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: 7620466
• 负责人: NICHOLAS K TONKS
• 金额: $ 28.96万
• 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/7620466
• 关键词: Ablation; Active Sites; Apoptosis; Attenuated; Cell model; Cell physiology; Cells; Chemosensitization; Complex; Data; 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; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Protein Isoforms; Protein Kinase; Protein phosphatase; Proteins; RNA Interference; 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）：该修订的建议的广泛，长期目标是表征通过双重特异性磷酸酶（DSP）调节MAP激酶依赖性信号转导的新方面。 JNK是MAP激酶的一个亚组，它们是响应促炎性细胞因子和环境应激而被激活的，并且与调节增殖和凋亡有关。它们被认为是治疗多种主要人类疾病的治疗靶标，包括癌症，炎症以及神经退行性和代谢疾病。与迄今为止侧重于DSP下调JNK信号传导的研究相反，广泛的初步数据表明2 DSP，JSP1（JNK刺激磷酸酶1）和密切相关的酶DSP18/JSP2具有增强JNK活化激活的潜力。拟议的研究的目的是定义这些DSP在调节JNK途径中的作用，并检验了它们可以作为JNK信号反应中特异性的决定因素的假设。具体目的是：（1）分析细胞模型中JSP1表达的细胞信号的影响，包括使用RNA干扰。 （2）对JSP1进行结构功能分析，重点是鉴定其生理底物。 （3）要表征JSP1最接近的DSP18，以确定它是否也充当JNK信号的调节剂。 （4）通过分析JSP1基因敲除小鼠的表型以及对来自这些小鼠的组织和细胞中JNK信号的分析来表征JSP1的功能。这项研究的健康相关性在于潜在的治疗意义。 JNK被认为是几种主要人类疾病的治疗靶标。大量JNK同工型以及它们在各种细胞功能中的重要性都表明，旨在直接抑制活性位点JNK的药物可能会发挥广泛的效果，从而限制其效用。相反，如果证明JSP1或DSP18/JSP2可以调节特定JNK同工型的激活或激活JNK以响应特定的刺激，则这些DSP的抑制剂可能会在更受限制的上下文中减弱JNK信号，并可能增强其治疗潜力。