The JNK Signalsome and its Functions

JNK Signalsome 及其功能

• 批准号: 7608711
• 负责人: JING LIU
• 金额: $ 28.69万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608711
• 关键词: Affect; Apoptosis; Architecture; Biochemical; Biological Process; Cell Death; Cues; Data; Development; Diabetes Mellitus; Embryonic Development; Event; Genetic; Goals; Heart Hypertrophy; Human; Immune response; Inflammation; JUN gene; Knock-out; MAPK8 gene; MAPK9 gene; Malignant Neoplasms; Mediating; Mitogen-Activated Protein Kinases; Molecular; N-terminal; Obesity; Pathway interactions; Phosphorylation; Phosphotransferases; Physiological; Play; Prevention; Protein Isoforms; Protein Kinase; Proteins; Recruitment Activity; Regulation; Research; Role; SAPK; Screening procedure; Signal Pathway; Signal Transduction; Staging; Stimulus; Stress; TNF gene; TRAF2 gene; Therapeutic; Ubiquitination; Yeasts; Zinc Fingers; cancer type; extracellular; human disease; novel; novel strategies; protein complex; public health relevance; response; stress activated protein kinase; tumorigenesis; yeast two hybrid system

DESCRIPTION (provided by applicant): c-Jun N-terminal protein kinase (JNK; also known as stress-activated protein kinase, SAPK) plays a central role in proliferation, differentiation, programmed cell death and transformation. Overwhelming evidence implicates that JNK is a key regulator in many pathophysiological events including inflammation, immune responses, diabetes, obesity, heart hypertrophy, and oncogenesis. However, the molecular mechanism by which JNK activity is regulated by distinct extracellular stimuli is still incompletely understood. In this proposal, we will investigate whether JNK activation by distinct extracellular stimuli is mediated by a JNK signalsome, which is a dynamic protein complex that includes JNK-associated, stimulus-specific modulators or regulators (SMOR). Using both genetic and biochemical approaches, we recently found that JNK forms a protein complex and its activity can be regulated by stimulus-specific regulators. Furthermore, we found that two ubiquitously expressed JNK isoforms, JNK1 and JNK2, are differentially regulated by various extracellular stimuli. Thus, we hypothesize that the stimulus-specific JNK signalsome determines JNK activation by environmental stimuli and/or embryonic development cues. This proposal is novel, as it will identify the JNK signalsome } a dynamic and functional protein complex for JNK activation, and determine the molecular mechanisms by which JNK1 and JNK2 are differentially regulated at different developmental stages. This study will put forward a novel paradigm regarding the molecular mechanism underlying the regulation of the JNK mitogen-activated protein kinase subfamily by extracellular stimuli and the rationale in targeting JNK for prevention and treatment of human diseases and cancer. PUBLIC HEALTH RELEVANCE: The cell signaling network is composed of many important signaling pathways, including the stress activated protein kinase JNK pathway, which plays a central role in many pathophysiological events and has been implicated in numerous human diseases and certain types of cancer. However, it is difficult to target JNK for therapeutic purposes without affecting normal physiological functions in human. This proposal studies the molecular mechanism by which stimulus-specific modulators or regulators control JNK activation by specific extracellular stimuli, thereby providing a novel strategy to target the unique modulators or regulators of JNK, rather than JNK itself, for prevention and treatment of human diseases and cancer.

描述（由申请人提供）：c-Jun N端蛋白激酶（JNK；也称为应激激活蛋白激酶，SAPK）在增殖、分化、程序性细胞死亡和转化中发挥核心作用。压倒性的证据表明，JNK 是许多病理生理事件的关键调节因子，包括炎症、免疫反应、糖尿病、肥胖、心脏肥大和肿瘤发生。然而，JNK 活性受不同细胞外刺激调节的分子机制仍不完全清楚。在本提案中，我们将研究不同细胞外刺激的 JNK 激活是否由 JNK 信号体介导，JNK 信号体是一种动态蛋白复合物，包括 JNK 相关的刺激特异性调节剂或调节剂 (SMOR)。通过遗传和生化方法，我们最近发现 JNK 形成蛋白质复合物，其活性可以通过刺激特异性调节因子进行调节。此外，我们发现两种普遍表达的 JNK 亚型 JNK1 和 JNK2 受到各种细胞外刺激的差异调节。因此，我们假设刺激特异性 JNK 信号体通过环境刺激和/或胚胎发育线索决定 JNK 激活。该提议是新颖的，因为它将鉴定 JNK 信号体（一种用于 JNK 激活的动态功能蛋白复合物），并确定 JNK1 和 JNK2 在不同发育阶段差异调节的分子机制。这项研究将提出一个新的范式，涉及细胞外刺激调节 JNK 丝裂原激活蛋白激酶亚家族的分子机制，以及靶向 JNK 预防和治疗人类疾病和癌症的基本原理。公共健康相关性：细胞信号网络由许多重要的信号通路组成，包括应激激活蛋白激酶 JNK 通路，该通路在许多病理生理事件中发挥核心作用，并与许多人类疾病和某些类型的癌症有关。然而，在不影响人体正常生理功能的情况下，很难以 JNK 为靶点进行治疗。该提案研究了刺激特异性调节剂或调节剂通过特定的细胞外刺激控制JNK激活的分子机制，从而提供了一种新的策略来针对JNK的独特调节剂或调节剂，而不是JNK本身，用于预防和治疗人类疾病和癌症。