The JNK Signalsome and its Functions

描述（由申请人提供）：c-Jun N-末端蛋白激酶（JNK;也称为应激活化蛋白激酶，SAPK）在增殖、分化、程序性细胞死亡和转化中起重要作用。大量证据表明JNK是许多病理生理学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。在这个建议中，我们将调查是否JNK激活不同的细胞外刺激介导的JNK信号体，这是一个动态的蛋白质复合物，包括JNK相关的，刺激特异性调节剂或调节剂（SMOR）。最近，我们使用遗传学和生物化学方法发现JNK形成蛋白质复合物，其活性可由刺激特异性调节剂调节。此外，我们发现，两个普遍表达的JNK亚型，JNK 1和JNK 2，不同的细胞外刺激调节。因此，我们推测刺激特异性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（JNK活化的动态和功能性蛋白质复合物），并确定JNK 1和JNK 2在不同发育阶段差异调节的分子机制。本研究将为阐明细胞外刺激对JNK丝裂原活化蛋白激酶亚家族调控的分子机制以及靶向JNK防治人类疾病和癌症提供新的思路。公共卫生相关性：细胞信号传导网络由许多重要的信号传导途径组成，包括应激活化蛋白激酶JNK途径，其在许多病理生理学事件中起核心作用，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。该方案研究了刺激特异性调节剂或调节剂通过特异性细胞外刺激控制JNK激活的分子机制，从而提供了一种新的策略，以JNK的独特调节剂或调节剂为靶点，而不是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.