The JNK Signalsome and its Functions

描述（由申请人提供）：c-Jun n -末端蛋白激酶（JNK，也称为应激激活蛋白激酶，SAPK）在细胞增殖、分化、程序性细胞死亡和转化中起核心作用。大量证据表明，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控的分子机制仍不完全清楚。在本研究中，我们将研究不同细胞外刺激对JNK的激活是否由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）。利用遗传和生化方法，我们最近发现JNK形成一种蛋白质复合物，其活性可以由刺激特异性调节因子调节。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的激活。这一提议是新颖的，因为它将识别JNK信号体}一个动态和功能性的蛋白质复合物，用于JNK的激活，并确定JNK1和JNK2在不同发育阶段的差异调节的分子机制。本研究将为细胞外刺激调控JNK丝裂原活化蛋白激酶亚家族的分子机制提供一个新的范式，并为靶向JNK预防和治疗人类疾病和癌症提供理论依据。公共卫生相关性：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，它在许多病理生理事件中起核心作用，并与许多人类疾病和某些类型的癌症有关。然而，很难在不影响人体正常生理功能的情况下靶向JNK用于治疗目的。本课题研究了刺激特异性调节因子或调节因子通过细胞外特异性刺激控制JNK活化的分子机制，从而提供了一种针对JNK的独特调节因子或调节因子的新策略，而不是针对JNK本身，用于预防和治疗人类疾病和癌症。

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.