对JSP1基因敲除小鼠的表型分析及其来源的组织和细胞中JNK信号转导的分析，研究JSP1的功能。这项研究的健康相关性在于潜在的治疗意义。JNK被认为是人类几种主要疾病的治疗靶点。大量的JNK异构体及其在多种细胞功能中的重要性表明，直接在活性部位抑制JNK的药物可能会产生广泛的影响，从而限制其用途。相反，如果JSP1或DSP18/JSP2被证明调节特定JNK亚型的激活或在特定刺激下激活JNK，这些DSPs的抑制剂可能在更有限的背景下减弱JNK信号，可能增强其治疗潜力。